Predictability and durability of mitral valve repair in patients with severe degenerative mitral regurgitation in medium sized centres.

INTRODUCTION: Mitral valve repair (MVr) is now the treatment of choice to correct severe degenerative mitral regurgitation (MR). Repair rates vary greatly from centre to centre, and the concept of heart valve centres of excellence has been established. OBJECTIVE: The purpose of this study was to see whether large international centre repair rates, and outcomes, are transferrable to medium-sized centres with an interest in mitral repair. METHODS: Between 2011 and 2018, a total of 346 patients underwent mitral valve surgery by a single surgeon. Of these, 238 consecutive patients had repairs, or attempted repairs for degenerative MR, and are included in this study. RESULTS: The study sample consisted of 71% male patients and had a mean age of 64.4 ± 12.3 years; 66% of the study population had concomitant procedures. The overall repair rate in this cohort is 99%. Mean follow up was 3.7 ± 1.9 years. At 5 years, the freedom from MR ≥ 3+ was 95.9 ± 1.9% and at 7 years 91.1 ± 3.8%. Freedom from reoperation at 5 years was 92.9 ± 3.7%, while the 5 years actuarial survival was 89.1 ± 3.7%. On a multivariate analysis, predischarge echo grade was associated with higher risk of future reoperation (odds ratio (OR) = 21.82, p = 0.05). Only age (OR = 1.3, p = 0.03) was predictive of long-term survival. CONCLUSIONS: In specialised medium-sized heart centres, where the surgical team have undergone specialist mitral training, favourable short- and long-term outcomes are achievable with mitral repair rates similar to those from large international centres of excellence. In these heart centres, early surgery should be considered for all patients with severe degenerative MR.

Radiotherapy in adult low-grade glioma: nationwide trends in treatment and outcomes.

BACKGROUND: Management of WHO grade II gliomas (LGG) can include a combination of observation, surgery, radiotherapy (RT), and chemotherapy; however, optimal management remains unclear in regards to RT. OBJECTIVE: The current study seeks to investigate the usage of RT in LGG and its effect on survival outcomes. METHODS: Patients with diagnosis codes specific for LGG were queried from the National Cancer Database (NCDB) during the years 2004-2016. Kaplan-Meier curves with log-rank testing, univariate and multivariate Cox regression analysis, and comparisons of estimated 3- and 7-year survival were performed to investigate the effect of RT on overall survival. RESULTS: 19,382 patients with LGG were identified with histologically confirmed disease. Kaplan-Meier testing demonstrated RT impacted survival in patients undergoing biopsy or no surgery (p < 0.0001), no chemotherapy (p < 0.0001), and in regimens with early RT (p < 0.0001) and high-dose RT (p < 0.0001). Cox multivariate regression demonstrated RT and age less than 40 (HR 0.93, 95% CI 0.89-0.97, p = 0.001), no chemotherapy (HR 0.82, 95% CI 0.77-0.87, p < 0.001), and astrocytoma histology (HR 0.72, 95% CI 0.66-0.79, p < 0.001) were associated with improved survival. 3-year survival of RT versus non-RT groups showed increased survival rates for age less than 40 years (+ 5.7%, p < 0.0001), no surgery or biopsy (+ 8.1%, p < 0.0001), no chemotherapy (+ 10.3%, p < 0.0001), mixed glioma (+ 6.7%, p < 0.0001), astrocytoma (+ 7.1%, p < 0.0001), and in regimens with early RT (+ 7.6%, p < 0.0001) and high-dose RT (+ 4.7%, p < 0.0001). CONCLUSION: This nationwide analysis of LGG patients found that RT was associated with improved survival outcomes in patients less than 40 years of age, with histology subtypes of astrocytoma and mixed glioma, undergoing biopsy or no surgery, and in regimens with early RT and high-dose RT.

Serum NGAL can act as an early renal safety biomarker during long-term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B.

Tubular renal toxicity is a side-effect of long-term therapy with nucleos(t)ide analogue(s) (NA) in chronic hepatitis B (CHB). There are no established surrogate markers in plasma of early NA-related toxicity. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein produced by tubular cells following renal damage. We aimed therefore to retrospectively compare conventional renal markers (estimated glomerular filtration rates (eGFR) and urinary protein/creatinine ratio uPCR) with a sensitive biomarker (NGAL) in CHB patients on long-term NA therapy and assess the ability of new markers to predict NA-related renal toxicity (new onset of nonalbumin proteinuria). A total of 192 naïve CHB patients (median age 41 years, 78% males, 25% HBeAg+, 35% cirrhosis) were NA treated for at least 5 years (median 8.34 years, range 5.54-11.1 years). The eGFR and uPCR were compared at baseline and last clinical visit with serum NGAL concentrations measured by ELISA at same time-points and assessed according to the presence/absence of nonalbumin proteinuria at last visit. While baseline and last visit eGFR were similar (median:78 vs 84 mL/min), serum NGAL concentrations increased during therapy (median:9.4 vs 16.4 ng/mL, P < .05). The proportion of patients with proteinuria (uPCR > 15) increased between baseline and last visit (4.6% vs 21.4%, P < .05), with 30 (16%) patients having de novo nonalbumin proteinuria at last visit. High baseline NGAL concentrations were exclusive to patients with de novo nonalbumin proteinuria (median:31.7 vs 7.8 ng/mL, P < .01) and baseline NGAL levels >25 mg/mL were predictive of nonalbumin proteinuria at last visit (AUROC = 0.813). In conclusion, serum NGAL can act as a surrogate marker of early renal injury (de novo nonalbumin proteinuria) in CHB on long-term NA therapy.

Examining the connectivity between different cellular processes in the Barrett tissue microenvironment.

In Barrett associated tumorigenesis, oxidative phosphorylation and glycolysis are reprogrammed early in the disease sequence and act mutually to promote disease progression. However, the link between energy metabolism and its connection with other central cellular processes within the Barrett microenvironment is unknown. The aim of this study was to examine the relationship between metabolism (ATP5B/GAPDH), hypoxia (HIF1α), inflammation (IL1ß/SERPINA3), p53 and obesity status using in-vivo and ex-vivo models of Barrett oesophagus. At the protein level, ATP5B (r = 0.71, P < 0.0001) and p53 (r = 0.455, P = 0.015) were found to be strongly associated with hypoxia. In addition, levels of ATP5B (r = 0.53, P = 0.0031) and GAPDH (r = -0.39, P = 0.0357) were positively associated with p53 expression. Moreover, we demonstrate that ATP5B (r = 0.8, P < 0.0001) and GAPDH (r = 0.43, P = 0.022) were positively associated with IL1ß expression. Interestingly, obesity was negatively associated with oxidative phosphorylation (r = -0.6016, P = 0.0177) but positively associated with glycolysis (r = 0.743, P = 0.0015). Comparable correlations were exhibited in the ex-vivo explant tissue between metabolism, p53, hypoxia, inflammation and angiogenesis (P < 0.05). We have shown that metabolism is closely linked with many cellular processes in the Barrett tissue microenvironment.

Multidisciplinary treatment of olfactory neuroblastoma: Patterns of failure and management of recurrence.

PURPOSE: Esthesioneuroblastoma is an uncommon malignancy of the head and neck for which there is no defined treatment protocol. The purpose of this study is to report our experience with the treatment and patterns of failure of this disease. METHODS AND MATERIALS: From 1994 to 2012, 37 previously unreported patients with esthesioneuroblastoma were evaluated, and 32 eventually treated for cure at 2 academic medical centers. All patients were staged with Kadish criteria. The mean and median follow-ups were 96.1 and 76.5 months respectively (range 6-240 months). RESULTS: The Kadish stage was A in 6 patients, B in 13 patients, and C in 13 patients. Four patients were initially treated with concurrent chemo-radiation therapy. Twenty-eight patients were treated with primary surgery. Two (2) underwent open medial maxillectomy and 26 underwent craniofacial resection (open - 17, endoscopic - 9). Three patients received curative surgical resection only. Seven patients failed either within the cranial axis or distantly, 6 of the 7 are dead of disease, 10-194 months following initial treatment. Six patients had isolated neck recurrences, 4/6 were salvaged with neck dissection and additional chemo-radiation and remain alive 30-194 months following initial treatment. Estimated overall survival rate at 10 years was 78% based on Kadish and T stages. CONCLUSION: In this retrospective analysis of 32 patients, Kadish stage C and stage T3/T4 tumors were associated with worse outcome. Total radiation dose of 60 Gy, margin status, patient age, were not found to have significant prognostic value.

A locally invasive giant cell tumor of the skull base: case report.

Giant cell tumors (GCTs) are rare, usually affecting the epiphyses in long bones of the extremities. They seldom occur in the skull, where they preferentially affect the sphenoid and temporal bones. Considered to be benign, locally aggressive lesions, they may cause cranial nerve deficits by compression but infrequently invade the dura and parenchyma of the brain. Several case reports with follow-up describe gross total resection of skull base GCT to be curative. Anything short of total resection usually results in recurrence within 4 years. Radiation therapy, although controversial, is reserved for lesions that cannot be completely resected. Some argue, however, against the use of radiation because there are reported cases of malignant transformation. Here we describe the case of a large GCT that was invasive to the dura, temporal lobe, as well as the third division of the trigeminal nerve, and to date gross total resection has been curative of this lesion. The patient has not undergone radiation therapy.

Two-week referrals for suspected head and neck cancer: two cycles of audit, 10 years apart, in a district general hospital.

OBJECTIVE: To analyse trends in two-week rule referrals for head and neck cancer over 10 years. METHOD: Data from two-week referrals received by the Wirral University Hospital NHS Trust between 1 January and 30 June 2012 were compared with similar data from 2002. RESULTS: A total of 357 referrals were received during the 6-month audit period, compared with 149 during the whole of 2002. Cancer pick-up rates were 9 per cent and 5 per cent in the first and second cycles, respectively. CONCLUSION: The annual number of two-week referrals made to our department increased by over 450 per cent in 10 years, but the resulting cancer pick-up rate fell by nearly 50 per cent. Whilst cancer patients need to be seen quickly, the current system is inefficient in parts. Modifications to the treatment pathway should be considered to improve patient care quality and reduce pressure on ENT departments.

A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy.

PURPOSE: To identify the psychiatric and epilepsy variables predictive of postsurgical seizure outcome after anterotemporal lobectomy (ATL). METHODS: Retrospective study of 100 consecutive patients with temporal lobe epilepsy (TLE) who underwent ATL. The mean (+/- SD) follow-up period was 8.3 (+/- 3.1) years. Three types of surgical outcomes were examined at 2 years after surgery and at last contact: class IA (no disabling seizures no auras), class IA + IB (no disabling seizures), and class IA + IB + IC (no or rare disabling seizures in the first postsurgical year). Logistic regression analyses were performed separately for the three types of surgical outcomes. The epilepsy-related independent variables included age at onset, cause of TLE (mesial temporal sclerosis, lesional and cryptogenic TLE), extent of resection of mesial structures, neuropathologic abnormalities, having only complex partial seizures, and duration of the seizure disorder. The psychiatric independent variables included a postsurgical and presurgical lifetime history of mood, anxiety, attention deficit hyperactivity, and psychotic disorders. RESULTS: The absence of a psychiatric history was an independent predictor of all three types of surgical outcomes. In addition, a larger resection of mesial structures was a predictor for class IA outcome, and having only complex partial seizures (vs generalized tonic-clonic seizures) was a predictor for class IA + IB and IA + IB + IC. Having mesial temporal sclerosis (vs other causes of TLE) was a predictor for class IA + IB + IC as well. CONCLUSIONS: These data indicate that a lifetime psychiatric history may be predictive of a worse postsurgical seizure outcome after an anterotemporal lobectomy.

Multivessel percutaneous coronary intervention: a review of the literature and fallacies in its interpretation.

Since its inception in the 1960s, coronary revascularization has established itself as a fundamental therapy for treating the acute and chronic manifestations of atherosclerotic coronary disease. Catheter-based techniques were realized in the late 1970s and have evolved from balloon dilatation of simple, discrete stenoses to complex, multivessel interventions across the spectrum of coronary disease presentations. In retrospect, there were two defining technological developments the introduction of coronary stenting which enabled more stable acute outcomes and the evolution of drug-eluting stents which ameliorated the effect of neointimal hyperplasia the dominant cause of delayed loss of efficacy. The role of catheter-based intervention in multivessel disease is well established in the treatment of ST-elevation myocardial infarction and acute coronary syndromes. On the contrary, in the arena of in stable coronary disease, its utility is keenly debated. The pace of development in cardiovascular pharmacology has rendered early investigation of best treatment strategies largely obsolete, while newer revascularization techniques have successfully extended the remit of catheter-based multivessel intervention strategies to include left main stem disease, bifurcation stenosis and chronic occlusions. Consequently complete revascularization is now available via a percutaneous approach and conventional beliefs relating to choice of revascularization strategy deserve re-assessment. The authors present a contemporary review of the literature and a challenge against fallacies in its interpretation.

Magnetic resonance imaging in rectal cancer downstaged using neoadjuvant chemoradiation: accuracy of prediction of tumour stage and circumferential resection margin status.

OBJECTIVE: The aim was to examine the accuracy of magnetic resonance imaging (MRI) in predicting circumferential resection margin (CRM) involvement, T- and N-stage in patients with locally advanced carcinoma of the rectum, who had undergone long-course downstaging chemoradiation (CRT). METHOD: Patients with rectal cancer were selected for long-course downstaging CRT if their tumour was considered to threaten (< or = 1 mm) or involve the CRM on MRI. Eighty such patients had a repeat MRI at a median of 6 weeks post-CRT followed by surgical excision soon thereafter. The findings on the post-CRT MRI were compared with histological examination of the surgical specimen. RESULTS: For CRM involvement, post-CRT restaging MRI had an accuracy of 81% (65/80) a sensitivity of 54% (7/13), a specificity of 87% (58/67), a positive predictive value of 44% (7/16) and a negative predictive value of 91% (58/64). Accuracy for T- and N-staging was 43% (34/80) and 78% (62/80), respectively. 38% of T-stages were overstaged and 20% understaged. 4% of N-stages were overstaged and 19% understaged. The 13 patients with histological positive CRM had worse clinical outcomes than the 67 patients with negative CRM in terms of disease-free survival (relative risk of reduced DFS 4.6, P = 0.001) and overall survival (relative risk of death 3.6, P = 0.016). CONCLUSION: Magnetic resonance imaging has good specificity and negative predictive value for predicting an uninvolved CRM post downstaging CRT in locally advanced rectal cancer although sensitivity and positive predictive value for an involved CRM were unsatisfactory. The shortcomings of MRI stem from poor differentiation of viable tumour from posttreatment changes and inability to identify small nodal and tumour deposits. Clinical correlates in this group of patients have confirmed the importance of achieving a clear CRM at surgery.

A prospective audit of hypospadias correction in a regional paediatric surgery centre.

AIM: To prospectively review the management and treatment of hypospadias in a single regional centre, and in particular, to assess the spectrum of cases treated, techniques used and to determine the nature of the complications. METHODS: One hundred and fifty-three consecutive boys undergoing hypospadias repair during a 36-month period were included in the study. Information was collected prospectively and included the site of the urethral meatus, presence of chordee, surgical technique employed, use of urinary diversion, and the prescription of postoperative antibiotics and analgesics. Patients were assessed in the clinic following surgery at which time information on outcome and complications was obtained. RESULTS: One hundred and fifty-seven procedures for hypospadias were performed. Single-stage reconstruction was performed in 145 boys. GRAP (glanular reconstruction and preputioplasty) repair was the most common operation employed (n=112). The overall fistula rate was 11.7 % with the majority of patients having a satisfactory functional and cosmetic outcome following surgery. CONCLUSION: A variety of techniques can be employed to provide satisfactory correction of hypospadias with an increasing emphasis on single-stage day case procedures. GRAP repair is the favoured option for distal hypospadias and incorporates preservation of the prepuce.

Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine.

We sought to determine if plasticity in the ventral tegmental area (VTA) of the midbrain is involved in learning to associate morphine exposure with a specific environment. For this, we tested whether activation of glutamate receptors and protein kinase A is needed for the acquisition and expression of a morphine-conditioned place preference (CPP). Rats received bilateral microinjections of either the NMDA antagonist AP5 (0.48 nmol/0.3 microl), the AMPA antagonist CNQX (0.21 nmol/0.3 microl), or vehicle into the VTA prior to each of three morphine-conditioning sessions. Both the AMPA and NMDA receptor antagonists blocked the development of morphine CPP when given into the VTA but not when given outside the VTA. In similar studies the protein kinase A (PKA) inhibitor, Rp-cAMPS (13 nmol/0.3 microl), blocked the acquisition of morphine CPP when given into the VTA immediately after morphine conditioning. In separate experiments, glutamate antagonists, or Rp-cAMPS, immediately prior to the preference test blocked the expression of morphine CPP when microinjected into the VTA. These data indicate that the VTA is an important site for synaptic modifications involved in the learning and memory of environmental cues predicting reward, and that glutamate input and PKA activation are crucial to this process.

4S neuroblastoma: the long-term outcome.

BACKGROUND: Stage 4S neuroblastoma is associated with a high rate of spontaneous maturation and involution, with survival rates of 70-90%. There is little long-term follow-up data describing the disease status or late effects. The aim of this study was to assess the clinical outcome and imaging findings in long-term survivors of 4S neuroblastoma. METHODS: The patient population was identified from a single centre over 26 years. Twenty-five of 31 consecutive patients were long-term survivors. Five died from disease progression and one from cerebral palsy related complications. All survivors underwent clinical examination. Abdominal ultrasound scanning, liver function tests, hepatitis viral screen, and urinary catecholamines were performed. RESULTS: The mean age at diagnosis was 8 +/- 9 weeks with a mean age when studied of 11 years and 10 months +/- 8 years. Twenty of 25 had no significant clinical findings, three had disease associated clinical abnormalities (neurological, multiple subcutaneous nodules). Three patients had treatment related effects (small testes, urethral stricture, radiation induced soft tissue hypoplasia, post-surgical Horners syndrome). Persistant adrenal enlargement and calcification was noted in three patients. Twelve patients had abnormal liver ultrasound findings ranging from mildly coarse echotexture to structural changes without evidence of hepatic dysfunction or infection. Treatment did not correlate with abnormal hepatic ultrasound findings. CONCLUSIONS: The majority of long-term survivors of stage 4S neuroblastoma have no clinically or radiologically significant sequelae but do have residual abnormalities. These findings have implications for subsequent management of unrelated medical conditions in this patient group.

The generation of highly enriched osteoclast-lineage cell populations.

Osteoclasts form when hematopoietic cells are stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL) or tumor necrosis factor-alpha (TNFalpha). Osteoclast precursors derive from M-CSF-dependent proliferating hematopoietic cells but cannot yet be purified from mixed populations. M-CSF stimulation of bone marrow cells results in large numbers of nonadherent, proliferating macrophage precursors. These rapidly form adherent bone marrow macrophages (BMM). BMM and their precursors can be isolated free from mesenchymal and lymphocytic cells. BMM precursors derived from CBA-strain mouse bone marrow, when cocultured with ST2 cells (which express RANKL and M-CSF), formed numerous mononuclear osteoclasts, which resorbed bone and expressed tartrate-resistant acid phosphatase (TRAP) and calcitonin receptors (CTR). Addition of approximately 10 BMM precursors to ST2 cultures resulted in over 80% of these cocultures forming functional osteoclasts, suggesting that they are a highly enriched source of osteoclast progenitors. Supporting this, recombinant RANKL/M-CSF-stimulated BMM precursors formed populations in which all cells expressed TRAP. While only a small proportion of these cells (8.6%) expressed CTR, with transforming growth factor-beta (TGFbeta) present RANKL/M-CSF-stimulated BMM precursors formed almost pure (98.4%) CTR-positive osteoclasts after 7 days. This suggests that TGFbeta stimulated the maturation rate of these cells. Passaged or viably frozen BMM precursors gave rise to BMM that also all formed osteoclasts lineage cells after RANKL/M-CSF stimulation. These data suggest that BMM precursors derived from CBA mice are an expanded pool of osteoclast progenitors. These can be employed to generate osteoclast populations of high purity and in large numbers when stimulated by TGFbeta, which greatly augments the osteoclastogenic effects of RANKL.

Indications for admission to the surgical intensive care unit after radical cystectomy and urinary diversion.

PURPOSE: We analyzed the practice of mandatory surgical intensive care unit admission after radical cystectomy, and defined objective criteria to predict active treatment requirements and surgical intensive care unit stay. MATERIALS AND METHODS: We retrospectively reviewed the records of 115 consecutive patients admitted to the surgical intensive care unit after radical cystectomy and urinary diversion during the 36-month study period of January 1996 to December 1998. An Acute Physiology and Chronic Health Evaluation II score was calculated from postoperative patient parameters at admission to the unit. Active treatment mandating admission was defined as postoperative invasive cardiopulmonary monitoring, administration of vasopressors or inotropic medications, monitoring or treatment for life threatening complications, or mechanical ventilation for longer than 12 hours. We analyzed the correlation of outcome variables with the requirements for active treatment and surgical intensive care unit stay, and developed a stratification model of low versus high risk. Low risk was defined as a calculated likelihood of less than 10% for requiring active treatment postoperatively. RESULTS: Mean stay in the surgical intensive care unit plus or minus standard error was 34.4 +/- 3.1 hours. No active treatment was required in 63.5% of patients during the stay. The evaluation score, intraoperative complications and number of intraoperative transfusions were the strongest predictors of required postoperative active treatment. By combining these variables we developed a clinically applicable algorithm to stratify patients into a low and a high risk category. In patients at low and high risk the active treatment rate was 5.9% and 42.8% (p = 0.001), and the mean stay was 24.6 +/- 2.2 and 38.7 +/- 4.5 hours (p = 0.039), respectively. CONCLUSIONS: Mandatory surgical intensive care unit admission of all patients after radical cystectomy and urinary diversion does not appear indicated. A subset of patients at low risk for requiring active treatment may be identified who may be safely treated in an intermediate care setting after initial postoperative observation in the recovery room. The results of our retrospective analysis and risk stratification model should be validated in a prospective trial.

E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup.

PURPOSE: We analyze the expression of E-cadherin in bladder transitional cell carcinoma, areas of carcinoma in situ and lymph node metastases, and determine the value of E-cadherin immunoreactivity for predicting disease progression and survival of patients with bladder transitional cell carcinoma. MATERIALS AND METHODS: The study group consisted of 77 patients who underwent radical cystectomy. Formalin fixed paraffin sections were processed with a hot, citric acid antigen retrieval method, followed by immunostaining with anti-E-cadherin monoclonal antibody and a standard avidin biotin complex technique. E-cadherin expression was also evaluated in carcinoma in situ sections (18) and in regional lymph node metastases (17). RESULTS: Loss of normal membrane E-cadherin immunoreactivity was found in 59 (77%) patients. Abnormal expression of E-cadherin was associated with muscle invasive disease (p = 0.010) and lymph node metastasis (p = 0.044). Of the 18 carcinoma in situ specimens 15 (83%) and of the 17 metastatic lymph nodes 13 (76%) had abnormal E-cadherin expression. Concordance rates of E-cadherin status in carcinoma in situ areas and metastatic lymph nodes with the primary tumors were 85% and 88%, respectively. At a median followup of 128 months, abnormal E-cadherin expression was significantly associated with disease progression (p = 0.0219) and bladder cancer specific survival (p = 0.037). E-cadherin expression and pathological stage but not grade were independent predictors of disease progression (p = 0.042, 0.047 and 0.158, respectively). CONCLUSIONS: In bladder cancer altered E-cadherin expression is associated with the degree of invasiveness, lymph node metastasis and increased risk of death from bladder cancer. Furthermore, E-cadherin status is an independent predictor of disease progression in patients treated with cystectomy for transitional cell carcinoma of the bladder.

Vascular endothelial growth factor restores corporeal smooth muscle function in vitro.

PURPOSE: The therapeutic use of vasculogenic growth factors has been successfully demonstrated in models of organ ischemia. We determined whether vascular endothelial growth factor (VEGF) would reverse corporeal smooth muscle dysfunction in the hypercholesterolemic rabbit model of erectile dysfunction. MATERIALS AND METHODS: A total of 36 New Zealand White rabbits were fed a normal (12) or 1% cholesterol (24) diet and treated after 6 weeks with 0.9 mg. VEGF or vehicle. At 6 weeks 24 rabbits received a single intracavernous dose and 12 received a single intravenous bolus of either drug. Ten days after injection corporeal smooth muscle function was analyzed after relaxation to acetylcholine and sodium nitroprusside using isometric tension studies. Corporeal sections were assessed for smooth muscle content with f-actin staining and VEGF expression by immunohistochemical study and enzyme-linked immunosorbent assay. RESULTS: Endothelium dependent (acetylcholine) and nitric oxide mediated (sodium nitroprusside) smooth muscle relaxation were impaired in cholesterol fed animals (p = 0.021 and 0.003, respectively). Intracavernous VEGF treatment restored sodium nitroprusside mediated relaxation to normal (p = 0.015) and intravenous VEGF restored acetylcholine and sodium nitroprusside mediated relaxation (p = 0.014 and 0.018, respectively). Decreased smooth muscle content was noted in cholesterol fed animals versus normal diet controls (p = 0.008), which was not affected by VEGF treatment (p = 0.450). Corporeal endothelial cell content was increased after intracavernous but not intravenous VEGF treatment (p = 0.001 and 0.385, respectively). VEGF expression was augmented after treatment with recombinant VEGF (p <0.001). CONCLUSIONS: VEGF administration variably mitigated the impairment of corporeal smooth muscle relaxation in the hypercholesterolemic rabbit model of erectile dysfunction.

Comparison of macrophage responses to oxidized low-density lipoprotein and macrophage colony-stimulating factor (M-CSF or CSF-1).

Modification of low-density lipoprotein (LDL), for example by oxidation, could be involved in foam cell formation and proliferation observed in atherosclerotic lesions. Macrophage colony-stimulating factor (CSF-1 or M-CSF) has been implicated in foam cell development. It has been reported previously that oxidized LDL (ox.LDL) and CSF-1 synergistically stimulate DNA synthesis in murine bone-marrow-derived macrophages (BMM). The critical signal-transduction cascades responsible for the proliferative response to ox.LDL, as well as their relationship to those mediating CSF-1 action, are unknown. We report here that ox.LDL stimulated extracellular signal-regulated protein kinase (ERK)-1, ERK-2 and phosphoinositide 3-kinase activities in BMM but to a weaker extent than optimal CSF-1 concentrations at the time points examined. Inhibitor studies suggested at least a partial role for these kinases, as well as p70 S6-kinase, in ox.LDL-induced macrophage survival and DNA synthesis. For the DNA synthesis response to CSF-1, the degree of inhibition by PD98059, wortmannin and rapamycin was significant at low CSF-1 concentrations but was reduced as the CSF-1 dose increased. Using BMM from CSF-1-deficient mice (op/op) and a neutralizing antibody approach, we found no evidence for an essential role for endogenous CSF-1 in ox.LDL-mediated survival or DNA synthesis; likewise, with the same approaches, no evidence was obtained for an essential role for endogenous granulocyte/macrophage-CSF in ox.LDL-mediated macrophage survival and, in contrast with the literature, ox.LDL-induced macrophage DNA synthesis.

Does a ureteral access sheath facilitate ureteroscopy?

PURPOSE: Ureteral access sheaths were initially developed to facilitate difficult ureteroscopic access. However, to our knowledge no formal evaluations have been performed to assess the routine use of ureteral access sheaths. Therefore, we prospectively analyzed intraoperative time, symptomatic outcome, major complications, stone-free rate and overall costs related to the routine use of a new ureteral access sheath during standard ureteroscopic procedures. MATERIALS AND METHODS: Patients undergoing 6.5Fr semirigid or 7.5Fr flexible ureteroscopy were prospectively randomized to unaided ureteroscopy with no access sheath or ureteroscopy via a 12-14Fr ureteral access sheath. Patients who required ureteral dilatation were randomized to the ureteral access sheath used as a dilator or a standard 18Fr ureteral balloon dilator. Patients were evaluated postoperatively on days 0, 1 and 6 with a questionnaire to assess pain, irritative symptoms and complications. The stone-free rate and long-term complications were determined by excretory urography or computerized tomography at 3 months. RESULTS: Enrolled in the study were 59 consecutive patients, who underwent a total of 62 ureteroscopic procedures. Of the 47 patients (76%) who did not require ureteral dilatation 23 (49%) underwent ureteroscopy via the ureteral access sheath and 24 (51%) underwent unaided ureteroscopy. Seven of the 15 patients (28%) who required ureteral dilatation underwent access sheath dilatation, while balloon dilatation was performed in 8. There was no significant difference in postoperative symptoms, complication rate or stone-free status in the access sheath and nonaccess sheath groups in patients not requiring ureteral dilatation (p <0.05). A significant increase in postoperative symptoms was noted when the balloon was used as a dilator compared to the access sheath. Operative time and costs in all patients who underwent access sheath dilatation were less than in those in whom the access sheath was not used. In the 15 patients who required dilatation 71% of access sheath and 100% of balloon dilatations were successful. CONCLUSIONS: Routine use of a ureteral access sheath appears to facilitate semirigid and flexible ureteroscopy by decreasing operative time and costs, allowing direct visualization of ureteroscope insertion with simple ureteral re-entry and assisting renal and ureteral access with minimal associated morbidity. A ureteral access sheath should be considered for routine ureteroscopic procedures.

Indications for surgical intensive care unit admission of postoperative urologic patients.

OBJECTIVES: To analyze the practice of surgical intensive care unit (SICU) admission of postoperative urologic patients and to define objective criteria to predict active treatment requirements and length of stay in the SICU. METHODS: The records of 90 consecutive patients admitted to the SICU postoperatively in the 12-month period from January 1996 to December 1996 were retrospectively reviewed. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated from patient parameters acquired within the first 12 hours. The correlation of outcome variables to the length of stay and the requirements for active treatment in the SICU were analyzed and used to develop a risk stratification model. This algorithm was subsequently validated on a population of 46 patients who underwent radical cystectomy the following year. RESULTS: Only the preoperative American Society of Anesthesia class, the event of an intraoperative complication, and the APACHE II score were statistically significant (P <0.05) predictors of length of stay and active treatment. The patients were subsequently categorized into high and low-risk groups, which were found to have mean SICU stays of 39.9 +/- 3.92 hours and 20.2 +/- 0.45 hours, respectively (P = 0. 001), and an active SICU-specific treatment rate of 58.0% and 14.3%, respectively (P = 0.001). These results were confirmed in the validation population. CONCLUSIONS: Postoperative risk stratification may be helpful in predicting SICU requirements in the immediate postoperative period and in identifying patients at lower or higher risk of an adverse outcome.