Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α.

Mutant forms of p53 protein often possess protumorigenic functions, conferring increased survival and migration to tumor cells via their "gain-of-function" activity. Whether and how a common polymorphism in TP53 at amino acid 72 (Pro72Arg; referred to here as P72 and R72) impacts this gain of function has not been determined. We show that mutant p53 enhances migration and metastasis of tumors through the ability to bind and regulate PGC-1α and that this regulation is markedly impacted by the codon 72 polymorphism. Tumor cells with the R72 variant of mutant p53 show increased PGC-1α function along with greatly increased mitochondrial function and metastatic capability. Breast cancers containing mutant p53 and the R72 variant show poorer prognosis compared with P72. The combined results reveal PGC-1α as a novel "gain-of-function" partner of mutant p53 and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis.

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

Diastereoselective FeCl3·6H2O/NaBH4 Reduction of Oxime Ether for the Synthesis of ß-Lactamase Inhibitor Relebactam.

Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.

Erosion rates of 3.5-cm artificial urinary sphincter cuffs are similar to larger cuffs.

OBJECTIVE: To compare long-term outcomes and erosion rates of 3.5-cm artificial urinary sphincter (AUS) cuffs vs larger cuffs amongst men with stress urinary incontinence (SUI), with and without a history of pelvic radiotherapy (RT). PATIENTS AND METHODS: We reviewed the records of all men who underwent AUS placement by a single surgeon between September 2009 and June 2017 at our tertiary urban medical centre. A uniform perineal approach was used to ensure cuff placement around the most proximal corpus spongiosum after precise spongiosal measurement. Patients were stratified by cuff size and RT status, and patient demographics and surgical outcomes were analysed. Cases of AUS revision in which a new cuff was not placed were excluded. Success was defined as patient-reported pad use of ≤1 pad/day. RESULTS: Amongst 410 cases included in the analysis, the 3.5-cm cuff was used in 166 (40.5%), whilst 244 (59.5%) received larger cuffs (≥4.0 cm). Over a median follow-up of 50 months, there was AUS cuff erosion in 44 patients at a rate nearly identical in the 3.5-cm cuff (10.8%, 18/166) and the ≥4-cm cuff groups (10.7%, 26/244, P = 0.7). On multivariate logistic regression, clinical factors associated with AUS cuff erosion included a history of pelvic RT, prior AUS cuff erosion, prior urethroplasty, and a history of inflatable penile prosthesis (IPP) placement. Patient demographics were similar between the cuff-size groups; including age, body mass index, comorbidities, smoking history, RT history, prior AUS, and prior IPP placement. Continence rates were high amongst all AUS patients, with similar success in both groups (82% for 3.5-cm cuff, 90% for ≥4-cm cuff, P = 0.1). CONCLUSIONS: After 8 years of experience and extended follow-up, the outcomes of the 3.5-cm AUS cuff appear to be similar to ≥4-cm cuffs for effectiveness and rates of urethral erosion. RT patients have a higher risk of cuff erosion regardless of cuff size.

Delayed Reconstruction of Bulbar Urethral Strictures is Associated with Multiple Interventions, Longer Strictures and More Complex Repairs.

PURPOSE: Prior to urethral reconstruction many patients with stricture undergo a variable period during which endoscopic treatments are performed for recurrent obstructive symptoms. We evaluated the association among urethroplasty delay, endoscopic treatments and subsequent reconstructive outcomes. MATERIALS AND METHODS: We reviewed the records of men who underwent primary bulbar urethroplasty from 2007 to 2014. Those with prior urethroplasty, penile and/or membranous strictures and incomplete data were excluded from analysis. Men were stratified by a urethroplasty delay of less than 5, 5 to 10 or greater than 10 years from diagnosis. RESULTS: A total of 278 primary bulbar urethroplasty cases with complete data were evaluated. Median time between stricture diagnosis and reconstruction was 5 years (IQR 2-10). Patients underwent an average ± SD of 0.9 ± 2.4 endoscopic procedures per year of delay. Relative to less than 5 and 5 to 10 years a delay of greater than 10 years was associated with more endoscopic treatments (median 1 vs 2 vs 5), repeat self-dilations (13% vs 14% vs 34%), strictures longer than 2 cm (40% vs 39% vs 56%) and complex reconstructive techniques (17% vs 17% vs 34%). An increasing number of endoscopic treatments was independently associated with strictures longer than 2 cm (OR 1.06, p = 0.003), which had worse 24-month stricture-free survival than shorter strictures (83% vs 96%, p = 0.0003). Each consecutive direct vision internal urethrotomy was independently associated with the risk of urethroplasty failure (HR 1.19, p = 0.02). CONCLUSIONS: Urethroplasty delay is common and often associated with symptomatic events managed by repeat urethral manipulations. Endoscopic treatments appear to lengthen strictures and increase the complexity of repair.

Plication for Severe Peyronie's Deformities Has Similar Long-Term Outcomes to Milder Cases.

INTRODUCTION: Penile plication (PP) for Peyronie's disease (PD) is an established treatment option for mild to moderate curvature, but scant data exist regarding its utility in severe deformities. AIM: To evaluate long-term outcomes among men undergoing PP for PD, comparing severe to mild/moderate penile deformities. METHODS: We performed a retrospective review of patients who underwent PP for PD between 2009 and 2017. All patients underwent multiple parallel tunical plication without degloving. Severe PD was defined as either curvature ≥60 degrees or biplanar curvature ≥35 degrees. Patient demographics and surgical outcomes were analyzed. A modified PD Questionnaire and International Index of Erectile Function (IIEF)-5 were administered by telephone. MAIN OUTCOME MEASURE: Long-term patient-reported outcomes were evaluated from a modified survey incorporating the PD Questionnaire and IIEF-5. RESULTS: Of 327 PP patients, 102 (31%) responded to the telephone survey at a median 59.5 months (interquartile range 28.3-84) since surgery. Patients were equally distributed into severe (n = 51) and mild/moderate (n = 51) groups. Despite a greater mean degree of curvature in severe compared to mild/moderate patients (71.6 degrees vs 37.7 degrees, respectively, P < .001), correction of penile curvature was achieved in 91% of patients, with a mean change of 60.7 degrees in severe cases compared to 31.4 degrees in mild/moderate cases (P < .001). Equal numbers of patients in severe and mild/moderate groups reported improvement of penile curvature (74.5% vs 74.5%, P = 1.0) and sexual function (51.0% vs 49.0%, P = .84). PD Questionnaire metrics were likewise similar between severe and mild/moderate patients (P > .1), as were rates of subjective penile shortening (62.7% vs 62.7%, P = 1.0) and IIEF-5, both pre-operatively (19.5 vs 19.7, P = .9) and post-operatively (19.4 vs 17.6, respectively, P = .15). On multivariate logistic regression, worsening sexual function was significantly associated with increased age (odds ratio 1.07, P = .01) and pre-operative IIEF (odds ratio 1.14, P = .02). CLINICAL IMPLICATIONS: PP should be considered in PD patients with severe deformities, as outcomes are favorable and comparable to those with milder curvature. STRENGTH & LIMITATIONS: This is a novel study evaluating long-term patient-reported outcomes after PP, comparing patients with severe deformity to those with mild/moderate curvature. The study was limited by retrospective design, relatively low survey response rate (31%), and lack of validated post-operative PD questionnaire. CONCLUSION: Long-term patient-reported outcomes of PP for severe PD deformities are comparable to mild/moderate cases, supporting broader application of PP beyond milder deformities. Reddy RS, McKibben MJ, Fuchs JS, et al. Plication for Severe Peyronie's Deformities Has Similar Long-Term Outcomes to Milder Cases. J Sex Med 2018;15:1498-1505.

Penoscrotal Decompression-Promising New Treatment Paradigm for Refractory Ischemic Priapism.

BACKGROUND: For prolonged ischemic priapism, outcomes after distal shunt are poor, with only 30% success for priapic episodes lasting longer than 48 hours. AIM: To present a novel, glans-sparing approach of corporal decompression through a penoscrotal approach for cases of refractory ischemic priapism (RIP) after failed distal shunt procedures. METHODS: We describe the technique and present our initial experience with penoscrotal decompression (PSD) for treatment of RIP after failed distal shunt. We compared outcomes of patients with RIP undergoing surgical management using PSD or malleable penile prosthesis (MPP) placement after failed distal penile shunt procedures (2008-2017). OUTCOMES: Our initial experience showed favorable outcomes with PSD compared with early MPP placement in patients with RIP whose distal shunt failed. RESULTS: Of 14 patients with RIP undergoing surgical management after failed distal penile shunt procedures, all patients presented after a prolonged duration of priapism (median = 61 hours) after which the priapism was refractory to multiple prior treatments (median = 3, range = 1-75) including at least 1 distal shunt. MPP was inserted in 8 patients (57.1%), whereas the most recent 6 patients (42.9%) underwent PSD. All patients with PSD (6 of 6, 100%) were successfully treated with corporal decompression without additional intervention and noted immediate relief of pain postoperatively. In contrast, 37.5% of patients (3 of 8) undergoing MPP after failed distal shunt procedures required a total of 8 revision surgeries during a median follow-up of 41.5 months. The most common indications for revision surgery after MPP placement included distal (4 of 8, 50%) and impending lateral (2 of 8, 25%) extrusion. CLINICAL IMPLICATIONS: PSD is a simple, effective technique in the management of RIP after failed distal shunt procedures with fewer complications than MPP placement. STRENGTHS AND LIMITATIONS: Although PSD is effective in the management of RIP after failed distal shunt procedures, long-term assessment of erectile function and ease of future penile prosthetic implantation is needed. CONCLUSION: Corporal decompression resolves RIP through a glans-sparing approach and avoids the high complication rate of prosthetic insertion after failed distal shunt procedures. Fuchs JS, Shakir N, McKibben MJ, et al. Penoscrotal Decompression-Promising New Treatment Paradigm for Refractory Ischemic Priapism. J Sex Med 2018;15:797-802.

Refined nomogram incorporating standing cough test improves prediction of male transobturator sling success.

AIMS: To develop a decision aid in predicting sling success, incorporating the Male Stress Incontinence Grading Scale (MSIGS) into existing treatment algorithms. METHODS: We reviewed men undergoing first-time transobturator sling for stress urinary incontinence (SUI) from 2007 to 2016 at our institution. Patient demographics, reported pads per day (PPD), and Standing Cough Test (SCT) results graded 0-4, according to MSIGS, were assessed. Treatment failure was defined as subsequent need for >1 PPD or further procedures. Parameters associated with failure were included in multivariable logistic models, compared by area under the receiver-operating characteristic curves. A nomogram was generated from the model with greatest AUC and internally validated. RESULTS: Overall 203 men (median age 67 years, IQR 63-72) were evaluated with median follow-up of 45 months (IQR 11-75 months). A total of 185 men (91%) were status-post radical prostatectomy and 29 (14%) had pelvic radiation history. Median PPD and SCT grade were both two. Eighty men (39%) failed treatment (use of ≥1 PPD or subsequent anti-incontinence procedures) at a median of 9 months. History of radiation (P = 0.03), increasing MSIGS (P < 0.0001) and increasing preoperative PPD (P < 0.0001) were associated with failure on univariate analysis. In a multivariable model with AUC 0.81, MSIGS, and PPD remained associated (P = 0.002 and <0.0001 respectively, and radiation history P = 0.06), and was superior to models incorporating PPD and radiation alone (AUC 0.77, P = 0.02), PPD alone (AUC 0.76, P = 0.02), and a cutpoint of >2 PPD alone (AUC 0.71, P = 0.0001). CONCLUSIONS: MSIGS adds prognostic value to PPD in assessing success of transobturator sling for treatment of SUI.

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure.

Preeclampsia is associated with hypertension, small-for-gestational-age babies, and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activation of NK cells, and that reducing NK cells in RUPP would prevent hypertension, intrauterine growth restriction, and inflammation in response to placental ischemia. RUPP was induced on gestation day (GD) 14 in pregnant rats. NK cells were depleted by i.p. administration of anti-asialo GM1 antibody on GDs 15 and 17. Placental and circulating NK cells were quantified via flow cytometry, mean arterial pressure (MAP), fetal weights, and cytokines were measured on GD 19. Total placental NK cells were 7.4 ± 2% of gated cells in normal pregnant (NP; n=10) and 16.5 ± 3% of gated cells in RUPP (n=10) rats. Furthermore, cytolytic placental NK cells also increased in RUPP. Depletion of NK cells in RUPP (RUPP + anti-ASGM1) significantly improved MAP and fetal weights. MAP was 108 ± 2 mmHg in NP, 125 ± 2 mmHg in RUPP, and 112 ± 2 mmHg in RUPP + anti-ASGM1 (n=12). Fetal weight was 2.32 ± 0.05 in NP, 1.8 ± 0.04g in RUPP, and increased to 2.0 ± 0.04g in RUPP + anti-ASGM1. Placental interferon-γ (IFN-γ) was 40.4 ± 5.2 pg/mg in NP, 72.17 ± 3.2 pg/mg in RUPP, and 44.0 ± 6.5 pg/mg in RUPP + anti-ASGM1 (P<0.05). Placental tumor necrosis factor-α (TNF-α) was 17.9 ± 1.7 pg/mg in NP, 23.9 ± 2.2 pg/mg in RUPP, and 12.9 ± 2.3 pg/mg in RUPP + anti-ASGM1 (P<0.05). Depletion of NK cells significantly lowered MAP, intrauterine growth restriction, and inflammation in RUPP rats indicating that cytolytic NK cells are important in preeclampsia pathophysiology.

Synchronous Ipsilateral High Submuscular Placement of Prosthetic Balloons and Reservoirs.

INTRODUCTION: Synchronous ipsilateral high submuscular placement of artificial urinary sphincter (AUS) pressure-regulating balloons (PRBs) and inflatable penile prosthesis (IPP) reservoirs in a single submuscular tunnel is a novel strategy that could be advantageous for patients who have had major pelvic surgery. AIM: To report our initial experience with synchronous ipsilateral vs bilateral placement of AUS PRBs and IPP reservoirs in men undergoing implant surgery. METHODS: We retrospectively reviewed all patients undergoing synchronous AUS and IPP placement from 2007 through 2015 by a single surgeon at our tertiary center. Patients were stratified according to ipsilateral vs bilateral placement of the AUS PRB and IPP reservoir. MAIN OUTCOME MEASURES: Reoperation rates because of infectious or erosive complications and mechanical failure were assessed. RESULTS: Of the 968 implant surgeries during the study period, 47 men had synchronous device placement, of whom 17 (36%) underwent ipsilateral placement of the PRB and reservoir. During a median follow-up of 19 months (range = 1-84 months), reoperations were necessary in 12 of 47 (26%) and were similar between groups (ipsilateral, 5 of 17, 29%; bilateral, 7 of 30, 23%; P = .73). Most reoperations were due to AUS-related complications (10 of 12, 83%) and nearly all patients with reoperation (10 of 12, 83%) had compromised urethras (ie, prior urethral surgery, radiation, or prior AUS implantation). The most common indication for reintervention was cuff erosion (4 of 47, 9%), with no difference between groups (ipsilateral, 3 of 17, 18%; bilateral, 1 of 30, 3%; P = .13). CONCLUSION: Synchronous ipsilateral high submuscular placement of urologic prosthetic balloons could safely facilitate prosthetic surgery in patients with a history of major pelvic and inguinal surgery.

Preoperative Urine Culture Results Correlate Poorly With Bacteriology of Urologic Prosthetic Device Infections.

INTRODUCTION: Although preoperative negative urine culture results and treatment of urinary tract infections are generally advised before artificial urinary sphincter (AUS) and penile prosthesis (PP) surgery to prevent device infection, limited evidence exists to support this practice. AIM: To evaluate the relation between preoperative urine culture results and the bacteriology of prosthetic device infections. METHODS: Men undergoing AUS and/or PP placement at a tertiary referral center from 2007 through 2015 were analyzed. A total of 713 devices were implanted in 681 patients (337 AUSs in 314 patients and 376 PPs in 367 patients), of whom 259 (36%) did not have preoperative urine culture and were excluded. The remaining 454 patients received standard broad-spectrum perioperative antibiotics. Two patient groups were identified based on preoperative urine cultures: group 1 had negative urine culture results and group 2 had untreated asymptomatic positive urine culture results identified postoperatively. MAIN OUTCOME MEASURES: Device infection was diagnosed clinically and cultures obtained from the explanted device and tissue spaces were compared with preoperative urine culture results. RESULTS: Although multivariate analysis showed that patients undergoing AUS placement had a 4.5-fold greater risk of positive urine culture results (114 of 250, 45%) compared with those undergoing PP placement (36 of 204, 18%; P < .001), infection rates between device types were similar (8 of 250 for AUSs [3%] and 7 of 204 for PPs [3%]; P = .89). At a median follow-up of 15 months, device infection occurred in 15 of 454 devices (3%) implanted and no differences in infection rates were noted between urine culture groups (10 of 337 in group 1 [3.3%] and 5 of 117 in group 2 [4.3%]; P = .28). Remarkably, only 1 of 15 device infections (7%) had the same organism present at preoperative urine culture. CONCLUSIONS: Despite the finding that patients with AUS placement had a 4.5 times higher rate of positive urine culture results than patients with PP placement, preoperative urine culture results appeared to show little correlation with the bacteriology of prosthetic device infections.

Standing cough test for evaluation of post-prostatectomy incontinence: a pilot study.

INTRODUCTION: We implemented a standardized Standing Cough Test (SCT) for assessment of men with post-prostatectomy incontinence (PPI) and stratified results according to an objective clinical grading scale in an attempt to facilitate male anti-incontinence surgical procedure selection. MATERIALS AND METHODS: SCT was routinely performed during the initial outpatient consultation for PPI. Incontinence severity was recorded based on a novel Male Stress Incontinence Grading Scale (MSIGS) to stratify PPI. Each patient was assigned an incontinence grade score of 0 through 4 during the SCT. Men with mild stress urinary incontinence (SUI) (grades 0-2) were offered sling surgery while those with heavier SUI (grades 3-4) were offered artificial urinary sphincter (AUS). MSIGS grade was correlated to preoperative patient-reported pads per day (PPD), and patient-reported outcomes of anti-incontinence surgery were assessed. RESULTS: Among 62 consecutive PPI patients, 20 (32%) were graded as mild based on SCT, while the majority (42/62, 68%) were graded as moderate-severe. Average time from prostatectomy to treatment was 6 years. MSIGS grade demonstrated a strong correlation with preoperative PPD (r = 0.74). Among the 53 patients who underwent surgery for PPI, 14 with mild SUI received a sling, while 39 (74%) more severe cases received an AUS. Patient-reported improvement was high overall in both groups (median 95%). CONCLUSION: Most men with chronic PPI present for definitive treatment in a delayed manner after prostatectomy despite having severe incontinence. The SCT provides immediate, objective information about the severity of PPI which strongly correlates with patient-reported pads-per-day and may expedite anti-incontinence surgical procedure selection.

Inflatable penile prosthesis as tissue expander: what is the evidence?

OBJECTIVE: Many patients who undergo inflatable penile prosthesis (IPP) replacement are often upsized to larger cylinders, suggesting the IPP may serve as a tissue expander and increase internal penile length. The objective of this study is to evaluate whether cylinder length increases with subsequent IPP insertion. MATERIALS AND METHODS: We queried American Medical Systems and Coloplast Patient Information Form databases to identify patients who underwent IPP placement and replacement between 2004-2013. Patients were grouped by device type and time to replacement (<2 or ≥2 years). We selected the 2-year mark for subgroup analysis to allow time for tissue expansion to occur and to exclude patients who underwent early explantation (e.g. erosion or infection). RESULTS: Two thousand, seven hundred and forty nine patients (1,532 AMS 700 LGX, 717 AMS 700 CX, and 500 Coloplast Titan) met the inclusion criteria. Mean time between implants was earlier for LGX (29 months) than CX (39 months) and Titan (48 months) patients (p<0.001). Patients who underwent device replacement at <2 years did not experience an increase in mean cylinder length. On the contrary, patients who underwent device replacement at ≥2 years did experience significant increases in mean cylinder length (LGX 1.2 cm, CX 1.1 cm, and Titan 0.9 cm, p<0.001). The mean increases in length at ≥2 years were similar between the 3 devices (p=0.20). Sixty percent of patients demonstrated increases of >0.5 cm and 40% demonstrated increases of ≥1 cm. CONCLUSIONS: As demonstrated, the IPP may provide tissue expansion over time. Further evaluation is needed to determine if increased cylinder length correlates to increased functional length and patient satisfaction.

Reduced uterine perfusion pressure T-helper 17 cells cause pathophysiology associated with preeclampsia during pregnancy.

Preeclampsia is associated with chronic inflammation and an imbalance among T-helper cell subtypes with an increase in T-helper 17 (TH17) cells. The objective of this study was to determine a role for TH17s, from the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia, in the etiology of hypertension and chronic inflammation during pregnancy. CD4+/CD25- T cells were isolated from rat spleens, cultured in TH17 media, and were verified as TH17s via flow cytometry. On day 12 of gestation, 1×106 TH17 cells from RUPP rats were adoptively transferred into NP rats, carotid catheters were inserted on day 18, and on day 19, mean arterial pressure (MAP) was recorded, serum and plasma were collected, and oxidative stress and production of agonistic autoantibodies to the ANG II type I receptor (AT1-AA) were analyzed. MAP increased from 100.3 ± 1.7 mmHg in normal pregnant (NP; n = 17) to 124.8 ± 2.1 mmHg in RUPP (n = 22; P < 0.0001) and to 110.8 ± 2.8 mmHg in NP+RUPP TH17 (n = 11). Pup weights in NP+RUPP TH17s were decreased to 1.92 ± 0.09 g from 2.39 ± 0.14 in NP rats (P < 0.01). AT1-AA significantly increased from 0.1 ± 0.2 beats/min in NP to 15.6 ± 0.7 beats/min in NP+RUPP TH17s. IL-6 was 22.3 ± 5.7 pg/ml in NP and increased to 60.45 ± 13.8 pg/ml in RUPP (P < 0.05) and 75.9 ± 6.8 pg/ml in NP+RUPP TH17 rats (P < 0.01). Placental and renal oxidative stress were 238 ± 27.5 and 411 ± 129.9 relative light units·min-1·mg-1 in NP and 339 ± 104.6 and 833 ± 331.1 relative light units·min-1·mg-1 in NP+RUPP TH17, respectively. In conclusion, RUPP TH17 cells induced intrauterine growth restriction and increased blood pressure, AT1-AA, IL-6, and tissue oxidative stress when transferred to NP rats, indicating a role for autoimmune associated TH17 cells, to cause much of the pathophysiology associated with preeclampsia.

Catalytic, asymmetric, and stereodivergent synthesis of non-symmetric ß,ß-diaryl-α-amino acids.

We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected ß,ß-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc ß,ß-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia.

The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (TRegs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4(+)/CD25(+) T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 ± 2 mmHg in NP (n = 12) to 127 ± 2 mmHg in RUPP (n = 21) but decreased to 118 ± 2 mmHg in RUPP+NP TRegs (n = 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-α and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 ± 58.7 and 603 ± 88.1 RLU·min(-1)·mg(-1) in RUPP and significantly decreased to 178 ± 27.8 and 171 ± 55.6 RLU·min(-1)·mg(-1), respectively, in RUPP+NP TRegs; AT1-AA was 17.81 ± 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 ± 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-α, and AT1-AA, which have been shown to increase blood pressure during pregnancy.

Spleen tyrosine kinase inhibition attenuates airway hyperresponsiveness and pollution-induced enhanced airway response in a chronic mouse model of asthma.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by airways hyperresponsiveness (AHR), reversible airflow obstruction, airway remodeling, and episodic exacerbations caused by air pollutants, such as particulate matter (PM; PM <2.5 µm in diameter [PM(2.5)]) and ozone (O(3)). Spleen tyrosine kinase (Syk), an immunoregulatory kinase, has been implicated in the pathogenesis of asthma. OBJECTIVE: We sought to evaluate the effect of Syk inhibition on AHR in a chronic mouse model of allergic airways inflammation and pollutant exposure. METHODS: We used a 12-week chronic ovalbumin (OVA) sensitization and challenge mouse model of airways inflammation followed by exposure to PM(2.5) plus O(3). Respiratory mechanics and methacholine (MCh) responsiveness were assessed by using the flexiVent system. The Syk inhibitor NVP-QAB-205 was nebulized intratracheally by using a treatment-based protocol 15 minutes before assessment of MCh responsiveness. RESULTS: Syk expression increased significantly in the airway epithelia of OVA-sensitized and OVA-challenged (OVA/OVA) mice compared with OVA-sensitized but PBS-challenged (OVA/PBS) control mice. OVA/OVA mice exhibited AHR to MCh, which was attenuated by a single administration of NVP-QAB-205 (0.3 and 3 mg/kg). PM(2.5) plus O(3) significantly augmented AHR to MCh in the OVA/OVA mice, which was abrogated by NVP-QAB-205. Total inflammatory cell counts were significantly higher in the bronchoalveolar lavage fluid from OVA/OVA than OVA/PBS mice and were unaffected by PM(2.5) plus O(3) or NVP-QAB-205. CONCLUSION: NVP-QAB-205 reduced AHR and the enhanced response to PM(2.5) plus O(3) to normal levels in an established model of chronic allergic airways inflammation, suggesting that Syk inhibitors have promise as a therapy for asthma.

Asymmetric dimethylarginine in chronic obstructive pulmonary disease (ADMA in COPD).

L-arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in L-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed L-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of L-arginine metabolites (L-arginine, L-ornithine, L-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of L-ornithine, the product of arginase activity, correlated directly with L-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of L-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.

Anesthetic Management of Intra-aortic Balloon Pump-Induced Systolic Anterior Motion of the Mitral Valve During Coronary Artery Bypass Grafting.

The intra-aortic balloon pump (IABP) is a mechanical device that increases myocardial oxygen perfusion and indirectly increases cardiac output through afterload reduction. Since its inception, the IABP has been a mainstay of cardiac support devices, utilized as a temporizing measure in patients with or prone to developing cardiogenic shock that are awaiting definitive treatment. Systolic anterior motion (SAM) of the mitral valve is a well-described phenomenon that can precipitate hemodynamic collapse by obstructing the left ventricular outflow tract in a subset of patients with cardiac pathology, most notably hypertrophic obstructive cardiomyopathy (HOCM). This report describes the case and anesthetic management of a patient who had an IABP placed for support and later developed SAM and hemodynamic compromise after induction of general anesthesia during a coronary artery bypass surgery.