Using genomic resources for linkage analysis in Peromyscus with an application for characterizing Dominant Spot.

BACKGROUND: Peromyscus are the most common mammalian species in North America and are widely used in both laboratory and field studies. The deer mouse, P. maniculatus and the old-field mouse, P. polionotus, are closely related and can generate viable and fertile hybrid offspring. The ability to generate hybrid offspring, coupled with developing genomic resources, enables researchers to conduct linkage analysis studies to identify genomic loci associated with specific traits. RESULTS: We used available genomic data to identify DNA polymorphisms between P. maniculatus and P. polionotus and used the polymorphic data to identify the range of genetic complexity that underlies physiological and behavioral differences between the species, including cholesterol metabolism and genes associated with autism. In addition, we used the polymorphic data to conduct a candidate gene linkage analysis for the Dominant spot trait and determined that Dominant spot is linked to a region of chromosome 20 that contains a strong candidate gene, Sox10. During the linkage analysis, we found that the spot size varied quantitively in affected Peromyscus based on genetic background. CONCLUSIONS: The expanding genomic resources for Peromyscus facilitate their use in linkage analysis studies, enabling the identification of loci associated with specific traits. More specifically, we have linked a coat color spotting phenotype, Dominant spot, with Sox10, a member the neural crest gene regulatory network, and that there are likely two genetic modifiers that interact with Dominant spot. These results establish Peromyscus as a model system for identifying new alleles of the neural crest gene regulatory network.

Daily fluctuations in blood glucose with normal aging are inversely related to hippocampal synaptic mitochondrial proteins.

Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals. We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses. Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.

Vasectomy reversal provides long-term pain relief for men with the post-vasectomy pain syndrome.

PURPOSE: The post-vasectomy pain syndrome is a rare but serious and debilitating complication of vasectomy. For men with the post-vasectomy pain syndrome vasectomy reversal is a surgical option after medical management has failed. However, there is a paucity of data in the literature defining its therapeutic efficacy. In this study we better define the role and effect of vasectomy reversal in the treatment of men with the post-vasectomy pain syndrome. MATERIALS AND METHODS: Three urologists in Toronto, Ontario performed 149 publically funded vasectomy reversals between January 2000 and September 2010. The electronic health records were reviewed and 23 of the 149 (15%) procedures were performed for the post-vasectomy pain syndrome. Of these men who underwent 14 vasovasostomies 13 completed a telephone conducted questionnaire (response rate 56%). Patient demographics, preoperative and postoperative pain scores, and quality of life were retrospectively assessed. RESULTS: Orchialgia occurred a mean ± SD of 19 ± 42.5 months after vasectomy and the men (mean age 43.8 ± 5.2 years) experienced pain for 50.3 ± 34.9 months before vasovasostomy. After vasovasostomy improvement of pain occurred in 93% (13 of 14) and 50% were rendered pain-free with an average improvement in pain intensity scores of 65% (p <0.005). Of the men 15% (2 of 13) had a recurrence of pain to baseline but overall 79% (11 of 14) had a durable positive response. Quality of life was significantly improved after vasovasostomy (p <0.005) and 93% (13 of 14) of the patients said they would undergo the same operation again. CONCLUSIONS: Vasovasostomy is an effective treatment modality for the post-vasectomy pain syndrome, and it can achieve robust and durable long-term improvement in pain intensity and quality of life.

Predictors of early mortality after radical nephrectomy with renal vein or inferior vena cava thrombectomy - a population-based study.

UNLABELLED: Study Type - Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Surgical volume has been well established as a predictor of outcomes for several complex surgical procedures, yet few studies have evaluated this relationship with regards to radical nephrectomy with either renal vein or inferior vena cava thrombectomy. In addition, most published literature consists of single-institution series from centres of excellence. We performed a population-level analysis and identified surgeon volume as a significant predictor of short-term mortality for this procedure. Such findings have potential implications regarding future policy and regionalization of care. OBJECTIVE: • To study the short-term mortality associated with radical nephrectomy with renal vein or inferior vena cava thrombectomy and the variables associated with this adverse outcome. METHODS: • Using the Ontario Cancer Registry, we identified 433 patients in the province of Ontario, Canada undergoing radical nephrectomy with venous thrombectomy between 1995 and 2004. • We determined mortality rates at postoperative days 30 and 90. • Other variables analysed include pathological tumour characteristics, surgeon graduation year, hospital/surgeon academic status, surgery year and hospital/surgeon volume. • We used multivariable logistic regression to assess outcomes. RESULTS: • Overall mortality was 2.8% (30-day) and 5.8% (90-day). • Surgeons performing a single nephrectomy with venous thrombectomy performed 14% of the cases and had the highest 30-day (6.7%) and 90-day (10%) mortality. The mortality rate for surgeons performing more than one surgery was 2.1% (30-day) and 5.1% (90-day). • In recent years, this procedure was performed more commonly by the highest volume surgeons - 67% of cases in 2004 vs 40% in 1995. • Significant predictors of 30-day mortality included procedure year and low surgeon volume. • Significant predictors of 90-day mortality included procedure year, low surgeon volume, left-sided tumour and increasing hospital volume. CONCLUSIONS: • For radical nephrectomy with venous thrombectomy, surgeon volume predicts short-term mortality, emphasizing the importance of experience in patient outcome. • Despite a shift towards high-volume surgeons, 13.8% of cases continued to be performed by low-volume providers. • If these results are confirmed in other jurisdictions, radical nephrectomy with venous thrombectomy should be regionalized and performed by surgeons who manage these cases regularly.

Does patient age affect survival after radical cystectomy?

UNLABELLED: What's known on the subject? and What does the study add? Elderly patients have more years to compound comorbidities and it has previously been shown that comorbidity is an important predictor of overall survival in patients with bladder cancer, including those treated with radical cystectomy (RC). Other studies have also demonstrated higher stage at diagnosis, higher rate of upstaging on final pathology and a longer delay to definitive therapy for older patients. Because of these findings, elderly patients are being offered RC less often than younger patients. Whether or not this practice is justified has come under recent scrutiny and there has been much conflicting data in the literature. While some studies have shown worse outcomes for elderly patients, others have shown similar results for both elderly and younger patients. Large population-based databases have recently been used to try to determine whether age effects outcome after RC but their conclusions may not be as generalizable as ours for several reasons: billing code data was used to build patient cohorts, patients were generally recipients of Medicare, lack of pathological review, and lack of available and accurate clinical data. Our series is unique in that it comprises a large group of patients from two major tertiary care academic institutions using a very robust dataset. Pathological specimens were reviewed by dedicated genitourinary pathologists, including those recovered from peripheral hospitals. Our sample size is one of the largest single- or multi-institutional studies. OBJECTIVE: • To analyse the impact of patient age on survival after radical cystectomy (RC). PATIENTS AND METHODS: • After ethics review board approval, two databases of patients with bladder cancer (BC) undergoing RC at the University Heath Network, Toronto, Canada (1992-2008) and the University of Turku, Turku, Finland (1986-2005) were retrospectively analysed. • A total of 605 patients who underwent this procedure between June 1985 and March 2010 were included. • Patients were divided into four age groups: ≤ 59, 60-69, 70-79 and ≥ 80 years. • Demographic, clinical and pathological data were compared, as well as recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OAS) rates. RESULTS: • Compared with younger patients (age ≤ 79 years), elderly patients (age ≥ 80 years) had higher American Society of Anesthesiologists scores (P < 0.001), a greater number of lymph nodes removed during surgical dissection (P < 0.001), and underwent less adjuvant treatment (P < 0.001). • Choice of urinary diversion differed among the groups, with ileal conduit being used for all patients ≥ 80 years (P < 0.001). • No differences were noted between age groups with respect to RFS (P= 0.3), DSS (P= 0.4) or OAS (P= 0.4). CONCLUSION: • Although RC is an operation with significant morbidity, it is a viable treatment option for carefully selected elderly patients. Senior patients (≥ 80 years) should not be denied RC if they are deemed fit to undergo surgery. • Senior adults do not suffer from adverse histopathological features as compared with younger patients.

Immunosuppression without calcineurin inhibition: optimization of renal function in expanded criteria donor renal transplantation.

INTRODUCTION: To assess the efficacy of calcineurin inhibitor (CNI)-free immunosuppression vs. calcineurin-based immunosuppression in patients receiving expanded criteria donor (ECD) kidneys. PATIENT AND METHODS: Thirteen recipients of ECD kidneys were enrolled in this pilot study and treated with induction therapy and maintained on sirolimus, mycophenolate mofetil (MMF) and prednisone. A contemporaneous control group was randomly selected comprised of 13 recipients of ECD kidneys who had been maintained on CNI plus MMF and prednisone. RESULTS: For the study group vs. the control group, two-yr graft survival was 92.3% vs. 84.6% (p = NS), two-yr patient survival was 100% vs. 92.3% (p = NS) and the acute rejection rates were 23% vs. 31% (p = NS), respectively. Renal function was significantly better in the study group compared with control up to the six-month mark, after which, it remained numerically but not statistically significant. Complications were more common in the study group, but serious adverse events requiring discontinuation were rare. CONCLUSION: This pilot study demonstrates that CNI-free regimens can be safely implemented in patients receiving ECD kidneys with excellent two-yr patient and graft survival and good renal allograft function. Longer follow-up in larger randomized controlled trials are necessary to establish these findings.

Extraperitoneal vs Transperitoneal Robot-Assisted Radical Prostatectomy in the Setting of Prior Abdominal or Pelvic Surgery.

INTRODUCTION: During robot-assisted radical prostatectomy (RARP), the prostate may be approached extraperiteoneally (extraperitoneal robot-assisted radical prostatectomy [eRARP]) or transperitoneally (transperitoneal robot-assisted radical prostatectomy [tRARP]). The former avoids the abdominal cavity, which might be of benefit in patients who have had prior abdominal or pelvic surgery (PAPS). Our objective was to compare the outcomes of patients with PAPS undergoing either technique. METHODS: A retrospective review of patients treated with RARP from July 1, 2003 to December 31, 2014 with a minimum follow-up of 3 months was undertaken. Of 2927 patients, 620 were identified as having undergone RARP (without concomitant unrelated procedures) and PAPS (excluding patients with prior inguinal hernia repair with mesh or unclear surgical histories) for prostate adenocarcinoma without prior pelvic radiotherapy. Of these, 340 patients underwent eRARP and 280 patients underwent tRARP. RESULTS: Patients in the eRARP group were younger (61.04 years vs 62.32, p = 0.02), had a higher body mass index (29.65 vs 28.98, p = 0.09), lower American Society of Anesthesiologists scores (p = 0.03), and lower D'Amico risk classification disease (p < 0.0001). The two groups had similar rates of 1, 2, and >2 PAPS. On univariate analysis, the eRARP group had lower operative time (188.96 minutes vs 197.92 minutes, p = 0.003), extensive lysis of adhesions (0.9% vs 14.3%, p < 0.0001), length of hospital stay (LOS) (1.13 days ±0.45 vs 1.33 day ±1.08, p = 0.003), and higher estimated blood loss (210.74 mL vs 190.79 mL, p = 0.06). The eRARP group had a lower rate of gastrointestinal complications (0% vs 3.21%, p = 0.0007), a trend toward lower early post-operative complications (8.53% vs 12.86%, p = 0.08), and lower overall complications (9.41% vs 15%, p = 0.03). In regression analysis with model selection, only LOS was lower in the eRARP group (p = 0.02). CONCLUSIONS: Both methods are safe in patients with prior abdominal surgeries. A lower incidence of gastrointestinal complications and a shorter length of stay were noted in the extraperitoneal cohort.

Extraperitoneal vs. transperitoneal robot-assisted radical prostatectomy in patients with a history of prior inguinal hernia repair with mesh.

Robot-assisted radical prostatectomy (RARP) may be performed via an extraperitoneal (eRARP) or transperitoneal (tRARP) approach. There are no published studies comparing these two methods in patients with a history of prior inguinal hernia repair with mesh (IHRm), but the latter is often advocated in this setting. A retrospective review of patients who underwent RARP with prior IHRm who had a minimum follow-up of 3 months from July 1, 2003 to December 31, 2014 was undertaken. Of 2927 patients who underwent RARP for primary treatment of adenocarcinoma of the prostate, 286 patients had a clear history of IHRm. Of these, 116 patients underwent eRARP and 170 patients underwent tRARP. No differences were noted between the groups with respect to age, body mass index or American Society of Anesthesiology score. Patients in the tRARP group had higher D'Amico risk classification scores (p < 0.0001) and as such, underwent less nerve-sparing procedures (p < 0.0001) and had a higher rate of concomitant pelvic lymph node dissections (p < 0.0001). The tRARP group had a higher incidence of laparoscopic and bilateral IHRm. On univariate analysis, EBL was lower in the tRARP group (172.41 vs. 201.98, p = 0.05) but all other parameters were similar. After controlling for covariates using regression analysis with model selection, a trend was noted towards lower operating room time in the tRARP group (p = 0.0624) but no other differences were noted. The presence of prior IHRm does not seem to be a contraindication to eRARP. OR time may be lower with tRARP (trend) but all other quality indicators studied were similar.

Rate of Symptomatic Lymphocele Formation After Extraperitoneal vs Transperitoneal Robot-Assisted Radical Prostatectomy and Bilateral Pelvic Lymphadenectomy.

INTRODUCTION AND OBJECTIVE: With the peritoneum acting as a natural surface for lymphatic reabsorption, transperitoneal robot-assisted radical prostatectomy (tRARP) is thought to be associated with a lower incidence of symptomatic lymphoceles (SLs) compared with its extraperitoneal counterpart (eRARP) when bilateral pelvic lymph node dissection (BPLND) is performed. In this study, we aim to determine if there is a difference in SL formation and characteristics between the two approaches. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent eRARP or tRARP and BPLND by a single surgeon at a tertiary care academic center from July 1, 2003, to May 31, 2016. Patients with a history of prior pelvic radiotherapy, concomitant inguinal hernia repair, RARP without BPLND, or nonadenocarcinoma of the prostate were excluded. The resulting eRARP and tRARP groups were propensity matched for age, body mass index (BMI), American Association of Anesthesiologists (ASA) score, D'Amico risk classification, and pathological lymph node (LN) count. RESULTS: A total of 3183 RARPs were performed during this time period. After applying exclusion criteria and propensity score matching, 671 patients remained in each group. No statistically significant differences were noted between the groups with regard to age, BMI, ASA, pre-RARP prostate-specific antigen, D'Amico risk classification, biopsy and pathological Gleason sum score, pathological T stage, or margin status. The tRARP group had a higher clinical T stage (p = 0.0015), length of stay (LOS; p = 0.005), pathological N stage (4.92% vs 1.36%, p = 0.0002), and high total LN count (7.22 ± 5.54 vs 5.78 ± 4.18 LNs, p < 0.0001). The eRARP group had higher operating room times (197.4 ± 48.96 minutes vs 192.2 ± 44.12 minutes, p = 0.04) and estimated blood loss (218.4 ± 152.0 mL vs 179.9 ± 119.4 mL, p < 0.0001). No differences were noted in the frequency of SL formation [eRARP: 19/671 (2.83%) vs tRARP: 10/671 (1.49%), p = 0.09] or any clinical characteristics of the SL. Logistic regression analysis showed no effect of LN count (p = 0.071), pathological N stage (p = 0.111), or both combined (p = 0.085) on SL formation. CONCLUSIONS: In this cohort, the rate and clinical characteristics of SL were similar among patients treated with eRARP or tRARP and BPLND. The low event rate of SL in each group and trends favoring higher SL with LN yield and pN1 disease in the tRAPR group may deem the study underpowered to make definitive conclusions.

The role of urinary cytology when diagnostic workup is suspicious for upper tract urothelial carcinoma but tumour biopsy is nonconfirmatory.

INTRODUCTION: We sought to determine the value of obtaining preoperative urinary cytology when diagnostic workup of an upper tract mass is suspicious for upper tract urothelial carcinoma (UTUC), but biopsy fails to confirm the diagnosis. METHODS: Using billing code data, 239 patients were identified as having undergone radical nephroureterectomy (RNU) by 16 urologists from September 29, 1998 to July 31, 2015. Of this group, 19 adult patients had a presumed preoperative diagnosis of UTUC in a native kidney, at least three months of followup, no history of concurrent radical cystectomy with RNU, and negative/non-diagnostic tissue biopsy. These patients were divided into three groups: Group A had no urinary cytology taken (n=6); Group B had upper and/or lower tract cytology performed with neither positive nor atypical (n=7); Group C had upper and/or lower tract cytology performed with at least one positive or atypical (n=6). RESULTS: Demographic information and diagnostic workup was similar between the groups, although Group A had more patients with a history of prior radical cystectomy for bladder cancer (p=0.02). One patient in Group B had benign tissue on final pathology. All patients in Groups A and C had malignancy on final pathology and overall, the three groups had similar rates of malignancy. CONCLUSIONS: When a composite of clinical findings suggest UTUC, performing urinary cytology may not be necessary. A negative result in this setting should not be used to rule out UTUC, as this is often discordant with final pathology. A positive cytology result may help solidify the diagnosis when other findings are less clear.

Outcome of third renal allograft retransplants versus primary transplants from paired donors.

BACKGROUND: Third kidney retransplants have technical and immunologic hurdles that may preclude success, which is of particular importance in the contemporary context of discrepancy between organ supply and demand. METHODS: The outcomes of third renal transplant recipients (TRTR) were compared with those receiving a first transplant from paired donor kidneys to assess transplant success and complication rates. The Ontario-based Trillium Gift of Life Network database was used to identify deceased donors (n=28) who donated one kidney to a TRTR and the mate kidney to a primary renal transplant recipient (PRTR) from June 1977 to August 2006. RESULTS: As anticipated, TRTR were sensitized versus PRTR based on % panel reactive antibodies (24%+/-34% vs. 7%+/-14%, P=0.03). Delayed graft function (46% vs. 22%, P=0.05) and biopsy-proven rejection episodes (50% vs. 29%, P=0.01) occurred more frequently with TRTR despite greater frequency of induction therapy (74% vs. 35%, P=0.004). However, 1- and 5-year patient survival were similar at 93%, 83% and 96%, 87% for TRTR and PRTR, respectively. Accordingly, 1- and 5-year allograft survival censored for mortality, were comparable at 78%, 66% and 78%, 75%. Renal function was similar in both groups. Bacterial infections (43% vs. 18%, P=0.001) and wound problems (28% vs. 11%, P=0.09) were the only postoperative complications to occur more frequently in the TRTR. CONCLUSION: We conclude that third renal transplantation should not be discouraged based on functional outcomes alone.

Post-traumatic pseudolipoma of the forehead.

A forehead lipoma is a rare finding in a child, and one that penetrates the underlying layers of muscle and bone to attach to dura has not previously been reported. Two such cases, both in children who underwent uneventful deliveries aided by forceps, are presented. Both lesions were present at birth and, based on clinical findings, were originally thought to be dermoid cysts. Dermoid cysts could not be ruled out with computed tomography and magnetic resonance imaging. Histopathology identified fibrofatty tissue consistent with lipoma. Both lesions extended from the subcutaneous tissue through the frontalis muscle and frontal bone to the dura. Given these findings and the history of forceps delivery, the most likely diagnosis is post-traumatic pseudolipoma. This lesion should be considered in the differential diagnosis of congenital lesions of the forehead, particularly if there is a history of forceps delivery or other trauma to the area.

Outcomes and quality of life of adults undergoing continent catheterizable vesicostomy for neurogenic bladder.

OBJECTIVES: To evaluate the functional outcomes and quality of life of adult patients with neurogenic bladders who had undergone Casale Spiral Monti vesicostomy. METHODS: Twelve patients who underwent Casale Spiral Monti vesicostomy from May 1999 to December 2004 were evaluated with the Medical Outcomes Study 36-item short-form health survey to assess for postoperative quality of life. Complications and patient reported continence were also documented. RESULTS: The 12 patients (mean age 27.4 years) were followed up for a mean of 2.8 years. All 12 reported excellent urinary continence after the procedure, with only 7 patients who had the capacity to self-catheterize. Two patients reported wearing one light pad per day over the stoma. Two patients required one endoscopic dilation each for stomal stenosis, and one patient was readmitted 3 weeks postoperatively for the management of paralytic ileus. Eight patients reported no urinary tract infection since the operation. All 12 patients reported being very satisfied with the procedure. CONCLUSIONS: The results of this study have demonstrated that Casale Spiral Monti vesicostomy can have dramatic positive effects on the quality of life in adults with a neurogenic bladder by granting them social independence, convenient bladder management, and excellent continence rates.