Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington's disease.

Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in the astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K+ that underlie striatal hyperexcitability in HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation.

Peroral endoscopic myotomy (POEM) as a treatment for pediatric achalasia: multicenter study and first results. / Miotomía endoscópica por vía oral (POEM) como tratamiento para la acalasia pediátrica: estudio multicéntrico y primeros resultados.

INTRODUCTION: Laparoscopic Heller miotomy of achalasia has been classically recognized as the gold standard management in children. There is increasing experience with the peroral endoscopic miotomy (POEM) approach in pediatrics, although the series published are scarce. The objective of this study was to present our experience in primary or secondary treatment of pediatric achalasia by POEM and its clinical success rate. METHODS: We performed a retrospective review of pediatric patients with achalasia who underwent POEM in some national centers from October 2016 to January 2023. We evaluated clinical efficacy (Eckardt score ≤3), demographic characteristics, intraoperative, preoperative and postoperative, complications, and follow-up. RESULTS: Fifteen POEM were performed in fourteen pediatric patients (aged 12 to 18 years) with achalasia. POEM was the first line treatment in 11 patients, but 4 (21.3%) had previous treatment: 1 (7,1%) pneumatic balloon dilation and 2 (14,2%) laparoscopic Heller myotomy and 1 (7,1%) previous POEM. The average age was 15 years (SD±1,9). The baseline Eckardt score was 7,5 (SD:±1,8), with the baseline GERD score being 6 (SD:±2,9). There was a Clavien-Dindo grade 2 postoperative adverse event corresponding to mild pneumonia (7,1%). The postoperative Eckardt and GERD score after 12 months of follow-up were 0.7 (SD±1,2) and 0,5 (SD±0,7). The study has a success rate greater than 93%. CONCLUSIONS: POEM seems a safe and effective procedure, with a short postoperative period for treatment of pediatric achalasia.

Do patients with Peyronie's disease perceive penile curvature in adults and children differently than the general population?

BACKGROUND: As perception of penile curvature varies widely, we sought to understand how adults perceive curvature and how these opinions compare with those of patients with curvature, specifically Peyronie's disease (PD). AIM: To investigate the perspectives of curvature correction from adults with and without PD, as well as differences within demographics. METHODS: A cross-sectional survey was administered to adult patients and nonpatient companions in general urology clinics at 3 institutions across the United States. Men, women, and nonbinary participants were recruited. Patients were grouped as having PD vs andrology conditions without PD vs general urology conditions plus companions. The survey consisted of unlabeled 2-dimensional images of penis models with varying degrees of curvature. Participants selected images that they would want surgically corrected for themselves and their children. Univariable and multivariable analyses were performed to identify demographic variables associated with willingness to correct. OUTCOMES: Our main outcome was to detect differences in threshold to correct curvature between those with and without PD. RESULTS: Participants were grouped as follows: PD (n = 141), andrology (n = 132), and general (n = 302) . Respectively, 12.8%, 18.9%, and 19.9% chose not to surgically correct any degree of curvature (P = .17). For those who chose surgical correction, the mean threshold for correction was 49.7°, 51.0°, and 51.0° (P = .48); for their children, the decision not to correct any degree of curvature was 21.3%, 25.4%, and 29.3% (P = .34), which was significantly higher than correction for themselves (P < .001). The mean threshold for their children's correction was 47.7°, 53.3°, and 49.4° for the PD, andrology, and general groups (P = .53), with thresholds no different vs themselves (P = .93). On multivariable analysis, no differences were seen in demographics within the PD and andrology groups. In the general group, participants aged 45 to 54 years and those who identified as LGBTQ (lesbian, gay, bisexual, transgender, queer) had a higher threshold for correction as compared with their counterparts when factoring other demographic variables (63.2° vs 48.8°, P = .001; 62.1° vs 50.4°, P = .05). CLINICAL IMPLICATIONS: With changing times and viewpoints, this study stresses the importance of shared decision making and balancing risks and benefits to correction of penile curvature. STRENGTHS AND LIMITATIONS: Strengths include the broad population surveyed. Limitations include the use of artificial models. CONCLUSION: No significant differences were seen in the decision to surgically correct curvature between participants with and without PD, with participants being less likely to choose surgical correction for their children.

The Impact of Primary Tumor Surgery on Survival in HER2 Positive Stage IV Breast Cancer Patients in the Current Era of Targeted Therapy.

OBJECTIVE: We sought to examine the impact of primary tumor resection on survival in HER2+ stage IV breast cancer patients in the era of HER2 targeted therapy. METHODS: We conducted a retrospective cohort study of women with HER2+ stage IV breast cancer in the National Cancer Database from 2010 to 2012 comparing those who did and did not undergo definitive breast surgery. RESULTS: Of 3231 patients, treatment included primary site surgery in 35.0%; chemo/targeted therapy in 89.4%; endocrine therapy in 37.7%; and radiation in 31.8%. Surgery was associated with Medicare/other government (OR 1.36, 95% CI 1.03-1.81) or private insurance (OR 1.93, 95% CI 1.53-2.42) versus none/Medicaid, radiation (OR 2.10, 95% CI 1.76-2.51), chemo/targeted therapy (OR 1.99, 95% CI 1.47-2.70), and endocrine therapy (OR 1.73, 95% CI 1.40-2.14). Non-Hispanic Black versus White patients (OR 0.68, 95% CI 0.53-0.87) were less likely to have surgery. Overall mortality was associated with insurance (Medicare/other government versus none/Medicaid, HR 0.36, p < 0.0001), receipt of chemo/targeted therapy (HR 0.76, p = 0.008), endocrine therapy (HR 0.70, p = 0.0006), and radiation therapy (HR 1.33, p = 0.0009), NH Black versus White race/ethnicity (HR 1.39, p = 0.002), visceral versus bone-only metastases (HR 1.44, p = 0.0003), and lowest versus highest income quartile (HR 1.36, p = 0.01). Propensity score analysis showed surgery was associated with improved survival versus no surgery (HR 0.56, 95% CI 0.40-0.77). CONCLUSIONS: Surgery of the primary site for metastatic HER2+ breast cancer is associated with improved overall survival in selected patients.

Primary and reoperative hypospadias repair in adults--are results different than in children?

PURPOSE: There is widespread belief that hypospadias surgery in adults has a greater urethroplasty complication rate than similar repair in children. We compared outcomes of primary and reoperative hypospadias repair in adults vs children. MATERIALS AND METHODS: We evaluated prospectively maintained databases of consecutive boys and adults, defined as Tanner 4 or greater, treated with primary or reoperative hypospadias repair from 2000 to 2013. We searched for urethroplasty complications, including fistula, glans dehiscence, stricture/stenosis and diverticulum. All operations were done with the goal of creating a neomeatus at the normal location at the tip of the glans. Univariate and multivariate analyses were done to determine whether pubertal status impacted urethroplasty complications. RESULTS: A total of 1,140 patients were operated on by a single surgeon, including 69 adults with a mean age of 23 years. Complications developed in 209 cases (18%), including 124 of 883 primary repairs (14%) and 85 of 257 reoperations (33%). There was no difference in outcomes between adults and children. Complications were noted in 1 of 8 men (12.5%) vs 123 of 871 children (14%) with primary repair (p = 0.9) and in 16 of 61 (26%) vs 69 of 196 (35%) with reoperation (p = 0.2). Multivariate analysis showed that a proximal meatus and reoperation were risk factors for complications but not pubertal status. CONCLUSIONS: In contrast to popular belief, our data do not indicate a greater risk for urethroplasty complications after hypospadias surgery performed in adulthood. Repair in adults can be done using the same techniques as in children with the same goal of a neomeatus at the tip of the glans.

Silicon particles as trojan horses for potential cancer therapy.

BACKGROUND: Porous silicon particles (PSiPs) have been used extensively as drug delivery systems, loaded with chemical species for disease treatment. It is well known from silicon producers that silicon is characterized by a low reduction potential, which in the case of PSiPs promotes explosive oxidation reactions with energy yields exceeding that of trinitrotoluene (TNT). The functionalization of the silica layer with sugars prevents its solubilization, while further functionalization with an appropriate antibody enables increased bioaccumulation inside selected cells. RESULTS: We present here an immunotherapy approach for potential cancer treatment. Our platform comprises the use of engineered silicon particles conjugated with a selective antibody. The conceptual advantage of our system is that after reaction, the particles are degraded into soluble and excretable biocomponents. CONCLUSIONS: In our study, we demonstrate in particular, specific targeting and destruction of cancer cells in vitro. The fact that the LD50 value of PSiPs-HER-2 for tumor cells was 15-fold lower than the LD50 value for control cells demonstrates very high in vitro specificity. This is the first important step on a long road towards the design and development of novel chemotherapeutic agents against cancer in general, and breast cancer in particular.

Correction of hidden penis during Gomco clamp circumcision in the office.

Hidden penis is considered to be a contraindication for clamp circumcision due to high likelihood of healing with concealment. A new technique was created for penoscrotal skin tacking during Gomco circumcision, where the sutures are placed externally instead of internally. Of 716 boys who did not have penoscrotal skin tacking performed, 11 (1.5%) developed concealment. None of the 57 boys who had penoscrotal skin tacking developed concealment. Adding just a couple of minutes to the procedure and with no documented side effects, external penoscrotal skin tacking during Gomco circumcision appears to be a promising addition to the pediatric urology armamentarium.

Urologist validation of an artificial intelligence-based tool for automated estimation of penile curvature.

INTRODUCTION: Severity of penile curvature (PC) is commonly used to select the optimal surgical intervention for hypospadias, either alone or in conjunction with other phenotypic characteristics. Despite this, current literature on the accuracy and precision of different PC measurement techniques in hypospadias patients remains limited. PURPOSE: Assess the feasibility and validity of an artificial intelligence (AI)-based model for automatic measurement of PC. MATERIAL AND METHODS: Seven 3D-printed penile models with variable degrees of ventral PC were used to evaluate and compare interobserver agreement in estimation of penile curvatures using various measurement techniques (including visual inspection, goniometer, manual estimation via a mobile application, and an AI-based angle estimation app. In addition, each participant was required to complete a questionnaire about their background and experience. RESULTS: Thirty-five clinical practitioners participated in the study, including pediatric urologists, pediatric surgeons, and urologists. For each PC assessment method, time required, mean absolute error (MAE), and inter-rater agreement were assessed. For goniometer-based measurement, the lowest MAE achieved was derived from a model featuring 86° PC. When using either UVI (unaid visual inspection), mobile apps, or AI-based measurement, MAE was lowest when assessing a model with 88° PC, indicating that high-grade cases can be quantified more reliably. Indeed, MAE was highest when PC angle ranged between 40° and 58° for all the investigated measurement tools. In fact, among these methodologies, AI-based assessment achieved the lowest MAE and highest level of inter-class correlation, with an average measurement time of only 22 s. CONCLUSION: AI-based PC measurement models are more practical and consistent than the alternative curvature assessment tools already available. The AI method described in this study could help surgeons and hypospadiology researchers to measure PC more accurately.

Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure.

The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n = 11), proximal hypospadias (n = 21) and 46,XX POF (n = 36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF.

A practical approach to difficult urinary catheterizations.

Routine placement of transurethral catheters can be challenging in some situations, such as urethral strictures, severe phimosis and false passages. Intravaginal retraction of the urethral meatus can complicate Foley placement in postmenopausal females. In men, blind urethral procedures with mechanical or metal sounds without visual guidance or guidewire assistance are now discouraged due to the increased risk of urethral trauma and false passages. Newer techniques of urethral catheterization including guidewires, directed hydrophilic mechanical dilators, urethral balloon dilation, and direct vision endoscopic catheter systems are discussed, along with the new standardized protocol for difficult transurethral catheter insertions. Suprapubic catheter placement techniques, including percutaneous trocars and the use of the curved Lowsley tractor for initial suprapubic catheter insertion, are reviewed. Prevention and management of common catheter-related problems such as encrustation, leakage, Foley malposition, balloon cuffing and frequent blockages are discussed.

Gomco circumcision in the office in patients heavier than 5.5 Kg and/or older than 3 months.

INTRODUCTION: Although most pediatric urologists do not perform clamp circumcisions in boys older than 3 months or heavier than 5.5 kg, there are no universally accepted guidelines on the optimal patient age or weight. OBJECTIVE: To compare outcomes of office circumcision within and outside these traditional patient parameters. METHODS: This is a retrospective review of circumcisions performed by a single surgeon from 2019 to 2022. Demographics reviewed include age and weight at time of circumcision, gestational weeks at birth, as well as post-procedure: bleeding, planned and unplanned visits, adhesions/concealment, and interventions related to the circumcision. "Active Bleeding" was defined as bleeding occurring after discharge requiring intervention with pressure, sutures, or cautery. "All Bleeding" included Active Bleeding, and cases where bleeding was controlled at home with pressure, stopped by the time of arrival at clinic or emergency department, and immediate bleeding after circumcision controlled before discharge. RESULTS: During the study period, 773 Gomco circumcisions were performed. A total of 603 patients (78%) had post-procedure evaluation 2 weeks after circumcision. 574 patients (74%) were less than 5.5 kg and 199 (26%) over. Only age corrected for gestation was used in the study: 658 (85%) were younger than 3 months and 115 (15%) older. There was no significant difference in Active Bleeding based on weight (p = 0.3819) or age (p = 0.2798), and no difference in All Bleeding based on weight (p = 0.2072). There was a significant difference (p = 0.0258) in All Bleeding based on age. There was also a significant difference in unexpected visits based on weight (p = 0.0258) and age (p = 0.0131). With regards to adhesions, there was no statistical significant differences when comparing weight or age. However, older and heavier boys had significantly more concealment (5% vs <1%). DISCUSSION: Our study showed Active Bleeding rates 0.5-0.9% higher in the older and heavier group, although the difference did not reach statistical significance. We found a significantly increased rate of unexpected post-procedure visits of around 3.5-4.7% in those patients older than 3 months and heavier than 5.5 kg. Also, post -procedure concealment was significantly increased in the older and heavier boys. Modifications of the dressing for high risk groups could reduce the risk of bleeding, and efforts on pre-circumcision education of the families might ameliorate unexpected visits. Exlcuding patients with hidden penis or performing penoscrotal skin tacking at the time of the gomco circumcision could decrease concealment rates in the higher risk patients. CONCLUSIONS: Gomco clamp circumcision is safe in patients over 5.5 kg and older than 3 months, with a less than 1% higher risk of bleeding, which in the current study was controlled without the need for general anesthesia or transfusions. Broadening the inclusion criteria for office clamp circumcisions could reduce costs and make the procedure available to patients who cannot afford to have the surgery under general anesthesia.

Pediatric urologists' confidence and accuracy in estimating penile curvature.

BACKGROUND: Assessment and management of congenital penile curvature (PC) can be variable. Methods for correction of PC usually are dependent on degree of PC which is reliant on how degree is assessed. We sought to assess the confidence and accuracy of measuring PC and hence management using case-based examples. METHODS: A survey was emailed to members of the Societies for Pediatric Urology. Demographic information, management strategies for PC, and self-reported confidence in measuring PC were assessed. A Likert scale measured self-confidence. Case scenarios were used to assess ability to measure PC and methods of correction. The cases consisted of three computer-generated penis model images with arc-type ventral curvature and one image of lateral curvature in an infant. RESULTS: The response rate was 30% (108/355). The mean confidence score was 3.6 ± 0.8 (3-fairly confident; 4-very confident). In clinic, 89% of urologists used eyeball estimates to assess PC; 5% used both eyeball and goniometer. In the operating room, 71% used eyeball estimates, 8% used goniometer, and 16% used both. If sole decision-maker, urologists recommend surgical correction of PC over observation at median 30° (IQR 21-30°). At a median of 45°, there was a shift in corrective surgical preference from dorsal plication (DP) (IQR 30-54°) to ventral lengthening (IQR 34-60°). Urologists underestimated PC degree for all cases (summary table). For all cases, there was no association between years in practice or confidence level on estimated PC degree. In case 1, only 24% of urologists would correct a mean estimate of 23° PC; those who would correct had a higher mean PC estimate vs those who would not (28° vs 21°, p < 0.001). Case 2 and 4 had similar estimations and correction methods. In case 2, those who chose VL had a higher mean PC estimate vs those who did not (43° vs 37°, p < 0.01), but no estimate difference was seen for DP (p = 0.52). In case 4 with lateral PC, those who chose DP had a higher mean PC estimate vs those who did not (41° vs 33°, p = 0.049). Yet in case 3, there was no difference in PC estimate in urologists who chose VL vs not (57° vs 53°, p = 0.16). CONCLUSIONS: A uniform underestimation of PC existed despite self-reported confidence in the ability to measure PC. An increasing willingness to perform surgical correction was demonstrated with a shift towards VL for ventral curvature and less so for lateral curvature as PC worsens.

Does the lower instrumented vertebra have an effect on lumbar mobility, subjective perception of trunk flexibility, and quality of life in patients with idiopathic scoliosis treated by spinal fusion?

STUDY DESIGN: Cross-sectional study in patients with idiopathic scoliosis treated with spinal fusion. OBJECTIVES: To measure lumbar spine mobility in the study population; determine low back pain intensity (LBPi), subjective perception of trunk flexibility (TF), and quality of life using validated outcome instruments; and investigate correlations of the lower instrumented vertebra (LIV) with TF, LBPi, and quality of life. SUMMARY OF BACKGROUND DATA: The loss of range of motion resulting from spinal fusion might lead to low back pain, trunk rigidity, and a negative impact on quality of life. Nonetheless, these outcomes have not been conclusively demonstrated because lumbar mobility and LIV have not been correlated with validated outcome instruments. METHODS: Forty-one patients (mean age, 27 y) with idiopathic scoliosis treated by spinal fusion (mean time since surgery, 135 mo) were included. Patients were assigned to 3 groups according to LIV level: group 1 (fusion to T12, L1, or L2) 14 patients; group 2 (fusion to L3) 13 patients, and group 3 (fusion to L4, L5, or S1) 14 patients. At midterm follow-up, patients completed the Scoliosis Research Society (SRS)-22 Questionnaire and Quality of Life Profile for Spine Deformities to evaluate perceived TF, and rated LBPi with a numerical scale. Lumbar mobility was assessed using a dual digital inclinometer. RESULTS: Group 3 (fusion to L4, L5, or S1) showed statistically significant differences relative to the other groups, with less lumbar mobility and poorer scores for the SRS subtotal (P = 0.003) and SRS pain scale (P = 0.01). Nevertheless, LBPi and TF were similar in the 3 groups. TF correlated with SRS-22 subtotal (r = -0.38, P = 0.01) and pain scale (r = -0.42, P = 0.007) scores, and with LBPi (r = 0.43, P = 0.005). CONCLUSIONS: LIV correlated moderately with lumbar mobility, health-related quality of life (SRS-22), and spinal pain (SRS-22 pain subscale), but not with intensity of pain in the lumbar area or perceived TF.

A clinical and histological comparison of two different bone augmentation materials in the atrophic pre-maxilla.

This case study was conducted to compare the regenerative potential of bovine xenograft versus demineralized freeze-dried bone allograft in a thermoplastic biologic carrier in regards to achieving regeneration of bone width as well as potential bone height. The objective for the patient was to gain adequate bone volume for the placement of dental implants using the two different forms of graft material--one with a slow resorption time and the other in a gelatin matrix to provide dimensional stability. The results of this case report are inconclusive to demonstrate the superiority of one of the two graft materials over the other in reconstructing a severely atrophied maxilla. Both sites ultimately required a second guided bone regeneration (GBR) procedure prior to implant placement. It was speculated that adequate space maintenance might not have been achieved during the initial procedures.

[Trends in incidence and risk factors associated with the development of pancreatic cancer. Regional Institute of Neoplastic Diseases "Dr. Luis Pinillos Ganoza "- Iren North. 2008 - 2011]. / Tendencias en la incidencia y factores de riesgo asociados al desarrollo de cáncer de páncreas. Instituto Regional de Enfermedades Neoplásicas "Dr. Luis Pinillos Ganoza" - Iren Norte. 2008 - 2011.

OBJECTIVE: To determine trends in the prevalence and identify the main risk factors associated with the development of pancreatic cancer. MATERIALS AND METHODS: Study of trends in incidence and case-control population consisted of a total of 134 patients. Patients were grouped into: a) CASES: 67 patients diagnosed with pancreatic cancer treated at the Abdomen's Service of the Specialized Surgery Department of the Regional Institute of Neoplastic Diseases "Dr. Luis Pinillos Ganoza "- IREN North during the period 2008 to 2011; and b) CONTROLS: 67 patients diagnosed with gallstones and / or benign biliary disease treated at Belen Hospital in Trujillo during the period 2008 to 2011. RESULTS: The trend curve of incidence of pancreatic cancer showed a curve almost constant throughout the quadrennium 2008 to 2011, with incidence rates of 5.38%, 5.08%, 5.5% and 5.0% respectively. The overall incidence was 5.37%. The trend function was Y = (1756) ± (0.001) (x), with an R2 = 0.318 (p = 0.436). The main risk factors associated with pancreatic cancer were age bigger and equal to 60 years (p = 0.0001), male sex (p = 0.007), diabetes mellitus (p = 0.002) and family history of malignancy (p = 0.016). CONCLUSIONS: The trend in incidence in pancreatic cancer was low and constant in its appearance was significantly influenced by age, gender, and presence of diabetes mellitus and family history of cancer.