The Treatment of Lower Urinary Tract Dysfunction via Treatment of Obsessive-compulsive Disorder in a Pediatric Patient.

Lower urinary tract dysfunction in the pediatric patient can be associated with mental health issues, such as anxiety and obsessive-compulsive disorder (OCD). In fact, 20%-40% of pediatric patients with daytime urinary incontinence have concomitant diagnosis of mental health disease.1 Here, we present a case of lower urinary tract dysfunction in the setting of OCD, with symptom resolution following appropriate treatment of OCD. This case report demonstrates the importance of clinicians including mental health disorders in the differential of children with voiding dysfunction.

Initial observational management of hydronephrosis in infants with reduced differential renal function and non-obstructive drainage parameters.

INTRODUCTION: Hydronephrosis secondary to ureteropelvic junction (UPJ) obstruction is a common finding in infants with prenatally-diagnosed hydronephrosis and often results in pyeloplasty due to obstructive drainage parameters and/or renal function compromise. However, little is known regarding the natural history of hydronephrosis with reduced differential renal function (DRF) but non-obstructive drainage. OBJECTIVE: We sought to explore our experience with initial observational management of these patients. STUDY DESIGN: A retrospective review of our institutional database of all diuretic MAG-3 renal scans obtained between 2000 and 2016 was performed. We included patients with antenatally-detected unilateral hydronephrosis ≥ SFU grade 2, first MAG-3 scan prior to 18months of age, DRF <40% and post-furosemide half-time (T1/2) <20 min. Exclusion criteria were: hydroureter, VUR, solitary kidney, duplication anomalies. Outcomes of interest were a progression of T1/2 ≥ 20 min and/or further decline in DRF >5%. RESULTS: Of 704 patients with unilateral hydronephrosis, 91 had DRF≤40%, of which 29 (18 boys, 11 girls) met our inclusion criteria and were followed for a mean of 2.8 years (1.4 months-6.6 years). Mean age at first sonogram was 2.3 months. 2 patients had SFU grade 2, 16 had grade 3, and 9 had grade 4 hydronephrosis, and 2 unknown grade. Median half-time on initial MAG-3 scan across all patients was 10 min (3-20 min). Initial MAG3 scan was performed at a median of 2.3 months of age (0.3-17 months). 22/29 patients had >1 MAG3 scan. Of the 7 remaining, 5 were lost to follow-up and 2 demonstrated improvement in hydronephrosis. Worsening drainage occurred in 10/22(45%), median final T1/2 was 45.5 min 8 of these underwent pyeloplasty and 2 were lost to follow up. 4/22 patients (18%) had progressive decline in DRF (mean 8.3%, range 6-10%). 3/4 maintained non-obstructive drainage patterns and stable/improved hydronephrosis, and 1 underwent pyeloplasty. 13/18 remaining patients had stable DRF and 5 had improvement in DRF. 7(39%) of these underwent surgery for worsening drainage (Summary Figure). Overall, 7/29(24%) patients had sufficient resolution of hydronephrosis to be discharged from our care, 8(28%) are under continued observation, 9(31%) underwent pyeloplasty, and 5(17%) were lost to follow-up. In the observational group [median follow-up 4.5 years (3.7-6.6 years)], all 8 demonstrated improved non-obstructive drainage (T1/2 <20 minutes) and/or improvement in hydronephrosis. 4/10(40%) with DRF <35% underwent pyeloplasty versus 5/19(26%) with DRF 35-40%(p=0.67). CONCLUSION: Initial observational management of unilateral hydronephrosis with reduced DRF and nonobstructive drainage is recommended as most kidneys maintain nonobstructive drainage and do not demonstrate further decline in DRF. Even when DRF decreases, the majority remain non-obstructive. Worsening drainage over time more often leads to the decision for pyeloplasty rather than change in DRF.

Varenicline limits ischemia reperfusion injury following testicular torsion in mice.

BACKGROUND: Torsion of the spermatic cord and the resulting testicular ischemia leads to the production of inflammatory cytokines and cell death due to impaired aerobic metabolism. Following reperfusion of the testis, a robust innate inflammatory response furthers tissue injury due to the production of reactive oxygen species and disruption of normal capillary function. Blunting the innate immune response with antioxidants, anti-inflammatory medications and targeted genetic interventions reduces long term testicular injury in animal models of torsion, however these approaches have limited clinical applicability. Mediated via α7 nACh receptors, the cholinergic anti-inflammatory pathway limits NFKB signaling and prevents renal fibrosis following warm renal ischemia. We identified varenicline as an FDA approved α7 nAChR agonist and hypothesized that varenicline administration would decrease long-term testicular atrophy and fibrosis in a murine model of testicular torsion. METHODS: Using an established model, unilateral testicular torsion was induced in mature male CD1 mice by rotating the right testicle 720° for 2 h. In the treatment group, 4 doses of varenicline (1mg/grm) were administered via intraperitoneal injection every 12 h, with the first dose given 1 h after the creation of testicular torsion. The acute inflammatory response was evaluated 48 h following reperfusion of the testis. Long term outcomes were evaluated 30 days following testicular perfusion. RESULTS: 48 h following reperfusion, the testis of animals treated with varenicline demonstrated a significant reduction in the inflammatory response as measured by the acute immune cell infiltrate, myeloperoxidase activity, concentration of reduced glutathione and expression of downstream NF-KB targets. 30 days following reperfusion, animals treated with varenicline, demonstrated decreased testicular atrophy (Summary Figure), fibrosis and expression of pro-fibrotic genes. CONCLUSION: Activation of a central immunosuppressive cascade with varenicline after the onset of testicular torsion reduces ischemia reperfusion injury and prevents long term testicular atrophy and fibrosis. Further studies are needed to define the optimum dose and varenicline administration regimen. Our results suggest that varenicline offers a novel, FDA approved, adjunct to the current management of testicular torsion.

Macroscopic and microscopic imaging modalities for diagnosis and monitoring of urogenital schistosomiasis.

Urogenital schistosomiasis remains a major global challenge. Optimal management of this infection depends upon imaging-based assessment of sequelae. Although established imaging modalities such as ultrasonography, plain radiography, magnetic resonance imaging (MRI), narrow band imaging, and computerized tomography (CT) have been used to determine tissue involvement by urogenital schistosomiasis, newer refinements in associated technologies may lead to improvements in patient care. Moreover, application of investigational imaging methods such as confocal laser endomicroscopy and two-photon microscopy in animal models of urogenital schistosomiasis are likely to contribute to our understanding of this infection's pathogenesis. This review discusses prior use of imaging in patients with urogenital schistosomiasis and experimentally infected animals, the advantages and limitations of these modalities, the latest radiologic developments relevant to this infection, and a proposed future diagnostic standard of care for management of afflicted patients.

Relative to open surgery, minimally-invasive renal and ureteral pediatric surgery offers no improvement in 30-day complications, yet requires longer operative time: Data from the National Surgical Quality Improvement Program Pediatrics.

Purpose: Performance of minimally-invasive surgery (MIS) is increasing relative to open surgery. We sought to compare the contemporary rates of short-term complications of open versus laparoscopic renal and ureteral surgery in pediatric patients. Materials and Methods: A retrospective cross-sectional analysis of the National Surgical Quality Improvement Program Pediatrics database was performed of all cases in 2014 identified using CPT procedure codes for nephrectomy, partial nephrectomy (PN), ureteroneocystostomy (UNC), and pyeloplasty, and reviewed for postoperative complications. Univariate analysis was performed to determine 30-day complications, with comparison between open and MIS approaches. Receiver operator curve (ROC) analysis was performed to determine differences in body surface area (BSA) and age for open versus MIS. Results: Review identified 207 nephrectomies, 72 PN, 920 UNC, and 625 pyeloplasties. MIS was associated with older age and larger BSA except for cases of UNC. Apart from PN, operative durations were longer with MIS. However, only PN was associated with significantly longer length of hospital stay (LOS). There was no difference in incidence of all other 30-day complications. When evaluating BSA via ROC, the area under the curve (AUC) was found to be 0.730 and was significant. Children with a BSA greater than 0.408 m2 were more likely to have MIS (sensitivity, 66.9%; specificity, 69.3%). Regarding age, the AUC was 0.732. Children older than 637.5 days were more likely to have MIS (sensitivity, 72.8%; specificity, 63.3%). Conclusions: Pediatric MIS is associated with longer operative time for nephrectomy, but shorter LOS following PN. Surgical approach was not associated with difference in short-term complications.

Male Incontinence: The Etiology or Basis of Treatment.

CONTEXT: Elderly men are an increasing proportion of the aging population in the 21st century. Urinary incontinence reduces the quality of life and increases the burden of care for the aging population. OBJECTIVE: The primary objective of this review is to explore the etiopathology of common causes of incontinence in aging male patients. The focus is on the algorithm of the initial evaluation of these patients from both a primary care and a urologic standpoint. EVIDENCE ACQUISITION: A nonsystematic review of the literature was performed in September 2017. The data and evidence of this paper have been obtained by a PubMed search, and through official statements and recommendations from the International Consultation on Incontinence. Our search incorporated terms such as elderly, urinary incontinence, male, urodynamics, bladder outlet obstruction, BPH, neurologic, urethral stricture, spinal shock, and urethral sphincter injury. EVIDENCE SYNTHESIS: A total of 7204 papers were identified; 6838 were excluded for female populations and populations <65 yr. A broad differential diagnosis exists for urinary incontinence in aging male patients, and many patients will be found to have multifactorial incontinence, compounding the issue. Neurologic etiologies common in this population include cerebrovascular accidents, Parkinson's disease, and dementia. Spinal cord injuries and multiple sclerosis are less common. In this analysis, non-neurologic etiologies leading to incontinence are broadly grouped under bladder outlet obstruction, sphincter injury, overactive bladder, underactive bladder, polypharmacy, and urinary tract infections. CONCLUSIONS: We provide a review of the differential diagnosis of incontinence in an elderly male patient. There is a need for understanding etiopathology and recognizing that many patients may have a combination of the above. The assessment algorithm, modified from the International Continence Society, provides a pathway for the provider in evaluating and treating elderly patients. PATIENT SUMMARY: In this review, we have identified the sources of urinary incontinence in elderly male patients by neurologic and non-neurologic causes. We also discuss the basic evaluation and workup of an incontinent patient.

The prostatic utricle: An under-recognized condition resulting in significant morbidity in boys with both hypospadias and normal external genitalia.

INTRODUCTION: Pediatric presentations of a prostatic utricle have received only scant attention. Though recognized with increased frequency in boys with hypospadias, little is described about their incidence and potential for morbidity in boys with normal external genitalia. METHODS: We initially reviewed a cohort of 64 patients with hypospadias seen over a 3-year period to determine the frequency of investigative lower urinary tract studies and utricle identification. Children with disorders of sexual differentiation were excluded from this review. A subsequent group of 70 boys with hypospadias and 23 boys with normal external genitalia presenting with lower urinary tract symptoms (LUTS) who were found to have an unsuspected utricle were reviewed. This comparative group was investigated since symptomatology was the indication for evaluation, contrasting with those in the hypospadias group who were investigated because of hypospadias presence alone. RESULTS: In our initial review of 64 patients only 24 (37.5%) underwent an investigative study and six (9.4%) had a utricle. Three (50%) required surgical excision, allowing their hypospadias repair to proceed. Results in the subsequent group with hypospadias confirmed these findings with increased rates of investigation and identification. The boys with normal external male genitalia all required surgery since symptoms were the result of the utricle alone. Penile pain with voiding, hematuria, epididymitis, and urinary infection were the most common causes for interventions. CONCLUSIONS: The prostatic utricle should be considered as a cause of morbidity in boys with both normal external genitalia and those with hypospadias. Endoscopic or radiological evaluation (see Figure) should be undertaken in all boys with proximal hypospadias, boys with hypospadias and associated cryptorchidism, and those with hypospadias with associated urinary symptoms. Boys with normal external genitalia with lower urinary tract symptoms not explained with imaging should undergo cystoscopy, as an unidentified unsuspected utricle may be the underlying cause.

Proximally Directed Double-looped Epididymis and Vas Deferens Simulating Vas Duplication: The Importance of Precise Definition of Abnormal Ductal Anatomy in Cryptorchidism.

OBJECTIVE: Epididymal and vasal abnormalities are frequently recognized with undescended testes. The most common defect identified is the extended or elongated epididymis, an anomaly in which the epididymal tail extends distally beyond the testis before looping back upon itself, then following its normal course. Although the impact on fertility has not been established, the necessity of recognizing these vaso-epididymal abnormalities surgically is obvious as these frequently simulate a blind-ending spermatic cord leading to inadvertent excision or leaving the unseen testis more proximally in the abdomen. With this in mind, we describe a more complex vaso-epididymal structural abnormality with proximal extension of the epididymis and vas simulating duplication of these structures. METHODS: The varied surgical findings of a proximally directed double-looped abnormal epididymis and vas deferens associated with cryptorchid testes were identified in 15 children. In all instances, the epididymis extended proximally up the spermatic cord for at least 4 cm, simulating reduplication of the vas deferens and leading to bizarre ductal anatomy and confusing anatomical findings. RESULTS: In our practice, a number of abnormalities of the vaso-epididymal structures have been defined, but we isolated a number of situations in which identification of a proximally directed double-looped epididymis was noted during surgical exploration for cryptorchidism. Our review demonstrated several situations such as this where misidentification could have resulted in inadvertent transection of the vas deferens. CONCLUSION: The need for recognition of these unusual ductal abnormalities associated with cryptorchid testes is re-emphasized by these extreme examples to prevent surgical mishaps at orchidopexy.

Impact of Genetic and Epigenetic Variations Within the FADS Cluster on the Composition and Metabolism of Polyunsaturated Fatty Acids in Prostate Cancer.

BACKGROUND: In vitro and experimental animal studies have demonstrated that high levels of omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high ratios of n-6 to omega-3 (n-3) PUFAs are strongly associated with the development and progression of prostate cancer (PCA). However, epidemiological studies in humans have demonstrated inconsistent findings linking dietary PUFAs and PCA risk. We hypothesize that genetic and epigenetic variations within the fatty acid desaturase (FADS) gene cluster produce gene-diet interactions that may explain these disparate findings. This study tested the relationship of the genotype of a single nucleotide polymorphism, rs174537, and the methylation status of a CpG site, cg27386326, with PUFA composition, and markers of PUFA biosynthesis in PCA tissue. METHODS: Sixty PCA specimens from patients undergoing radical prostatectomy were genotyped, pyrosequenced and quantitated for fatty acids (FAs). RESULTS: Long-chain (LC)-PUFAs, such as arachidonic acid (ARA), were abundant in these specimens, with ARA accounting for 15.8% of total FAs. In addition, there was a positive association of the G allele at rs174537 with concentrations of ARA and adrenic acid and ratios of products to precursors within the n-6 PUFA pathway such that specimens from homozygous G individuals exhibited increasingly higher values as compared to specimens from heterozygous individuals and homozygous T individuals. Finally, the methylation status of cg27386326 was inversely correlated with tissue concentrations of LC-PUFAs and markers of LC-PUFA biosynthesis. CONCLUSIONS: These data reveal that genetic and epigenetic variations within the FADS cluster are highly associated with LC-PUFA concentrations and LC-PUFA biosynthetic capacity in PCA tissue. They also raise the potential that gene-PUFA interactions play an important role in PCA risk and severity. Prostate 76:1182-1191, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

Alterations in levels and ratios of n-3 and n-6 polyunsaturated fatty acids in the temporal cortex and liver of vervet monkeys from birth to early adulthood.

Deficiencies in omega-3 (n-3) long chain polyunsaturated fatty acids (LC-PUFAs) and increases in the ratio of omega-6 (n-6) to n-3 LC-PUFAs in brain tissues and blood components have been associated with psychiatric and developmental disorders. Most studies have focused on n-3 LC-PUFA accumulation in the brain from birth until 2years of age, well before the symptomatic onset of such disorders. The current study addresses changes that occur in childhood and adolescence. Postmortem brain (cortical gray matter, inferior temporal lobe; n=50) and liver (n=60) from vervet monkeys fed a uniform diet from birth through young adulthood were collected from archived tissues. Lipids were extracted and fatty acid levels determined. There was a marked reduction in the ratio of n-6 LC-PUFAs, arachidonic acid (ARA) and adrenic acid (ADR), relative to the n-3 LC-PUFA, docosahexaenoic acid (DHA), in temporal cortex lipids from birth to puberty and then a more gradual decrease though adulthood. This decrease in ratio resulted from a 3-fold accumulation of DHA levels while concentrations of ARA remained constant. Early childhood through adolescence appears to be a critical period for DHA accretion in the cortex of vervet monkeys and may represent a vulnerable stage where lack of dietary n-3 LC-PUFAs impacts development in humans.

The impact of polyunsaturated fatty acid-based dietary supplements on disease biomarkers in a metabolic syndrome/diabetes population.

BACKGROUND: Ingestion of polyunsaturated fatty acids (PUFAs) has been proposed to influence several chronic diseases including coronary heart disease (CHD) and type-2 diabetes (T2D).There is strong evidence that omega-3 (n-3) PUFAs provide protection against CHD and biomarkers of atherosclerosis. In contrast, there is more limited and inconsistent data for T2D. Few studies have examined the impact of n-3 PUFA-containing botanical oils on T2D. METHODS: Fifty-nine subjects with early-stageT2D or metabolic syndrome participated in an 8-week, randomized, single-blind, parallel intervention study and were provided PUFA-containing oils. Individuals received either corn oil (CO), a botanical oil (BO) combination (borage [Borago officinalis L.]/echium oil [Echium plantagineum L.]) or fish oil (FO). The BO combination was enriched in alpha-linolenic, gamma-linolenic, and stearidonic acids and the FO in eicosapentaenoic and docosahexaenoic acids. Serum fatty acids and other serum lipids(triglycerides and total, HDL and LDL cholesterol), as well as markers of inflammation (leptin, and C-reactive protein) and glucose regulation (glucose and hemoglobin A1c) were assessed from fasting participants at baseline and after the intervention. RESULTS: Compliance was verified by expected increases in specific PUFAs in each of the three oil arms. Participants in the CO group showed no differences in serum lipids, markers of inflammation or glucose regulation between pre- and post-treatment measures. Supplementation with BO significantly lowered total and LDL cholesterol levels and FO reduced serum triglycerides, hemoglobin A1c and increased HDL-cholesterol. CONCLUSION: Short-term dietary supplementation with BO and FO improved biomarkers associated with T2D/metabolic syndrome. TRIAL REGISTRATION: Clinicaltrial.gov NCT01145066.

Relationship between a common variant in the fatty acid desaturase (FADS) cluster and eicosanoid generation in humans.

Dramatic shifts in the Western diet have led to a marked increase in the dietary intake of the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (LA). Dietary LA can then be converted to arachidonic acid (ARA) utilizing three enzymatic steps. Two of these steps are encoded for by the fatty acid desaturase (FADS) cluster (chromosome 11, 11q12.2-q13) and certain genetic variants within the cluster are highly associated with ARA levels. However, no study to date has examined whether these variants further influence pro-inflammatory, cyclooxygenase and lipoxygenase eicosanoid products. This study examined the impact of a highly influential FADS SNP, rs174537 on leukotriene, HETE, prostaglandin, and thromboxane biosynthesis in stimulated whole blood. Thirty subjects were genotyped at rs174537 (GG, n = 11; GT, n = 13; TT, n = 6), a panel of fatty acids from whole serum was analyzed, and precursor-to-product PUFA ratios were calculated as a marker of the capacity of tissues (particularly the liver) to synthesize long chain PUFAs. Eicosanoids produced by stimulated human blood were measured by LC-MS/MS. We observed an association between rs174537 and the ratio of ARA/LA, leukotriene B4, and 5-HETE but no effect on levels of cyclooxygenase products. Our results suggest that variation at rs174537 not only impacts the synthesis of ARA but the overall capacity of whole blood to synthesize 5-lipoxygenase products; these genotype-related changes in eicosanoid levels could have important implications in a variety of inflammatory diseases.

MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1.

Human adipose tissue secretes a number of proinflammatory mediators that may contribute to the pathophysiology of obesity-related disorders. Understanding the regulatory pathways that control their production is paramount to developing effective therapeutics to treat these diseases. Using primary human adipose-derived stem cells as a source of preadipocytes and in vitro differentiated adipocytes, we found IL-8 and monocyte chemoattractant protein-1 (MCP-1) are constitutively secreted by both cell types and induced in response to serum deprivation. MicroRNA profiling revealed the rapid induction of microRNA 132 (miR-132) in these cells when switched to serum-free medium. Furthermore, miR-132 overexpression was sufficient to induce nuclear factor-kappaB translocation, acetylation of p65, and production of IL-8 and MCP-1. Inhibitors of miR-132 decreased acetylated p65 and partially inhibited the production of IL-8 and MCP-1 induced by serum deprivation. MiR-132 was shown to inhibit silent information regulator 1 (SirT1) expression through a miR-132 binding site in the 3'-untranslated region of SirT1. Thus, in response to nutritional availability, induction of miR-132 decreases SirT1-mediated deacetylation of p65 leading to activation of nuclear factor-kappaB and transcription of IL-8 and MCP-1 in primary human preadipocytes and in vitro differentiated adipocytes.