Coagulation Status Using Clot Wave Analysis in Patients With Prolonged Immobilization.

Background Prolonged immobilization is widely recognized as a risk factor for thromboembolism. In this prospective study, we investigated the changes in clot waveform analysis (CWA) parameters in prolonged immobilized patients following lower limb trauma. CWA is an advanced method for assessing global coagulation that involves continuously monitoring changes in light transmittance, absorbance, or light scattering during routine clotting tests. Additionally, we also aim to determine the CWA parameters between day one and after day three of immobilization. Methods A total of 30 patients with prolonged immobilization were enrolled in this study. The plasma of these patients was collected on the first day of their admission and subsequently obtained again after day three of immobilization. Prothrombin time (PT)-based CWA and activated partial thromboplastin time (aPTT)-based CWA were performed using the ACL TOP 300 CTS (Werfen: Bedford, USA) coagulation analyzer, which utilizes the optical method for clot detection. Plasma samples for 20 normal controls were recruited from a healthy blood donor. The CWA parameters generated during clot formation were analyzed. For the comparison of CWA parameters between patients with prolonged immobilization and healthy controls, the Mann-Whitney test was used. A paired t-test was used for the comparison of clot wave parameters between day one and after day three of immobilization. This study was approved by the Universiti Sains Malaysia Research Ethics Committee. Result The mean values of PT and aPTT in healthy controls were 11.66 seconds and 33.98 seconds, respectively. There was no statistically significant difference between the patients and the healthy controls in the median values of aPTT (P=0.935). However, patients with prolonged immobilization exhibited significantly higher median PT CWA parameter values than controls (P=0.007). These parameters included the delta change (P<0.001), peak time velocity (P=0.008), and height velocity (P<0.001). On the other hand, the delta change (P<0.001) and height velocity (P<0.001) of the aPTT CWA parameters were significantly higher in patients with prolonged immobilization than in controls. In patients with prolonged immobilization, there was no significant difference in PT CWA parameters between day one and after day three of immobilization, while for aPTT CWA, all parameters were higher on day three, except for the endpoint time. Conclusion Patients with prolonged immobilization exhibit increased PT and aPTT CWA parameters compared to normal controls. CWA parameters could aid in identifying patients at risk of developing thrombosis through changes in the clot waveform. However, further study is needed to fully utilize additional information from routine coagulation testing.

Haemostatic, Inflammatory, and Haematological Biomarkers Among Orthopaedic Patients With Prolonged Immobilization and the Risk of Hypercoagulable States.

Background Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with lower limb traumatic fractures. Orthopaedic patients who experience trauma in the lower limbs with prolonged immobilization may experience a hypercoagulable state, which could eventually lead to the development of VTE. Therefore, this study aims to evaluate the changes in hypercoagulable markers, including haemostatic, inflammatory, and haematological biomarkers in orthopaedic trauma patients with prolonged immobilization. Materials/method This prospective cohort study was conducted at Hospital Universiti Sains Malaysia from August 2020 to March 2022. Every patient with fractures in the lower limbs was screened for eligibility, and patients who required immobilization for more than five days without receiving anticoagulant prophylaxis were recruited for this study. The laboratory tests, including D-dimer, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), erythrocyte sedimentation rate (ESR), and platelet count, were serially measured on day one and day five of hospitalization. The biomarkers were analyzed using a paired t-test, with a p-value <0.05 as a significant result. Results A total of 54 patients with fractures in the lower limbs, ages ranging from 12 to 50 years old, were involved in this study. The paired t-test analysis demonstrated that several biomarkers showed a significant increase in mean difference between day one and day five of immobilization, which included fibrinogen, ESR, and platelet count. The mean differences for each biomarker with fibrinogen were 0.66 g/L (p<0.001, 95% CI of mean difference: -1.04, -0.27), ESR increased by 17.98mm/hr (p<0.001, 95% CI of mean difference: -24.69, -11.27), and platelet count increased by 128.59×109/L (p<0.001, 95% CI of mean difference: -166.55, -90.64) on day five of immobilization. D-dimer was elevated in all patients on both post-trauma days; however, no significant difference was observed in this biomarker between day one and day five of immobilization. Conclusion In conclusion, our study found that fibrinogen, ESR, and platelet count levels were significantly increased in orthopaedic trauma patients with prolonged immobilization. The increase in these biomarkers indicates the body's reaction to tissue injury after trauma, which may contribute to the hypercoagulable states. Further research with a larger sample size is warranted to assess the viability of these biomarkers as potential diagnostic indicators for the development of VTE related to hypercoagulability.

Haemostasis and Inflammatory Parameters as Potential Diagnostic Biomarkers for VTE in Trauma-Immobilized Patients.

Venous thromboembolism (VTE), which encompasses deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major public health concern due to its high incidences of morbidity and mortality. Patients who have experienced trauma with prolonged immobilization are at an increased risk of developing VTE. Plasma D-dimer levels have been known to be elevated in trauma patients, and they were closely correlated with the number of fractures. In other words, plasma D-dimer levels cannot be used as the only indicator of VTE in trauma cases. Given the limitations, further study is needed to explore other potential biomarkers for diagnosing VTE. To date, various established and novel VTE biomarkers have been studied in terms of their potential for predicting VTE, diagnostic performance, and improving clinical therapy for VTE. Therefore, this review aims to provide information regarding classic and essential haemostasis (including prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, thrombin generation, protein C, protein S, antithrombin, tissue factor pathway inhibitor, and platelet count) and inflammatory biomarkers (C-reactive protein, erythrocyte sedimentation rate, and soluble P-selectin) as potential diagnostic biomarkers that can predict the risk of VTE development among trauma patients with prolonged immobilization. Thus, further advancement in risk stratification using these biomarkers would allow for a better diagnosis of patients with VTE, especially in areas with limited resources.

The Role of Epigenetics in the Development and Progression of Multiple Myeloma.

Multiple myeloma (MM) is an exceptionally complicated and heterogeneous disease that is caused by the abnormal proliferation of malignant monoclonal plasma cells initiated in the bone marrow. In disease progression, a multistep process including differentiation, proliferation, and invasion is involved. Despite great improvement in treatment outcomes in recent years due to the substantial discovery of novel therapeutic drugs, MM is still regarded as an incurable disease. Patients with MM are afflicted by confronting remission periods accompanied by relapse or progression outcomes, which inevitably progress to the refractory stage. In this regard, MM may need new medications or modifications in therapeutic strategies to overcome resistance. A variety of genetic abnormalities (e.g., point mutations, translocations, and deletions) and epigenetic changes (e.g., DNA methylation, histone modification, and non-coding RNA) contribute to the pathogenesis and development of MM. Here, we review the significant roles of epigenetic mechanisms in the development and progression of MM. We also highlight epigenetic pathways as potential novel treatment avenues for MM, including their interplay, use of epigenetic inhibitors, and major involvement in immuno-oncology.

Comparing Minimally Invasive Sacrocolpopexy With Vaginal Uterosacral Ligament Suspension: A Multicenter Retrospective Cohort Study Through the Fellows' Pelvic Research Network.

IMPORTANCE: Comparing one-year surgical outcomes of two widely used surgical procedures for apical suspension. OBJECTIVES: The objective of this study is to compare anatomic outcomes after minimally invasive sacrocolpopexy (MISC) and vaginal uterosacral ligament suspension (vUSLS). STUDY DESIGN: This was a multicenter, retrospective cohort study through the Fellows' Pelvic Research Network. Patients with ≥ stage II pelvic organ prolapse (POP) who underwent MISC or vUSLS from January 2013 to January 2016, identified through the Current Procedural Terminology codes, with 1 year or longer postoperative data were included. Patients with prior POP surgery or history of connective tissue disorders were excluded. Anatomic success was defined as Pelvic Organ Prolapse Quantification System measurements: Ba/Bp ≤ 0 or C ≤ -TVL/2. Data were compared using χ 2 or Fisher exact tests. Continuous data were compared using Wilcoxon rank sum test. RESULTS: Three hundred thirty-seven patients underwent MISC (171 laparoscopic, 166 robotic) and 165 underwent vUSLS. The MISC group had longer operative time (205.9 minutes vs 187.5 minutes, P = 0.006) and lower blood loss (77.8 mL vs 187.4 mL; P < 0.001). Two patients (0.6%) in the MISC group had mesh exposure requiring surgical excision. Permanent suture exposure was higher after vUSLS (6.1%). At 1 year, anatomic success was comparable in the apical (322 [97%] MISC vs 160 [97%] vUSLS, P = 0.99) and posterior compartments (326 [97.6%] MISC vs 164 [99.4%] vUSLS; P = 0.28). Anterior compartment success was higher in the MISC group (328 [97.9%] vs 156 [94.9%], P = 0.04) along with longer total vaginal length (9.2 ± 1.8 vs 8.4 ± 1.5, P < 0.001). CONCLUSION: At 1 year, patients who underwent MISC or vUSLS had similar apical support. Low rates of mesh and suture exposures, less anterior recurrence, and longer TVL were noted after MISC.

Satisfaction and Regret Following Uterosacral Ligament Suspension and Sacrocolpopexy: A Prospective Multicenter Analysis From the Fellows' Pelvic Research Network.

OBJECTIVES: The primary objective was to compare levels of satisfaction, regret, and Patient Global Impression of Improvement (PGI-I) scores between women who underwent vaginal uterosacral ligament suspension (USLS) and minimally invasive sacrocolpopexy (SCP). Secondary objectives were to identify which preoperative counseling resources were most useful. METHODS: This was a multicenter, retrospective cohort study through the Fellows' Pelvic Research Network that included women who underwent a USLS or SCP between January 2013 and January 2016 with 1-year follow-up. Women completed the Decision Regret Scale for Pelvic Floor Disorders, Satisfaction with Decision Scale for Pelvic Floor Disorders, and PGI-I. Data were also collected on usefulness of various educational preoperative resources. RESULTS: A total of 175/367 (47.6%) women participated; 45 (25.7%) and 130 (74.3%) in the USLS and SCP groups, respectively. Mean Decision Scale for Pelvic Floor Disorders scores were 4.6 ± 0.8 and 4.5 ± 0.7 (P = 0.30) in the USLS and SCP groups, respectively, indicating a high level of satisfaction with surgical decision. The mean Decision Regret Scale for Pelvic Floor Disorders score was 1.5 ± 0.8 in USLS and 1.6 ± 0.8 in SCP (P = 0.53). The SCP group had higher PGI-I scores (1.7 ± 1.4 vs 2.0 ± 1.3, P = 0.02), indicating lower perceived postoperative improvement. Most women (151 [86.3%] of 175) reported that verbal counseling was sufficient and would not have found additional resources helpful. CONCLUSIONS: Women have high satisfaction and low regret with their decision to pursue surgical correction with USLS or SCP. Most are satisfied with only verbal preoperative counseling.

Risk factors for explantation due to infection after sacral neuromodulation: a multicenter retrospective case-control study.

BACKGROUND: Sacral neuromodulation is an effective therapy for overactive bladder, urinary retention, and fecal incontinence. Infection after sacral neurostimulation is costly and burdensome. Determining optimal perioperative management strategies to reduce the risk of infection is important to reduce this burden. OBJECTIVE: We sought to identify risk factors associated with sacral neurostimulator infection requiring explantation, to estimate the incidence of infection requiring explantation, and identify associated microbial pathogens. STUDY DESIGN: This is a multicenter retrospective case-control study of sacral neuromodulation procedures completed from Jan. 1, 2004, through Dec. 31, 2014. We identified all sacral neuromodulation implantable pulse generator implants as well as explants due to infection at 8 participating institutions. Cases were patients who required implantable pulse generator explantation for infection during the review period. Cases were included if age ≥18 years old, follow-up data were available ≥30 days after implantable pulse generator implant, and the implant was performed at the institution performing the explant. Two controls were matched to each case. These controls were the patients who had an implantable pulse generator implanted by the same surgeon immediately preceding and immediately following the identified case who met inclusion criteria. Controls were included if age ≥18 years old, no infection after implantable pulse generator implant, follow-up data were available ≥180 days after implant, and no explant for any reason <180 days from implant. Controls may have had an explant for reasons other than infection at >180 days after implant. Fisher exact test (for categorical variables) and Student t test (for continuous variables) were used to test the strength of the association between infection and patient and surgery characteristics. Significant variables were then considered in a multivariable logistic regression model to determine risk factors independently associated with infection. RESULTS: Over a 10-year period at 8 academic institutions, 1930 sacral neuromodulator implants were performed by 17 surgeons. In all, 38 cases requiring device explant for infection and 72 corresponding controls were identified. The incidence of infection requiring explant was 1.97%. Hematoma formation (13% cases, 0% controls; P = .004) and pocket depth of ≥3 cm (21% cases, 0% controls; P = .031) were independently associated with an increased risk of infection requiring explant. On multivariable regression analysis controlling for significant variables, both hematoma formation (P = .006) and pocket depth ≥3 cm (P = .020, odds ratio 3.26; 95% confidence interval, 1.20-8.89) remained significantly associated with infection requiring explant. Of the 38 cases requiring explant, 32 had cultures collected and 24 had positive cultures. All 5 cases with a hematoma had a positive culture (100%). Of the 4 cases with a pocket depth ≥3 cm, 2 had positive cultures, 1 had negative cultures, and 1 had a missing culture result. The most common organism identified was methicillin-resistant Staphylococcus aureus (38%). CONCLUSION: Infection after sacral neuromodulation requiring device explant is low. The most common infectious pathogen identified was methicillin-resistant S aureus. Demographic and health characteristics did not predict risk of explant due to infection, however, having a postoperative hematoma or a deep pocket ≥3 cm significantly increased the risk of explant due to infection. These findings highlight the importance of meticulous hemostasis as well as ensuring the pocket depth is <3 cm at the time of device implant.

Safety and Effectiveness of Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

Recent clinical trials have shown that while bivalirudin exhibits similar efficacy with heparin, it offers several advantages over heparin, such as a better safety profile. We aimed to evaluate the efficacy and safety of bivalirudin use during Percutaneous Coronary Intervention (PCI) in the treatment of angina and acute coronary syndrome (ACS). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, EMBASE, and Science Direct from January 1980 to January 2016. Randomized controlled trials (RCTs) comparing bivalirudin to heparin during the course of PCI in patients with angina or ACS were included. Outcome measures included all-cause mortality, myocardial infarction, revascularisation, stent thrombosis, stroke, and major bleeding. The selection, quality assessment, and data extraction of the included trials were done independently by four authors, and disagreements were resolved by consensus. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated. A total of 12 RCTs involving 44,088 subjects were included. Bivalirudin appeared to be non-superior compared to heparin in reducing all-cause mortality, myocardial infarction, revascularisation, and stroke. Bivalirudin appeared to be related to a higher risk of stent thrombosis when compared to heparin plus provisional use of a glycoprotein IIb/IIIa inhibitor (GPI) at day 30 (RR 1.94 [1.16, 3.24] p < 0.01). Overall, bivalirudin-based regimens present a lesser risk of major bleeding (RR 0.56 [0.44-0.71] p < 0.001), and Thrombolysis In Myocardial Infarction (TIMI) major bleeding (RR 0.56 [0.43-0.73]) compared with heparin-based regimens either with provisional or routine use of a GPI. However, the magnitude of TIMI major bleeding effect varied greatly (p < 0.001), depending on whether a GPI was provisionally used (RR 0.42 [0.34-0.52] p < 0.001) or routinely used (RR 0.60 [0.43 -0.83] p < 0.001), in the heparin arm. This meta-analysis demonstrated that bivalirudin is associated with a lower risk of major bleeding, but a higher risk of stent thrombosis compared to heparin.

Platinum drugs: from Pt(II) compounds, Pt(IV) prodrugs, to Pt nanocrystals/nanoclusters.

Platinum (Pt) based drugs, such as cisplatin, are widely used as anti-cancer agents, but their severe adverse reactions and resistance of cancer patients have limited their board clinical use. For the last few decades, Pt(II) compounds, Pt(IV) prodrugs as well as smart drug delivery systems have been developed to overcome these problems. However, most conventional strategies rely on the similar anti-cancer mechanism with cisplatin and consequently only achieve limited success. Recently, Pt nanocrystals/nanoclusters (Pt NCs), with a brand new anti-cancer mechanism, have shown a promising potential in targeted cancer therapy, especially in Pt resistance circumvention. This review is helpful to understand the research strategies of Pt drugs, particularly, the recent developments and medical applications of Pt NCs.

Predictors of early postoperative voiding dysfunction and other complications following a midurethral sling.

BACKGROUND: The rates reported for postoperative urinary retention following midurethral sling procedures are highly variable. Determining which patients have a higher likelihood of failing a voiding trial will help with preoperative counseling prior to a midurethral sling. OBJECTIVE: The objective of the study was to identify preoperative predictors for failed voiding trial following an isolated midurethral sling. STUDY DESIGN: A retrospective, multicenter, case-control study was performed by including all isolated midurethral sling procedures performed between Jan. 1, 2010 to June 30, 2015, at 6 academic centers. We collected demographics, medical and surgical histories, voiding symptoms, urodynamic evaluation, and intraoperative data from the medical record. We excluded patients not eligible for attempted voiding trial after surgery (eg, bladder perforation requiring catheterization). Cases failed a postoperative voiding trial and were discharged with an indwelling catheter or taught intermittent self-catheterization; controls passed a voiding trial. We also recorded any adverse events such as urinary tract infection or voiding dysfunction up to 6 weeks after surgery. Bivariate analyses were completed using Mann-Whitney and Pearson χ2 tests as appropriate. Multivariable stepwise logistic regression was used to determine predictors of failing a voiding trial. RESULTS: A total of 464 patients had an isolated sling (70.9% retropubic, 28.4% transobturator, 0.6% single incision); 101 (21.8%) failed the initial voiding trial. At follow-up visits, 90.4% passed a second voiding trial, and 38.5% of the remainder passed on the third attempt. For the bivariate analyses, prior prolapse or incontinence surgery was similar in cases vs controls (31% vs 28%, P = .610) as were age, race, body mass index, and operative time. Significantly more of the cases (32%) than controls (22%) had a Charlson comorbidity index score of 1 or greater (P = .039). Overactive bladder symptoms of urgency, frequency, and urgency incontinence were similar in both groups as was detrusor overactivity in those with a urodynamic evaluation (29% vs 22%, P = .136), but nocturia was reported more in the cases (50% vs 38%, P = .046). Mean (SD) bladder capacity was similar in both groups (406 [148] mL vs 388 [122] mL, P = .542) as was maximum flow rate with uroflowmetry and pressure flow studies. Cases were significantly more likely to have a voiding type other than detrusor contraction: 37% vs 25%, P = .027, odds ratio, 1.79 (95% confidence interval, 1.07-3.00). There was no difference in voiding trial failures between retropubic and transobturator routes (23.1% vs 18.9%, P = .329). Within 6 weeks of surgery, the frequency of urinary tract infection in cases was greater than controls (20% vs 6%, P < .001; odds ratio, 3.51 [95% confidence interval, 1.82-6.75]). After passing a repeat voiding trial, cases were more likely to present with acute urinary retention (10% vs 3%, P = .003; odds ratio, 4.00 [95% confidence interval, 1.61-9.92]). For multivariable analyses, increasing Charlson comorbidity index increased the risk of a voiding trial failure; apart from this, we did not identify other demographic information among the patients who did not undergo urodynamic evaluation that reliably forecasted a voiding trial failure. CONCLUSION: The majority of women will pass a voiding trial on the first attempt after an isolated midurethral sling. Current medical comorbidities are predictive of a voiding trial failure, whereas other demographic/examination findings are not. Patients failing the initial voiding trial are at an increased risk of postoperative urinary tract infection or developing acute retention after passing a subsequent voiding trial.

Patient Preferences for Abdominal Incisions Used for Pelvic Organ Prolapse Surgery.

OBJECTIVES: Approaches for performing sacrocolpopexy (laparotomy, laparoscopy, and robotically assisted) differ with regard to length of surgery, postoperative pain, and cosmetic appearance of skin incisions. The aim of our study is to better understand what factors influence patient preferences for surgical approach. METHODS: A cross-sectional study was performed using a survey. Females 18 years or older presenting to gynecologic offices were asked to complete a survey that included photographs of patient incisions 6 weeks postoperatively along with a schematic representation of each incision type (laparotomy with low transverse incision, traditional laparoscopy, and robotically assisted). Patients were first asked to rank each incision based on cosmetic appearance only. They were next given varying clinical scenarios associated with each surgical approach and asked if their preference of incision changed. A sample size of 90 subjects was needed in order to detect a 30% difference in incision preference based on appearance with an α of 0.05 and 80% power. RESULTS: One hundred fifty patients completed the survey. Based on cosmetic appearance alone, 70% chose laparoscopic surgery, 23% chose open, and 7% chose the robotic approach (P < 0.0001). The majority of the subjects would not change their incision preference of laparoscopy based on differing scenarios of postoperative pain (62.6%), length of surgery (65.3%), and length of hospital stay (73.6%). When asked to rank factors important in decision making, complication rate (53.9%) and surgeon experience with the procedure (32.8%) were ranked as most important. CONCLUSIONS: Based on cosmetic appearance, patients prefer the laparoscopic approach for abdominal sacrocolpopexy for pelvic organ prolapse surgery. However, complication rates and surgeon experience with the procedure are important factors in the patient's decision making.

Urogynecologic conditions: pelvic organ prolapse.

Chronic pelvic pain is a commonly encountered condition that often is multifactorial. Etiologies include gynecologic, urologic, gastrointestinal, and neurologic conditions. Laboratory tests, imaging, and surgical intervention are not always helpful in identifying the etiology of pelvic pain. For appropriate management of this complex disease process, a detailed history and physical examination, and a multidisciplinary approach are needed. Pelvic pain may be caused by endometriosis, pelvic inflammatory disease, adenomyosis, interstitial cystitis/painful bladder syndrome, or other factors. Evaluation may include keeping a pain diary; laboratory tests, such as a pregnancy test, urinalysis, or tests for sexually transmitted infections; ultrasonography of abnormalities detected on physical examination; and laparoscopy. Specific first-line treatments include nonsteroidal anti-inflammatory drugs and oral contraceptives for endometriosis; progestins, gonadotropin-releasing hormone analogs, aromatase inhibitors, or hysterectomy for adenomyosis; and education, food avoidance, and behavioral modifications for interstitial cystitis/painful bladder syndrome. Surgical options include nerve transection procedures, laparoscopic uterosacral nerve ablation, and presacral neurectomy, although data on effectiveness are limited.

Diagnosis and surgical treatment of stress urinary incontinence.

Stress urinary incontinence (SUI) is a major problem affecting more than 20% of the nation's female population, with increasing prevalence as our population continues to age. Incontinence places a great burden on individuals, and the economic effect is large. Stress urinary incontinence occurs when there is involuntary leakage of urine during coughing, laughing, sneezing, or physical activity. It can be diagnosed during physical examination and by using low-cost office diagnostics. Although nonsurgical treatments provide some benefit, surgical interventions have demonstrated superiority with respect to subjective and objective cure and better long-term improvement. Corrective surgeries for SUI can be grouped into four categories: 1) slings (midurethral slings and slings placed at the ureterovesical junction), 2) retropubic urethropexy, 3) urethral bulking agents, and 4) artificial sphincters. The success and failure of each approach needs to be assessed in the context of individual patients and their circumstances. Slings and retropubic urethropexy are considered first-line surgical options. Since the advent of minimally invasive retropubic midurethral slings such as the tension-free vaginal tape, transobturator tension-free vaginal tape, and single-incision sling, retropubic urethropexy have fallen out of favor. Warnings about mesh use may contribute to a resurgence of retropubic urethropexy procedures such as the Burch procedure. A Burch procedure should still be considered for patients who have an aversion to mesh or if they are undergoing concurrent abdominal approach surgery. Urethral bulking agents are usually reserved for patients with a fixed, nonmobile urethra who cannot tolerate an operative experience or have failed previous antiincontinence procedures. Artificial sphincters should be considered an operation of last resort.

Β-arrestin: a signaling molecule and potential therapeutic target for heart failure.

Currently, some of the most effective treatments for heart failure target GPCRs such as the beta-adrenergic receptors (ß1AR and ß2AR) and angiotensin II type IA receptors (AT1aR). Ligands for these receptors not only function by blocking the deleterious G-protein mediated pathway leading to heart failure, but also signal via G-protein independent pathways that involve receptor phosphorylation by G-protein receptor kinases (GRKs) leading to recruitment of the multifunctional protein, ß-arrestin. Originally thought to play a role in GPCR desensitization and internalization, ß-arrestin has recently been shown to mediate signaling independent of classical second messengers in a way that is often protective to the heart. The multi-functionality of ß-arrestin makes it an intriguing molecule in the development of the next generation of drugs for cardiac diseases with the potential to simultaneously inhibit deleterious G-protein dependent pathways while activating beneficial ß-arrestin mediated signaling. In this review, we explore various facets of ß-arrestin signaling and offer a perspective on its potential role as a key signaling molecule in the treatment of heart failure. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Functional selectivity in adrenergic and angiotensin signaling systems.

ß-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of ß-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of ß-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein ß-arrestin. Also highlighted are the concept of "biased signaling" through ß-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of ß-blockers and angiotensin receptor blockers.

KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma.

PURPOSE: NK cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a "missing ligand" KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: One hundred sixty-nine patients treated with autologous HSCT for stage IV neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to the presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were done for overall and progression-free survival. RESULTS: Sixty-four percent of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking a HLA ligand had a 46% lower risk of death [hazard ratio, 0.54; 95% confidence interval (95% CI), 0.35-0.85; P = 0.007] and a 34% lower risk of progression (hazard ratio, 0.66; 95% CI, 0.44-1.0; P = 0.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/KIR2DL3 experienced the highest 3-year survival rate of 81% (95% CI, 64-100). Survival was more strongly associated with "missing ligand" than with tumor MYCN gene amplification. CONCLUSION: KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma.