Citations

ABSTRACT HIV-1 and certain other retroviruses initiate plus-strand synthesis in the center of the genome as well as at the standard retroviral 3′ polypurine tract. This peculiarity of reverse transcription results in a central DNA “flap” structure that has been of controversial functional significance. We mutated both HIV-1 flap-generating elements, the central polypurine tract (cPPT) and the central termination sequence (CTS). To avoid an ambiguity of previous studies, we did so without affecting integrase coding. DNA flap formation was disrupted but single-cycle infection was unaffected in all target cells tested, regardless of cell cycle status. Spreading HIV-1 infection was also normal in most T cell lines, and flap mutant viruses replicated equivalently to the wild type in nondividing cells, including macrophages. However, spreading infection of flap mutant HIV-1 was impaired in non- vif -permissive cells (HuT78, H9, and primary human peripheral blood mononuclear cells [PBMCs]), suggesting APOBEC3G (A3G) restriction. Single-cycle infections confirmed that vif -intact flap mutant HIV-1 is restricted by producer cell A3G/F. Combining the Δ vif and cPPT-CTS mutations increased A3G restriction synergistically. Moreover, RNA interference knockdown of A3G in HuT78 cells released the block to flap mutant HIV-1 replication. Flap mutant HIV-1 also accrued markedly increased A3G-mediated G→A hypermutation compared to that of wild-type HIV-1 (a full log 10 in the 0.36 kb downstream of the mutant cPPT). We suggest that the triple-stranded DNA structure, the flap, is not the consequential outcome. The salient functional feature is central plus-strand initiation, which functions as a second line of defense against single-stranded DNA editing by A3 proteins that survive producer cell degradation by Vif.

BACKGROUND: When surgeons perform total hip arthroplasty for hips with a high dislocation related to developmental dysplasia of the hip, obtaining long-term stable implant fixation and optimizing patient function remain challenges. The purpose of this paper was to evaluate the results of cementless arthroplasty with a simultaneous subtrochanteric shortening osteotomy in a group of patients with Crowe type-IV developmental dysplasia of the hip. METHODS: In a retrospective study, we evaluated the results and complications of twenty-eight consecutive primary cementless total hip arthroplasties in twenty-four patients (twenty women and four men), all of whom had Crowe type-IV developmental dysplasia of the hip. The arthroplasty was performed in combination with a subtrochanteric shortening osteotomy and with placement of the acetabular component at the level of the anatomic hip center. The patients were evaluated at a mean of 4.8 years postoperatively. RESULTS: The mean Harris hip score increased from 43 points preoperatively to 89 points at the time of final follow-up (p < 0.01). Twelve (43%) of the twenty-eight hips had an early or late complication or a reoperation. Two (7%) of the twenty-eight subtrochanteric osteotomies were followed by nonunion. There was one instance of isolated loosening of the femoral stem. One acetabular component loosened, and one acetabular liner disengaged. Four hips dislocated postoperatively. All remaining components were well-fixed at the time of the last radiographic follow-up. No sciatic neurapraxic injuries were identified. CONCLUSIONS: Cementless total hip arthroplasty combined with a subtrochanteric femoral shortening osteotomy in patients with a high hip dislocation secondary to developmental dysplasia was associated with high rates of successful fixation of the implants and healing of the osteotomy site and a mean postoperative Harris hip score of 89 points. The complication rate, however, was substantially higher than that associated with primary total hip arthroplasty in patients with degenerative arthritis. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions to Authors for a complete description of levels of evidence. ORIGINAL ABSTRACT CITATION: “Total Hip Arthroplasty with Shortening Subtrochanteric Osteotomy in Crowe Type-IV Developmental Dysplasia” (2009;91:2213-21).

Abstract Heat shock protein 90 (HSP90), which regulates the functions of multiple oncogenic signaling pathways, has emerged as a novel anticancer therapeutic target, and multiple small-molecule HSP90 inhibitors are now in clinical trials. Although the effects of HSP90 inhibitors on oncogenic signaling pathways have been extensively studied, the effects of these agents on tumor suppressor signaling pathways are currently unknown. Here, we have examined how HSP90 inhibitors affect LATS1 and the related protein LATS2, two kinases that relay antiproliferative signals in the Hippo tumor suppressor pathway. Both LATS1 and LATS2 were depleted from cells treated with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG), radicicol, and PU-H71. Moreover, these kinases interacted with HSP90, and LATS1 isolated from 17-AAG–treated cells had reduced catalytic activity, thus showing that the kinase is a bona fide HSP90 client. Importantly, LATS1 signaling was disrupted by 17-AAG in tumor cell lines in vitro and clinical ovarian cancers in vivo as shown by reduced levels of LATS1 and decreased phosphorylation of the LATS substrate YAP, an oncoprotein transcriptional coactivator that regulates genes involved in cell and tissue growth, including the CTGF gene. Consistent with the reduced YAP phosphorylation, there were increased levels of CTGF, a secreted protein that is implicated in tumor proliferation, metastasis, and angiogenesis. Taken together, these results identify LATS1 and LATS2 as novel HSP90 clients and show that HSP90 inhibitors can disrupt the LATS tumor suppressor pathway in human cancer cells. Cancer Res; 70(21); 8642–50. ©2010 AACR.

Abstract Engagement of the transforming growth factor-β (TGF-β) receptor complex activates multiple signaling pathways that play crucial roles in both health and disease. TGF-β is a key regulator of fibrogenesis and cancer-associated desmoplasia; however, its exact mode of action in these pathologic processes has remained poorly defined. Here, we report a novel mechanism whereby signaling via members of the ERBB or epidermal growth factor family of receptors serves as a central requirement for the biological responses of fibroblasts to TGF-β. We show that TGF-β triggers upregulation of ERBB ligands and activation of cognate receptors via the canonical SMAD pathway in fibroblasts. Interestingly, activation of ERBB is commonly observed in a subset of fibroblast but not epithelial cells from different species, indicating cell type specificity. Moreover, using genetic and pharmacologic approaches, we show that ERBB activation by TGF-β is essential for the induction of fibroblast cell morphologic transformation and anchorage-independent growth. Together, these results uncover important aspects of TGF-β signaling that highlight the role of ERBB ligands/receptors as critical mediators in fibroblast responses to this pleiotropic cytokine. Cancer Res; 70(19); 7421–30. ©2010 AACR.

OBJECTIVES: The objective of this study was to examine factors that are associated with aggression that is responsive versus refractory to individualized optimization of stimulant monotherapy among children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children who were aged 6 to 13 years and had ADHD, either oppositional defiant disorder or conduct disorder, significant aggressive behavior, and a history of insufficient response to stimulants completed an open stimulant monotherapy optimization protocol. Stimulant titration with weekly assessments of behavior and tolerability identified an optimal regimen for each child. Families also received behavioral therapy. Parents completed the Retrospective-Modified Overt Aggression Scale (R-MOAS) at each visit. Children were classified as having stimulant-refractory aggression on the basis of R-MOAS ratings and clinician judgment. Differences that pertained to treatment, demographic, and psychopathology between groups with stimulant monotherapy–responsive and –refractory aggression were evaluated. RESULTS: Aggression among 32 (49.3%) of 65 children was reduced sufficiently after stimulant dosage adjustment and behavioral therapy to preclude adjunctive medication. Those who responded to stimulant monotherapy were more likely to benefit from the protocol's methylphenidate preparation (once-daily, triphasic release), showed a trend for lower average dosages, and received fewer behavioral therapy sessions than did children with stimulant-refractory aggression. Boys, especially those with higher ratings of baseline aggression and of depressive and manic symptoms, more often exhibited stimulant-refractory aggression. CONCLUSIONS: Among children whose aggressive behavior develops in the context of ADHD and of oppositional defiant disorder or conduct disorder, and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy often culminates in reduced aggression that averts the need for additional agents.

Background— After repair of aortic coarctation, patients may develop restenosis, aneurysms, and pseudoaneurysms at the site of prior repair. We assessed the outcomes of late reintervention on the descending aorta after aortic coarctation repair. Methods and Results— From March 1954 to July 2008, 130 patients had operations or endovascular procedures on the descending aorta after previous coarctation repair. We excluded patients who had complex left-sided cardiac lesions or interrupted aortic arch. Mean age at reintervention was 32±24 years and 28% were female. The interval between coarctation repair and reintervention was 17±13 years. Seventy-four percent of patients had hypertension. Reasons for reintervention were restenosis (n=122 [94%]), aneurysm (n=4 [3%]), and pseudoaneurysm (n=4 [3%]). Ninety-five patients (73%) underwent operative procedures including an extra-anatomic conduit (n=41), patch repair (n=32), interposition graft (n=14), end–end anastomosis (n=6), and subclavian flap (n=2). Thirty-five patients underwent endovascular treatment (balloon dilatation, n=22 or stenting, n=13). There was no early mortality. In the surgical group, 5 patients required early reoperation for bleeding and 5 patients had early vocal cord paralysis. One patient in the endovascular group had aortic rupture at the time of intervention requiring urgent operation. Survival was 97% at 10 years. At 5 years, freedom from a second repeat procedure on the descending aorta was 96% in the surgical group and 72% in the endovascular group ( P <0.001). Five years after reintervention, fewer patients required treatment for hypertension (57% versus 74% , P <0.001) and a median of 1 antihypertensive medication was prescribed compared with a median of 2 medications preintervention. Conclusions— Operative and endovascular management of recoarctation can be performed safely with good late outcomes.

Background— Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body’s response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. Methods and Results— In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P =0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240±65 versus 300±87.5 minutes; P <0.001), in the length of ICU stay (19.5±17.8 versus 43±17.0 hours; P <0.001), time to extubation (4.6±6.8 versus 9.3±5.7 hours; P <0.001), hospital stay (6±2 versus 9±2 days; P <0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P <0.001), and blood requirements (31 versus 61% of patients; P <0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P <0.001). Conclusions— No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66068876.

ABSTRACTIntroductionOver the past 20 years our knowledge of premature ejaculation (PE) has significantly advanced. Specifically, we have witnessed substantial progress in understanding the physiology of ejaculation, clarifying the real prevalence of PE in population-based studies, reconceptualizing the definition and diagnostic criterion of the disorder, assessing the psychosocial impact on patients and partners, designing validated diagnostic and outcome measures, proposing new pharmacologic strategies and examining the efficacy, safety and satisfaction of these new and established therapies. Given the abundance of high level research it seemed like an opportune time for the International Society for Sexual Medicine (ISSM) to promulgate an evidenced-based, comprehensive and practical set of clinical guidelines for the diagnosis and treatment of PE.AimDevelop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts.MethodReview of the literature.ResultsThis article contains the report of the ISSM PE Guidelines Committee. It affirms the ISSM definition of PE and suggests that the prevalence is considerably lower than previously thought. Evidence-based data regarding biological and psychological etiology of PE are presented, as is population-based statistics on normal ejaculatory latency. Brief assessment procedures are delineated and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients.ConclusionDevelopment of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. Therefore, it is strongly recommended that these guidelines be re-evaluated and updated by the ISSM every 4 years.