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Autosomal dominant polycystic kidney disease (ADPKD), caused by PKD1 and PKD2 gene mutations, is one of the most common genetic diseases, affecting up to 1 in 500 people. Mutations of PKD1 account for over 85% of ADPKD cases. However, mechanisms of disease progression and explanations for the wide range in disease phenotype remain to be elucidated. Moreover, functional roles of PKD1 in the renal stromal compartment are poorly understood. In this work, we tested if Pkd1 is essential for development and maintenance of the renal stromal compartment and if this role contributes to pathogenesis of polycystic kidney disease using a novel tissue-specific knockout mouse model. We demonstrate that deletion of Pkd1 from renal stromal cells using Foxd1-driven Cre causes a spectrum of defects in the stromal compartment, including excessive apoptosis/proliferation and extracellular matrix deficiency. Renal vasculature was also defective. Further, mutant mice showed epithelial changes and progressive cystogenesis in adulthood modeling human ADPKD. Altogether, we provide robust evidence to support indispensable roles for Pkd1 in development and maintenance of stromal cell derivatives by using a novel ADPKD model. Moreover, stromal compartment defects caused by Pkd1 deletion might serve as an important mechanism for pathogenesis of ADPKD.

The study of strategic organization involves many delicious ironies, one of which is the goal to prescribe general paths to sustainable competitive advantage. Twenty years after Collis and a few good men and women originally exposed and confronted the infinite regress problem in the resource-/capabilities-based theories, we revisit this problem to resolve it. We consider the linkages between the infinite hierarchical levels that form the paths to the origins of sustainable competitive advantages in both the resource-based view and the dynamic capabilities view. We find that there are logical factors that limit the number of levels that need to be traversed to reach the origins. We discuss the implications to academics, managers and policy-makers from our resolution to the infinite regress problem to provide a more crystal clear understanding of the strenuous objective that continues to challenge all strategic theory.

IgG2 heavy chain deposition disease (HCDD) is extremely rare. To date, only 4 cases have been reported in medical literature. To our knowledge, we report the first case of IgG2 HCDD accompanied by kappa plasma cell dyscrasia.

Background Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR. Methods Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength. Results Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06). Conclusions A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.

Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression.We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years).Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg≥1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P0.0001 and P0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g≥1 and ptc≥1) with detectable donor-specific antibodies was observed in some recipients (20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P0.001).Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.

Reproductive tract abnormalities and male infertility have higher incidence in autosomal dominant polycystic kidney disease (ADPKD) patients than in general population. In this work, we revealed that Pkd1, whose mutations account for 85% of ADPKD cases, is essential for male reproductive tract development. Disruption of Pkd1 caused a spectrum of defects in the murine male reproductive tract. The earliest visible defect in Pkd1-/- reproductive tract was cystic dilation of the efferent ducts, which are derivatives of the mesonephric tubules. Epididymis development was delayed or arrested in the Pkd1-/- mice. No sign of epididymal coiling was seen in the Pkd1 null mice. Disruption of Pkd1 in epithelia alone using the Pax2-cre mice was sufficient to cause efferent duct dilation and coiling defect in the epididymis, suggesting that Pkd1 is critical for epithelial development and maintenance in male reproductive tract. In-depth analysis showed that Pkd1 is required to maintain tubulin cytoskeleton and important for Tgf-β/Bmp signal transduction in the epithelia of male reproductive tract. Altogether, our results provide the first direct evidence for developmental roles of Pkd1 in male reproductive tract and provide new insights in reproductive tract abnormalities and infertility in ADPKD patients.

Our analysis of recent survey data of US small- and medium-sized enterprises explores the question of how these entrepreneurial ventures can do well by doing good—i.e., how they can build a competitive advantage with their social and environmental practices. We focus on several firm characteristics and choices involving motivations and capabilities. We use hierarchical OLS to analyze the survey data to find that an orientation to, commitments to, and dynamic flexibility in, the firm’s CSR and green policies are significant factors in a firm’s CSR- and green-based competitive advantages. So, while some tradeoffs are likely between activities aimed at financial performance and those also aimed at improving social/environmental performance, opportunities do exist for small- and medium-sized enterprises to do both well and good. We consider several implications for theory and practice that continue in this instrumentalist perspective.

BACKGROUND Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30% of cases and can lead to allograft loss. Serum soluble urokinase-type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS. METHODS We conducted a retrospective study of 25 adults with posttransplantation FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function, and resolution of histologic changes. RESULTS A median (interquartile range) of 15 (10-23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pretreatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4806 pg/mL; P=0.02). Overall, mean±SD of proteinuria improved from 5.1±3.8 to 2.1±2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57%±33% to 22%±22% (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6-44.2) to 39.3 (28.8-63.4; P

In this essay, we address the research question of when is the business model idea useful? We argue that the use of the term “business model” as a “description” of how a traditional venture operates is strong on redundancy and weak on theoretical grounding. We argue that the idea behind a “model” of value creation, especially involving nonmonetary exchanges is, however, of great importance moving forward. Up to this point, there has been a quite practical approach used in understanding the idea and its effects. But now, there is a need to transition from the “idea-as-given” perspective to a “not-given” perspective in order to place the business model in a theoretical perspective where it can be understood in more abstract terms and then applied in new ways. That transition leads to new research questions, a new determination of the idea’s value in nontraditional contexts, and new effects on existing related theories and on policies to control potential effects.

We extend the knowledge-based view with a new typology and its application to post-IPO firm performance. The typology categorizes knowledge development activity along the dimensions of familiarity (whether the firm has experience with the knowledge or it is new) and source (whether the firm creates it independently or with partners). We use this typology to determine direct and interaction effects of knowledge development activity on survival, RoA, and Tobin's q of newly public firms. Using a sample of 1,056 high-technology manufacturing IPOs in 1990�2005, we find that focused, internal knowledge development correlates with higher performance. We also find a positive interaction effect in combining focused, internal and diversifying, alliance-based knowledge development, and a negative interaction effect in combining diversifying, internal and alliance-based knowledge development.

In this article, we provide a contrasting view to that of the original authors about the impact of their Research Note on the promise of entrepreneurship (ENT) research. We draw on citations in the top general business journals to assess where, how, and why the Note was referenced. This leads to a consideration of issues related to citation “quality” and the various types of “impact” that can exist. In light of such issues related to the Note, and in light of the present state of legitimacy of the field, we argue that the Note may have in fact had a negative impact, specifically on theory development unique to ENT. We conclude with directions for moving forward in fulfilling the promise of the ENT field.

Disseminated intravascular coagulation (DIC)-positive kidneys have historically been turned down for fear of poor outcomes. Higher severity injuries, which are prone to DIC, are typically seen in younger, otherwise healthy potential donors. The continued kidney allograft shortage has generated interest in the use of these DIC-positive grafts. There have been some reports of acceptable outcomes of renal transplantation using kidneys from donors with DIC. There are multiple clinical series demonstrating good outcomes from DIC-positive kidneys when the extent of glomeruli containing fibrin thrombi is less than 50% and donor renal function is preserved. These grafts are frequently associated with a period of delayed graft function.We report 2 transplants with kidneys from brain dead donors with known DIC.Both donors had renal failure and pretransplant renal biopsies showing 100% of the glomeruli containing fibrin thrombi. The recipients experienced delayed graft function requiring hemodialysis which was discontinued on postoperative days 18 and 39 for cases 1 and 2, respectively. Both patients are now over 14 months posttransplant with stable allograft function.Until clearer organ selection criteria are established, caution should be exercised when considering the use of kidneys with a similar phenotype and allocation decisions made by a multidisciplinary transplant team on a case-by-case basis.

The entrepreneurship and dynamic capabilities literature adds to our understanding of how strategic change can drive firm performance. We draw on a recent survey of US SMEs to determine whether entrepreneurial ventures have dynamic capabilities, and, if so, whether differences in the characteristics of those ventures lead to differences in how dynamic capabilities benefit firm performance. We find that most entrepreneurial ventures report having such capabilities and that their differences in age and size lead to differences in how dynamic capabilities affect firm performance. We consider how these results redefine the overlap of the dynamic capabilities view literature with the entrepreneurship literature, because the redeployment of resources to create and adapt to opportunities that defines what are dynamic capabilities lies at the core of what is entrepreneurial activity.

Our analysis of survey data of US small and medium-sized enterprises (SMEs) explores (1) whether firms have ‘dynamic’ capabilities that change their ethics-focused operational capabilities; (2) what effects those dynamic capabilities have on both ethical and competitive performance; and, (3) whether those effects are contingent on a firm’s entrepreneurial characteristics. Our survey reveals that about a quarter of SMEs self-report high levels of these ethics-focused dynamic capabilities. We use hierarchical OLS to analyze the survey data to find that the general effect of these capabilities is positive on an SME’s ethical performance, and that the performance effects are contingent on an SME’s degree of entrepreneurial orientation and sensitivity to changes in the business context. The main implication is that the extent of heterogeneity in types, roles, and performance effects of ‘higher-than-operations-level’ capabilities is likely underestimated in current dynamic capabilities theory and application.

We continue the conversation in SO! about possible beneficial relationships between the fields of entrepreneurship and strategic organization, consistent with SO!’s ambition of reducing the distances currently separating fields that share research phenomena (Baum et al., 2003). We do so with a focus on how entrepreneurship (ENT) – as a field with a central focus on dynamic, complex, disequilibrium problems (Bygrave, 1989; Herron et al., 1991) – can add to the understanding of strategic organization (SO). We complement the approaches taken in past SO!apbox essays that have advocated how ENT insights (e.g., on newer and smaller firms, on individual-level versus organizational-level processes, on social welfare, on left-censoring issues, on constrained, bricolagelike resource use, on opportunity recognition, and on other ‘entrepreneurial’ capabilities – Baker and Pollock, 2007; Phillips and Tracey, 2007) can inform SO research.

Background. Venous neointimal hyperplasia is the most common cause of arteriovenous (AV) fistula and graft dysfunction following dialysis access surgery. However, the pathogenetic impact of pre-existing venous neointimal hyperplasia at the time of AV access creation on final clinical success is currently unknown in the setting of advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The aim of this study was to perform a detailed histological, morphometric, and immunohistochemical analysis of vein specimens in advanced CKD and ESRD patients collected at the time of new vascular access placement. Methods. Vein samples from 12 patients were collected at the time of AV access creation near the site of AV anastomosis. Histological, immunohistochemistry and morphometric studies were performed on these vein samples. Results. Examination of the tissue specimens obtained at the time of surgery showed neointimal hyperplasia in 10 of 12 specimens, ranging from minimal to very severe. The majority of cells within the neointima were myofibroblasts with a minority of contractile smooth muscle cells present. Conclusion. Our work represents a detailed description of the morphometric and cellular phenotypic lesions present in the veins of CKD and ESRD patients, prior to dialysis access placement. These studies (i) suggest the future possibility of a new predictive marker (pre-existing venous neointimal hyperplasia) for AV dialysis access dysfunction and (ii) open the door for the future development of novel local therapies for optimization of the venous substrate on which the dialysis access is created.

Proton receptors are G protein-coupled receptors that accept protons as ligands and function as pH sensors. One of the proton receptors, GPR4, is relatively abundant in the kidney, but its potential role in acid-base homeostasis is unknown. In this study, we examined the distribution of GPR4 in the kidney, its function in kidney epithelial cells, and the effects of its deletion on acid-base homeostasis. We observed GPR4 expression in the kidney cortex, in the outer and inner medulla, in isolated kidney collecting ducts, and in cultured outer and inner medullary collecting duct cells (mOMCD1 and mIMCD3). Cultured mOMCD1 cells exhibited pH-dependent accumulation of intracellular cAMP, characteristic of GPR4 activation; GPR4 knockdown attenuated this accumulation. In vivo, deletion of GPR4 decreased net acid secretion by the kidney and resulted in a nongap metabolic acidosis, indicating that GPR4 is required to maintain acid-base homeostasis. Collectively, these findings suggest that GPR4 is a pH sensor with an important role in regulating acid secretion in the kidney collecting duct.

Allograft Duodenal Cuff Biopsy as Surrogate in Evaluation of Pancreatic Transplant Rejection - A Multicenter Data Effort

Summary Using the last decade of Center for Research on Security Prices data and the Capital Asset Pricing Model model to compare firms, we assess the origins, paths and destinations of extreme firm performance. We find that firms that will experience a run of persistent superior (inferior) performance are likely to start at a position of inferior (superior) performance, and that the runs of sustained performance are fairly linear. We also find that failed firms follow a path that reveals a resilience to decline rather than an accelerating acceptance of it, whereas extremely successful firms usually accelerated to their apexes. Overall, the results show that there are several distinct and important types of extreme performance that each require further study.

Background Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Methods Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m2) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Results Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Conclusions Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

PurposeThe aim is to present, explain and illustrate an improved method for decomposing an event‐based change in market value into its cash flow and risk elements.Design/methodology/approachThe approach is two‐fold. There is an algebraic comparison of the existing and improved decomposition to prove and delineate the benefits of the new method. There is an event study, using 130 firms, contrasting the results of the existing and improved methods.FindingsThe new, alternative method of decomposition is easier to use, provides a cleaner delineation of the components, and results in increased statistical significance in tests.Research limitations/implicationsResearchers now have access to an improved methodology for decomposing market value changes. Explicit limitations reveal when the new method provides benefits over the current method.Practical implicationsManagers considering strategic decisions now have an improved method to understand the main impacts on market value. For example, by decomposing the market's reaction to an acquisition announcement, managers can gauge better whether following through that decision is likely to have intended effects on the firm's cash flow and risk profile.Originality/valueThe value of this paper is the presentation of an improved method for event‐study type research, where delineation of the basis elements of changes in market value is required. Originality lies in the use of implied standard deviation (ISD) as an even more focused way to apply this new method when the target firms regularly trade financial options.

At the heart of business research is the identification and prioritization of the factors that create competitive advantage. Previous studies that decompose observed firm performance into industry and other effects have not considered the higher moments of the performance distribution (i.e., the excess kurtosis), nor estimated the correct null hypothesis level of those effects (i.e., of the industry effect). We address these issues to find that: (1) the industry effect impact on firm performance is likely overstated; and, (2) the interaction between the calculated component firm and industry effects is likely one that includes synergistic effects (i.e., the standard additive model of decomposition is likely mis-specified). We offer a new model, test it, and then discuss the resulting implications.

BACKGROUND: Obesity is increasing worldwide at an alarming rate. Particularly in Western countries, obesity and related problems have become a serious medical problem and an enormous socio-economic burden. DISCUSSION: Currently, surgery is the only avail-able treatment for patients with severe obesity which leads to sustained weight loss and cure of co-morbidities in the majority of the patients. The increase in the number of bariatric opera-tions and the occasional failure and complications of these surgical procedures have resulted in an increased need for revision surgery. Overall, 10-25 % of patients are expected to need a revision for failure of the primary bariatric procedure. The main indications for revision procedures are inadequate weight loss, surgery-related complications as well as surgical emergencies and long-term complications caused by malnutrition or -vitamin deficiencies. Unfortunately, there are currently no randomised trials to answer the ques-tion as to which operation should be performed in which patient and after which procedure. Deci-sions are often influenced by the expertise and preference of the operating surgeon as well as by patient’s preference. Thus, a systematic review of published data to this complex issue appears to be helpful and important for daily surgical prac-tise. CONCLUSIONS: Revision bariatric procedures are technically more complex and associated with increased postoperative complications. These operations should basically be performed in cen-tres with profound expertise in this field of surgery, and - whenever possible - laparoscopically. However, every abdominal surgeon should be able to diagnose and treat some acute complica-tions. After failed restrictive procedures, revision is recommended only in cases of complications but with adequate weight loss at the time of -fail-ure. Otherwise, conversion to combined procedures should be considered. After the failure of combined procedures, further weight loss or successful treatment of complications can be achieved by adding more restriction and / or malabsorption components. The latter is associated with an increased risk of nutri-tional sequelae.

We model the two-firm alliance as an iterated prisoners' dilemma game with an exit option and test several theoretical predictions in experimental studies regarding the effect of reputation information. Following the literature, we hypothesize that reputation benefits cooperation; however, our experimental results instead show that reputation decreases cooperation. A contingency explains this result while remaining consistent with the general proposition of reputation as beneficial in games of incomplete information. Implications include a recommendation for when to invest in reputation and whether the lemon's market story is applicable to alliance-related inefficiencies. Copyright © 2009 John Wiley & Sons, Ltd.

Branching morphogenesis of the metanephric kidney is critically dependent on the delicate orchestration of diverse cellular processes including proliferation, apoptosis, migration, and differentiation. Sphingosine-1-phosphate (S1P) is a potent lipid mediator influencing many of these cellular events. We report increased expression and activity of both sphingosine kinases and S1P phosphatases during development of the mouse metanephric kidney from induction at embryonic day 11.5 to maturity. Sphingosine kinase activity exceeded S1P phosphatase activity in embryonic kidneys, resulting in a net accumulation of S1P, while kinase and phosphatase activities were similar in adult tissue, resulting in reduced S1P content. Sphingosine kinase expression was greater in the metanephric mesenchyme than in the ureteric bud, while the S1P phosphatase SPP2 was expressed at greater levels in the ureteric bud. Treatment of cultured embryonic kidneys with sphingosine kinase inhibitors resulted in a dose-dependent reduction of ureteric bud tip numbers and increased apoptosis. Exogenous S1P rescued kidneys from apoptosis induced by kinase inhibitors. Ureteric bud tip number was unaffected by exogenous S1P in kidneys treated with N, N-dimethylsphingosine, although tip number increased in those treated with d,l- threo-dihydrosphingosine. S1P1 and S1P2 were the predominant S1P receptors expressed in the embryonic kidney. S1P1 expression increased during renal development while expression of S1P2 decreased, and both receptors were expressed predominantly in the metanephric mesenchyme. These results demonstrate dynamic regulation of S1P homeostasis during renal morphogenesis and suggest that differential expression of S1P metabolic enzymes and receptors provides a novel mechanism contributing to the regulation of kidney development.

Why do some firms succeed in a dynamic competitive environment when others fail? Recently, concepts and models addressing this question have increasingly clustered around the dynamic capabilities view (DCV). Citation counts suggest that the DCV is the new touchstone firm-based performance-focused theory (Teece et al. [1997], for example, had received 1180 citations in the ISI Web of Knowledge as of June 2008), and case studies of innovative firms such as IDEO (Hargadon and Sutton, 1997) have fueled interest. We take a step back to assess the ability of the DCV to explain successful change with logical consistency, conceptual clarity and empirical rigor, criteria suggested by Laudan (1977). Such an assessment is important not only because of the DCV’s popularity, but also because of the theoretical and practical significance of the issues it addresses. While the arguably static resource-based view (RBV) emphasizes the value of resources, the DCV addresses the need to explain changes in valuable resources, e.g. the erosion of asset stocks (Dierickx and Cool, 1989) and the changes in asset values (Miller and Shamsie, 1996). The DCV also addresses a practical need to understand how firms can change effectively, given perceptions that many competitive environments now change at increasing rates, and that firms have difficulty changing successfully (Beer and Nohria, 2000; Strebel, 1996). Our assessment identifies four major problems that limit the potential contribution of the DCV: (1) unclear value-added relative to existing concepts; (2) lack of a coherent theoretical foundation; (3) weak empirical support; and (4) unclear practical implications. Although potentially interrelated, each problem presents different difficulties and raises different questions.

Background. Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Methods. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Results. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. Conclusions. Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Summary We analyze the strategic issue of inter-firm resource transfer – i.e., the methods firms use to buy and sell assets. We introduce a typology of asset sale mechanisms delineated by levels of information uncertainty. We analyze this typology, by exploring how firms choose among the mechanisms and by exploring how they are rewarded by the financial markets for their choices. We find that factors involving the level of information asymmetry, the firm’s bargaining power, the firm’s current opportunities and pressures, and the firm’s ability to engage in the various mechanisms, all correlate with both choices and rewards.

We analyze how an incumbent defends its competitive advantage with a focus on the under-examined methods of actively defending against the threats posed by rival innovation. We describe, delineate and analyze the set of such defenses and their likely effects. The set of such defenses differs substantially from many standard defenses, such as those aimed at defeating the threat of imitation. The further study of these pre-emptive innovation defenses is important because these defenses are different and because they can substantially affect the sustainability of firm profits and the pace of different of types of innovation.

The resource-based view-related empirical literature has focused on one-industry–one-focal-resource studies to provide support for its core tenets. We complement that literature with a first empirical analysis of multiple strategic factors, including opposing factors, and covering multiple industries, based on a recent survey of turnaround professionals. We focus on two issues. First, we explore what factor characteristics correlate to differences in the level of impact on firm performance that different types of factors have. Second, we explore the balance between opposing strategic factors (i.e., beneficial versus detrimental factors) relating to which turnaround outcome occurs. Copyright © 2008 John Wiley & Sons, Ltd.

OBJECTIVE—Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis, and inflammation. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland, and kidney. The primary bile acids are the highest affinity endogenous ligands for FXR. The effects of FXR agonists in diabetic kidney disease, the main cause of end-stage renal disease, however, have not been determined. RESEARCH DESIGN AND METHODS—To identify the effect of FXR activation in modulation of diabetic nephropathy, we treated 1) C57BL/6J mice on low-fat diet or high-fat diet with FXR agonists (GW4064 or cholic acid) for 1 week; 2) C57BLKS/J-db/db mice and their lean mates with GW4064 for 1 week; and 3) C57BL/6J-db/db mice and their lean mates with cholic acid for 12 weeks. RESULTS—We found that FXR agonists modulate renal sterol regulatory element–binding protein-1 (SREBP-1) expression and lipid metabolism and renal expression of profibrotic growth factors, proinflammatory cytokines, and oxidative stress enzymes and decrease glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. In renal mesangial cells, overexpression of FXR or treatment with GW4064 also inhibited SREBP-1c and other lipogenic genes, transforming growth factor-β, and interleukin-6, suggesting a direct role of FXR in modulating renal lipid metabolism and modulation of fibrosis and inflammation. CONCLUSIONS—These results therefore indicate a new and important role for FXR in the kidney and provide new therapeutic avenues for the treatment of diabetic nephropathy.

There is growing evidence that sphingosine 1-phosphate (S1P) plays an important role in regulating the development, morphology, and function of the cardiovascular system. There is little data, however, regarding the relative contribution of endogenous S1P and its cognate receptors (referred to as S1P1–5) to cardiovascular homeostasis. We used S1P2 receptor knockout mice (S1P2−/−) to evaluate the role of S1P2 in heart and vascular function. There were no significant differences in blood pressure between wild-type and S1P2−/− mice, measured in awake mice. Cardiac function, evaluated in situ by using a Millar catheter, was also not different in S1P2−/− mice under baseline or stimulated conditions. In vivo analysis of vascular function by flowmetry revealed decreases in mesenteric and renal resistance in S1P2−/− mice, especially during vasoconstriction with phenylephrine. In intact aortic rings, the concentration-force relations for both KCl and phenylephrine were right shifted in S1P2−/− mice, whereas the maximal isometric forces were not different. By contrast, in deendothelialized rings the concentration-force relations were not different but the maximal force was significantly greater in S1P2−/− aorta. Histologically, there were no apparent differences in vascular morphology. These data suggest that the S1P2 receptor plays an important role in the function of the vasculature and is an important mediator of normal hemodynamics. This is mediated, at least in part, through an effect on the endothelium, but direct effects on vascular smooth muscle cannot be ruled out and require further investigation.

Surgical resection of tumors of the upper gastrointestinal (GI) tract represent complex procedures and are still associated with a relevant morbidity and mortality. A targeted preoperative risk analysis and patient selection with consideration of the nutritional status and comorbidities are important in order to reduce the perioperative complication rate.Anastomotic leaks still remain the most feared surgical complication and in addition to early recognition, immediate initiation of an appropriate therapy are essential. Conservative treatment can be considered for small and adequately drained fistulas as well as in cervical leakages. Indications for surgical reintervention are leaks that occur in the early postoperative course, fulminant defects with diffuse mediastinitis and conduit necrosis. The majority of anastomotic leaks can be successfully managed with minimally invasive endoscopic techniques, e.g. stent placement and endoluminal vacuum therapy. Delayed gastric emptying is frequently observed following esophageal resection and usually shows a satisfactory response to medicinal treatment and endoscopic interventions. The benefits of pyloroplasty in the primary intervention is still a matter of debate. Chylothorax is a rare but serious complication which should initially be managed with conservative measures.For the successful management of postoperative complications following surgical resection of tumors of the upper GI tract both an interdisciplinary approach and the availability of an appropriate infrastructure with defined algorithms are of paramount importance. Therefore, a concentration of these procedures in specialized centers would be highly desirable.

Transcription factor Nrf2 protects from experimental acute kidney injury (AKI) and is promising to limit progression in human chronic kidney disease (CKD) by upregulating multiple antioxidant genes. We recently demonstrated that deletion of Keap1, the endogenous inhibitor of Nrf2, in T lymphocytes significantly protects from AKI. In this study, we investigated the effect of Keap1 deletion on Nrf2 mediated antioxidant response in the renal tubular epithelial cells. We deleted Keap1 exon 2 and 3 in the renal tubular epithelial cells by crossing Ksp-Cre mice with Keap1 floxed (Keap1 f/f) mice. Deletion of Keap1 gene in the kidney epithelial cells of Ksp-Keap1 -/- mice and its effect on Nrf2 target gene expression was performed using PCR and real-time PCR respectively. Histological evaluation was performed on H&E stained sections. Complete blood count, serum and urine analysis were performed to assess systemic effects of defective kidney development. Student’s T test was used to determine statistical difference between the groups. Ksp-Cre resulted in the deletion of Keap1 exon 2 and 3 and subsequent upregulation of Nrf2 target genes, Nqo1, Gclm and Gclc in the kidney epithelial cells of Ksp-Keap1 -/- mice at baseline. Renal epithelial cell specific deletion of Keap1 in Ksp-Keap1 -/- mice caused marked renal pelvic expansion and significant compression of medullary parenchyma consistent with hydronephrosis in both (3 month-old) males and females. Kidneys from 6 month-old Ksp-Keap1 -/- mice showed progressive hydronephrosis. Hematological, biochemical and urinary analysis showed significantly higher red blood cell count (p = 0.04), hemoglobin (p = 0.01), hematocrit (p = 0.02), mean cell volume (p = 0.02) and mean cell hemoglobin concentration (p = 0.003) in Ksp-Keap1 -/- mice in comparison to Keap1 f/f mice. These unexpected findings demonstrate that Keap1 deletion in renal tubular epithelial cells results in an abnormal kidney development consistent with hydronephrosis and reveals a novel Keap1 mediated signaling pathway in renal development.

Papillary tumors originate from the various structures of the ampulla of Vater; therefore, these rare tumors represent a heterogeneous group of tumor entities. Intestinal differentiated adenomas are the most common benign lesions, whereas intestinal differentiated papillary carcinomas are the most common malignant tumors. Carcinomas with pancreaticobiliary differentiation have a poorer prognosis. Mesenchymal and neuroendocrine tumors are among the least frequent papillary tumors. Diagnosis is performed by side-view upper endoscopy and biopsy. In cases of suspected malignancy a complete staging with computed tomography (CT) and endoscopic ultrasound scanning is indicated to determine local tumor spread.Adenomas are removed by endoscopic snare papillectomy whereas the therapy of choice for papillary carcinomas is pancreatic head resection with systematic lymphadenectomy. Patients with papillary carcinomas are most likely to benefit from adjuvant therapy, which should be determined in an interdisciplinary consensus conference considering the histological differentiation of the tumor.

The surgical treatment of hepatopancreatobiliary (HPB) diseases requires complex operative procedures. Within the last decades the morbidity (36-50 %) and mortality (5 %) of these procedures could be reduced; nonetheless, postoperative complications still occur in 41.2 % of cases. Compared with hepatobiliary procedures, pancreatic surgery shows an increased rate of complications. Postoperative bleeding has a major effect on the outcome and the incidence is 6.7 % after pancreatic surgery and 3.2 % after hepatobiliary surgery. The major causes of early postoperative hemorrhage are related to technical difficulties in surgery whereas late onset postoperative hemorrhage is linked to anastomosis insufficiency, formation of fistulae or abscesses due to vascular arrosion or formation of pseudoaneurysms. In many cases, delayed hemorrhage is preceded by a self-limiting sentinel bleeding. The treatment is dependent on the point in time, location and severity of the hemorrhage. The majority of early postoperative hemorrhages require surgical treatment. Late onset hemorrhage in hemodynamically stable patients is preferably treated by radiological interventions. After interventional hemostatic therapy 8.2 % of patients require secondary procedures. In the case of hemodynamic instability or development of sepsis, a relaparotomy is necessary. The treatment concept includes surgical or interventional remediation of the underlying cause of the hemorrhage. Other causes of postoperative morbidity and mortality are arterial and portal venous stenosis and thrombosis. Following liver resection, thrombosis of the portal vein occurs in 8.5-9.1 % and in 11.6 % following pancreatic resection with vascular involvement. Interventional surgical procedures or conservative treatment are suitable therapeutic options depending on the time of diagnosis and clinical symptoms. The risk of morbidity and mortality after HPB surgery can be reduced only in close interdisciplinary cooperation, which is particularly true for vascular complications.

This article explains that the Internet bubble was a unique and unfortunately missed opportunity for strategic management academia to vastly increase the field's perceived legitimacy. This author challenges strategic management scholars to acknowledge this failure, understand it, and reconsider their responsibilitiesto the public and to the field.

We model the two-firm alliance as an iterated prisoners’ dilemma game with an exit option and test several theoretical predictions over two experimental studies. A new major effect on alliance performance arises by including the exit option (i.e., the option to end the alliance and receive a fixed payoff that is less than the payoff for mutual cooperation but greater than the payoff for mutual defection). The opportunity cost levels of the firms either directly or indirectly influence alliance cooperation and alliance payoffs through affecting the alliance strategies that the firms choose. Implications for partner selection, alliance selection and structuring, and strategy choices along the alliance lifespan, build on these results.

Contextual uncertainty and firm heterogeneity produce the potential for benefits from multi-party relationships, as well as the potential for inefficiencies in such relationships. We introduce the issue of shared control as a factor in the proper modeling of many multi-party relationships, such as that between a venture capitalist and entrepreneur. We find that adding this degree of freedom to the standard multi-party models (such as the principal-agent model) generates direct and indirect effects on the results. Under the most common circumstances, we predict that more potential for inefficiencies (e.g., pooling) will occur when parties share strategic control.

We address the following two questions: how upstream vertical alliance (UVA) activity affects the performance of small and medium-sized enterprises (SMEs); and how SME perceptions of that relationship influence the choice to engage in UVA activity. Using responses from a recent survey of business unit managers representing 200 SMEs, we find that UVA activity benefits SME performance when self-selection effects are controlled. Instead of being a source of differentiation advantages, UVA activity leverages the SME's existing advantages. And, while SME perceptions appear to drive the self-selection of UVA activity, those perceptions are inaccurate; the result is that the SMEs likely to benefit less from such activity engage in it more. Copyright © 2006 John Wiley & Sons, Ltd.

A subset of all R&D joint ventures is characterized by actions and payoffs most similar to a Prisoners’ Dilemma game. Firms may cooperate or defect in the venture. When it is unfeasible to obtain independent verification of the venture inputs and outcome, then the dominant solution to the Prisoners’ Dilemma – mutual defection – results. This paper proposes the use of a new revelation mechanism that truthfully determines whether defection has occurred in order to trigger penalties. Cooperation results. A simplified version of the solution is tested experimentally and shows a significant improvement in cooperation level results.

An analysis of the impact of alliance activity during the period 1989–1993 on the performance of organizations in the US computing industry reveals that: (1) the distribution of alliance activity is skewed to firms with greater market power, capacity, as well as greater technical, commercial, social and organizational capital; (2) self-selection is significant in explaining the effects of alliance activity on firm performance; and, (3) controlling for self-selection alliances creates value for the firms choosing them but they do so at a lower rate of return than do the firms’ core activities alone. We establish that without such controls, the effects of alliance activity are greatly underestimated.

Conflict exists over how supply chain management (SCM) affects small- and medium-sized enterprises (SMEs). On one hand, SCM can provide quality, cost, customer service, leverage and even risk reduction benefits for the SME. On the other hand, SCM exposes the SME to greater management and control hazards while reducing its private differentiation advantages. We test hypotheses relevant to the performance effects of SCM on SMEs using data collected from a recent survey of senior production managers. We find that SCM is negatively associated with SME performance after controlling for self-selection bias. We discuss several explanations for the result.

We present and solve a new, more accurate model of behavior within alliance activity. The model is essentially an iterated prisoners' dilemma with an exit option in each stage of the alliance. The proposed solution results in each partner receiving its opportunity cost as its expected average pay-off in the alliance. Managerial implications include: identification of where to focus efforts to improve alliance cooperation and performance; and an explanation for why more sophisticated partnership strategies than tit-for-tat are likely to be superior in this game. Copyright © 2005 John Wiley & Sons, Ltd.