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Acquired von Willebrand syndrome (AVWS) is a rare, non-hereditary bleeding disorder related to heterogeneous medical conditions such as hematological malignancies and cardiovascular and autoimmune diseases. We describe the clinical course of a 62-year-old man with polycythemia vera who experienced post-traumatic knee and leg swelling due to hemarthrosis. He was treated at another center with low molecular weight heparin due to misdiagnosed deep vein thrombosis further exacerbating the ongoing bleeding. At our center, he was diagnosed with AVWS with reduced von Willebrand factor (VWF):GPIbR plasma activity and loss of high molecular weight multimers (HMWM). He was treated with compressive bandages with resolution. Five months later, on clinical recurrence of knee and leg swelling, knee ultrasound scan showed the presence of chronic synovitis and a hemorrhagic Baker’s cyst with signs of rupture. The treatment consisted of chemical synovectomy with rifampicin and steroids preceded by systemic replacement therapy using plasma-derived factor VIII-VWF concentrate. At the end of the treatment cycle, our patient reported complete resolution of knee pain and restoration of joint range of motion and function. Ultrasound evaluation confirmed complete resolution of knee capsule distension and Baker’s cyst. Hemarthrosis is an anecdotal presentation of AVWS and chemical synovectomy was successful in treating this complication. A multidisciplinary approach allowed an effective management of this rare complication.

In soft tissue pelvic liposarcoma and leiomyosarcoma, it is unknown whether a specific tumor size cut-off may help to better predict prognosis, defined as cancer-specific survival (CSS). We tested whether different tumor size cut-offs, could improve CSS prediction.

Introduction: Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint. Methods: We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management. Results: In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients. Conclusions: The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.

Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD.

Genetic variation of the gene encoding for the only human enzyme of the T2 ribonucleases family (RNASET2) emerged in genome-wide association studies as a putative risk hotspot for Graves’ disease (GD). T2 ribonucleases activities include immune regulation, induction of cell apoptosis and differentiation. Several reports supported the hypothesis that RNASET2 represents a “danger” message addressed to the innate immune system in peculiar conditions. This was a longitudinal, case-control study. RNASET2 protein levels were assessed in blood samples from 34 consecutive newly diagnosed GD patients and in healthy controls. At enrollment, RNASET2 levels were significantly higher in GD patients (98.5 ± 29.1 ng/ml) compared to healthy controls (72.5 ± 27.9 ng/ml, p= 0.001). After 6 months of methimazole treatment, RNASET2 levels significantly decrease and return to levels similar to healthy controls (62.4 ± 22 ng/ml, p= 0.69). These preliminary results suggest that RNASET2 is overexpressed in patients with GD and might represent an “alarm signal” generated by thyroid cells in response to endogenous or environmental stress to alert the immune system.

ABSTRACTThe COVID-19 pandemic has had a profound societal impact with unprecedented impact on women’s labor force participation, including among academic mothers. Yet, persistent gendered and racialized inequities in academia remain structurally unaddressed, including in social work. We believe that as social work educators we are well-positioned to develop an academic culture that helps us refocus on what matters most; redefine excellence in teaching, service, and research; and make academic practice more equitable. To this end, we convened a group of social work academic mothers, representing various identities at teaching and research-intensive institutions, to offer collective perspectives and recommendations for structural change within the social work academy to buffer the impact of the COVID-19 pandemic and exacerbating racial and gendered disparities.

Gene therapy (GT) has rapidly attracted renewed interest as a treatment for otherwise incurable diseases, with several GT products already on the market and many more entering clinical testing for selected indications. Clonal tracking techniques based on vector integration enable monitoring of the fate of engineered cells in the blood of patients receiving GT and allow assessment of the safety and efficacy of these procedures. However, owing to the limited number of cells that can be tested and the impracticality of studying cells residing in peripheral organs without performing invasive biopsies, this approach provides only a partial snapshot of the clonal repertoire and dynamics of genetically modified cells and reduces the predictive power as a safety readout. In this study, we developed liquid biopsy integration site sequencing, or LiBIS-seq, a polymerase chain reaction technique optimized to quantitatively retrieve vector integration sites from cell-free DNA released into the bloodstream by dying cells residing in several tissues. This approach enabled longitudinal monitoring of in vivo liver-directed GT and clonal tracking in patients receiving hematopoietic stem cell GT, improving our understanding of the clonal composition and turnover of genetically modified cells in solid tissues and, in contrast to conventional analyses based only on circulating blood cells, enabling earlier detection of vector-marked clones that are aberrantly expanding in peripheral tissues.

L’énucléation de prostate au laser au Thullium (THULEP) et l’adénomectomie voie haute cœlioscopique robot-assistée (AVHR) sont deux traitements validés et efficaces pour le traitement chirurgical des volumineux adénomes de prostate (> 80g). Cependant, il n’existe que peu d’études à l’heure actuelle traitant une grande cohorte des patients afin de comparer la sécurité et la morbidité de ces deux procédures pour ces volumineuses glandes.

Recent studies demonstrated that allograft inflammatory factor-1 (AIF-1) and RNASET2 act as chemoattractants for macrophages and modulate the inflammatory processes in both vertebrates and invertebrates. The expression of these proteins significantly increases after bacterial infection; however, the mechanisms by which they regulate the innate immune response are still poorly defined. Here, we evaluate the effect of bacterial lipopolysaccharide injection on the expression pattern of these genes and the interrelation between them during innate immune response in the medicinal leech, an invertebrate model with a simple anatomy and a marked similarity with vertebrates in inflammatory processes. Collectively, prokaryotic-eukaryotic co-cultures and in vivo infection assays suggest that RNASET2 and AIF-1 play a crucial role in orchestrating a functional cross-talk between granulocytes and macrophages in leeches, resulting in the activation of an effective response against pathogen infection. RNASET2, firstly released by granulocytes, likely plays an early antibacterial role. Subsequently, AIF-1+RNASET2-recruited macrophages further recruit other macrophages to potentiate the antibacterial inflammatory response. These experimental data are in keeping with the notion of RNA­SET2 acting as an alarmin-like molecule whose role is to locally transmit a “danger” signal (such as a bacterial infection) to the innate immune system in order to trigger an appropriate host response.

Few data examined the potential survival benefit of chemotherapy (CHT) in the setting of metastatic upper urinary tract urothelial carcinoma (mUTUC). We hypothesized that a survival benefit might be associated with the use of CHT in nonsurgically treated primary mUTUC and tested this hypothesis within a large population-based cohort.

Recurrent joint bleeding leads to chronic arthropathy in severe hemophilia A and B. With the recent introduction of novel therapies and the increased availability of treatments for patients with hemophilia, a very tight control of bleeding is achievable, but some patients still experience synovitis oat target joints. A deeper knowledge of the synovial membranes in hemophilic synovitis may help the personalised treatment. However, very few data are available regarding the histopathological characteristics of the synovial membrane of patients with hemophilic arthropathy.

Data regarding the relationship between non–disease-specific (NDSM) and disease-specific mortality (DSM) in patients with surgically treated nonmetastatic retroperitoneal sarcoma (nmRPS) are lacking.

To report the endovascular treatment of a full metal jacket (FMJ) femoropopliteal chronic total occlusion (CTO) using a new ancillary retrograde technique.

•The benefit of partial nephrectomy is unknown according to age categories and stage.•T1a renal cell carcinoma patients benefit from partial nephrectomy at all ages.•T1b and T2 renal cell carcinoma patients do not benefit from partial nephrectomy.

Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT).

Polycomb group proteins are essential regulators of stem cell function during embryonic development and in adult tissue homeostasis. Bmi1, a key component of the Polycomb Repressive Complex 1, is highly expressed in undifferentiated neural stem cells (NSC) as well as in several human cancers including high‐grade gliomas—highly aggressive brain tumors. Using a conditional gene activation approach in mice, we show that overexpression of Bmi1 induces repressive epigenetic regulation of the promoter of Survivin, a well‐characterized antiapoptotic protein. This phenomenon is cell type‐specific and it leads to apoptotic death of progenitor cells exclusively upon commitment toward a neuronal fate. Moreover, we show that this is triggered by increased oxidative stress‐induced DNA damage. In contrast, undifferentiated NSC as well as glioma‐initiating cells display an open chromatin configuration at the Survivin promoter and do not undergo apoptotic death. These findings raise the possibility that normal and neoplastic stem cells depend on the same mechanism for surviving the hyperproliferative state induced by increased Bmi1 expression. STEMCells2013;31:190–202

Incontinence and impotence are the two chief drawbacks of radical prostatectomy (RP). Incontinence is the most relevant for most of the patients, even if there is high variability in terms of prevalence and definition of continence. Incontinence seems the result of several factors, the most important being the surgical injury of some structures and the biomechanical instability associated with vesicourethral anastomosis. In the posterior urethra, which guarantees the continence mechanism, two functionally independent regions can be recognized: the proximal and the distal. The proximal region can be identified with the bladder neck, while the distal region is the rhabdosphincter urethrae. Concerning the distal functional region, two kinds of strategy can be applied: the preservation of puboprostatic ligaments and urethral attachments, or the reconstruction of the urethral rhabdosphincter, which can be anterior, posterior or total. We describe our technique of choice for posterior reconstruction, first described by Rocco and then modified by Patel et al.

The Polycomb group protein Bmi1 is a key regulator of self‐renewal of embryonic and adult central nervous system stem cells, and its overexpression has been shown to occur in several types of brain tumors. In a Cre/LoxP‐based conditional transgenic mouse model, we show that fine‐tuning of Bmi1 expression in embryonic neural stem cell (NSC) is sufficient to increase their proliferation and self‐renewal potential both in vitro and in vivo. This is linked to downregulation of both the ink4a/ARF and the p21/Foxg1 axes. However, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage during embryonic cortical development, triggers apoptosis through a survivin‐mediated mechanism and leads to reduced brain size. Postnatally, however, increased self‐renewal capacity of neural stem/progenitor cells (NSPC) is independent of Foxg1 and resistance to apoptosis is observed in neural progenitors derived from NSC‐overexpressing Bmi1. Neoplastic transformation is absent in mice‐overexpressing Bmi1 aged up to 20 months. These studies provide strong evidence that fine tuning of Bmi1 expression is a viable tool to increase self‐renewal capacity of NSCs both in vitro and in vivo without eliciting neoplastic transformation of these cells. STEMCells2011;29:700–712

The purpose of this study was to evaluate monorchid patients’ long-term hormone levels and sexual function.Materials and Methods Between September and December 2005, 20 patients were reassessed, having undergone orchiectomy for testicular tumors at the Policlinico and at the National Tumor Institute in Milan between 1986 and 1996. Four patients had seminoma, three of them underwent radiotherapy; 15 patients with embryonal carcinoma subsequently underwent retroperitoneal lymphadenectomy, and one of them underwent chemotherapy; one patient had a Leydig cell tumour. The patients’ case histories were analysed; they underwent urological examination, endocrine test, scrotal ultrasound, and blood samples were taken for testosterone, FSH, LH, prolactin, E2, total cholesterol, triglyceride, beta-HCG, alpha-FP and LDH assays. Body mass index was calculated. Patients were also asked to fill in the IIEF questionnaire.Results Patients’ mean age was 30.7 years at the time of orchiectomy, and 44.7 at the time of endocrine/sexology follow up. Case histories showed that 2 patients suffered from arterial hypertension, for which they were receiving treatment, 2 patients were obese, none of the patients suffered from endocrine disorders. Upon ultrasound evaluation, the remaining testicle mean volume was 22.04 mL. All patients presented testosterone levels at the lower limits of the normal range (mean value 3.3 ng/ml). In 5 patients values were below the lower limit, indicating marked hypogonadism. Only one patient suffered from moderate erectile dysfunction.Conclusions Twenty-five per cent of patients showed low testosterone levels. In view of the long life expectancy of patients suffering from testicular tumors, it is fundamental to consider the long-term problems that a mutilation such as orchiectomy can involve. Patients undergoing orchidectomy in general should be considered to be at higher risk of andropause.

In this study, the effect of naphthalene on the induction of apoptosis and gene expression profiles in cord blood cells has been evaluated, as well as its activity on the BCL-2 related protein expression. After 6, 24, and 48 h of exposure to naphthalene (500 μM), a decrease in cell death was observed: the cells became more resistant to the toxicant and capable of surviving after the treatment. A Western blot analysis revealed an overexpression of BCL-2, c-JUN, c-FOS, and RAF-1 proteins, which are involved in the antiapoptotic response and in the regulation of cell growth, differentiation, and development. Furthermore, macroarray analysis showed that naphthalene modified cord blood gene expression, inducing IL-8 precursor and T-cell transcription factor and decreasing the level of RNA-binding protein FUS/TLS. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:286–294, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10091

In this study, the effect of naphthalene on the induction of apoptosis and gene expression profiles in cord blood cells has been evaluated, as well as its activity on the BCL‐2 related protein expression. After 6, 24, and 48 h of exposure to naphthalene (500 μM), a decrease in cell death was observed: the cells became more resistant to the toxicant and capable of surviving after the treatment. A Western blot analysis revealed an overexpression of BCL‐2, c‐JUN, c‐FOS, and RAF‐1 proteins, which are involved in the antiapoptotic response and in the regulation of cell growth, differentiation, and development. Furthermore, macroarray analysis showed that naphthalene modified cord blood gene expression, inducing IL‐8 precursor and T‐cell transcription factor and decreasing the level of RNA‐binding protein FUS/TLS. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:286–294, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10091

We applied cDNA selection methods to a genomic clone (YAC 761B5) from chromosome 21 located in the so‐called ‘Down critical region’ in 21q22.3. Starting from human fetal heart and brain mRNAs we obtained and sequenced several cDNA clones. One of these clones (Down region aspartic protease (DRAP), named also BACE2 according to the gene nomenclature) revealed a striking nucleotide and amino acid sequence identity with several motifs present in members of the aspartic protease family. In particular the amino acid sequences comprising the two catalytic sites found in all mammalian aspartic proteases are perfectly conserved. Interestingly, the predicted protein shows a typical membrane spanning region; this is at variance with most other known aspartic proteases, which are soluble molecules. We present preliminary evidence, on the basis of in vitro translation studies and cell transfection, that this gene encodes a glycosylated protein which localizes mainly intracellularly but to some extent also to the plasma membrane. Furthermore DRAP/BACE2 shares a high homology with a newly described β‐secretase enzyme (BACE‐1) which is a transmembrane aspartic protease. The implications of this finding for Down syndrome are discussed.

ObjectiveTo assess the incidence of arterial embolic events in patients with high rate, drug resistant, severely symptomatic paroxysmal and chronic atrial fibrillation who have undergone atrioventricular (AV) node ablation and permanent pacing. DesignMulticentre retrospective cohort study. Patients and managementFrom May 1987 to January 1997, AV node ablation was performed in 585 severely symptomatic patients (mean (SD) age 66 (11) years) with high rate, drug resistant paroxysmal atrial fibrillation (308) or chronic atrial fibrillation (277). Lone atrial fibrillation was present in 133 patients, while the remaining 452 suffered from dilated, ischaemic, or valvar heart disease. Patients underwent VVIR (454) or DDDR (131) pacemaker implantation, after AV node ablation. Antiplatelet agents were given to 202 patients, warfarin to 187 patients. ResultsDuring a follow up of 33.6 (24.2) months, thromboembolic events were observed in 17 patients (3%); the actuarial occurrence rates of thromboembolism were 1.1%, 3%, 4.2%, and 7.4% after one, three, five, and seven years, respectively. Among five variables, univariate analysis showed that only the presence of chronic atrial fibrillation at the time of ablation (relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.02 to 3.20, p = 0.04) and the need for warfarin treatment (RR = 1.6, 95% CI 1.00 to 2.71, p = 0.048) were associated with a significantly higher risk of occurrence of thromboembolic events. On multivariate analysis the only predictor of embolic events during the follow up was the presence of chronic atrial fibrillation. ConclusionsData from this large cohort of patients indicate a fairly low incidence (1.04% per year) of thromboembolic events after AV node ablation and pacing for drug refractory, high rate atrial fibrillation.

The most important determinant of plasma levels of Lp[a] are sequence differences at the highly polymorphic apolipoprotein[a] (apo[a]) locus. To define the sequences that mediate the regulation of apo[a] expression, we cloned a 370 kb DNA fragment that included a 130 kb apo[a] gene, and 40 kb 5'- and 200 kb 3'-flanking region from an individual with high plasma levels of Lp[a] using a YAC vector. This genomic clone was used to generate transgenic mice. In the YAC-apo[a] transgenic mouse, apo[a] was only expressed in the liver, as it is in humans. The mean serum level of apo[a] in 4-week-old YAC-apo[a] transgenic mice was 20 mg/dl. In the female mice the levels of apo[a] varied over a 1.5-fold range during the 4-day estrus cycle and the levels correlated directly with serum progesterone levels. The serum levels of apo[a] decreased to almost undetectable level in male mice after puberty and this decrease was reversed by castration. Ingestion of a high-fat diet resulted in a approximately 100-fold fall in hepatic apo[a] mRNA levels and >60-fold decrease in serum apo[a] levels.To delimit the control elements that mediate tissue-specific and sex hormone-responsive apo[a] transcription, we derived a reporter YAC in which 40 kb of 5' flanking sequences from the cloned apo[a] allele were linked to a luciferase reporter gene. Analysis of four independent transgenic lines revealed no hepatic luciferase expression, suggesting that important cis -acting elements located outside the apo[a] 5'-flanking region are necessary for in vivo expression of apo[a].

In this paper a model of the air flow and pressure inside the intake manifold of spark ignition engines is derived from mass and momentum balance equations. The model is capable to predict the physical phenomena inside the engine cycle. Linearization around a nominal point derived from a Mean Value Model allows to determine the tranfer functions relating the throttle angle variation and the poppet valve lift to pressure and air flow in the manifold. The knowledge of these tranfer functions can be the starting point for the design of more accurate pressure control schemes.

Plasma concentrations of the atherogenic lipoprotein(a) (Lp(a)) are predominantly determined by inherited sequences within or closely linked to the apolipoprotein(a) gene locus. Much of the interindividual variability in Lp(a) levels is likely to originate at the level of apo(a) gene transcription. However, the liver-specific apo(a) basal promoter is extremely weak and does not exhibit common functional variations that affect plasma Lp(a) concentrations. In a search for additional apo(a) gene control elements, we have identified two fragments with enhancer activity within the 40-kilobase pair apo(a)-plasminogen intergenic region that coincide with DNase I-hypersensitive sites (DHII and DHIII) observed in liver chromatin of mice expressing a human apo(a) transgene. Neither enhancer exhibits tissue specificity. DHIII activity was mapped to a 600-base pair fragment containing nine DNase I-protected elements (footprints) that stimulates luciferase expression from the apo(a) promoter 10-15-fold in HepG2 cells. Binding of the ubiquitous transcription factor Sp1 plays a major role in the function of this enhancer, but no single site was indispensable for activity. DHIII comprises part of the regulatory region of an inactive long interspersed nucleotide element 1 retrotransposon, raising the possibility that retrotransposon insertion can influence the regulation of adjacent genes. DHII enhancer activity was localized to a 180-base pair fragment that stimulates transcription from the apo(a) promoter 4-8-fold in HepG2 cells. Mutations within an Sp1 site or either of two elements composed of direct repeats of the nuclear hormone receptor half-site AGGTCA in this sequence completely abolished enhancer function. Both nuclear hormone receptor elements were shown to bind peroxisome proliferator-activated receptors and other members of the nuclear receptor family, suggesting that this enhancer may mediate drug and hormone responsiveness.

After induction, seven strains ofBotrytis cinerea released into the culture broth considerable amounts of laccase in a brief production time. The set-up of a suitable production process was studied with a selected strain in a 10-L fermenter. The optimum fermentation conditions were a 3% inoculum with a high degree of sporulation, a simple medium containing 20 g L-1 of glucose and 2 g L-1 of yeast extract at pH 3.5, 2 g L-1 gallic acid as inducer, added after 2 days of growth, an agitation speed of 300 rpm, an aeration rate of 1.2 vvm and a temperature of 24°C. By optimizing the culture conditions, the enzyme activity reached 28 U ml-1 in 5 days with a specific activity of 560 U mg-1 protein. The best procedure to obtain a suitable crude enzyme preparation was concentration of the supernatant medium to 10% of the initial volume by ultrafiltration, followed by a fractional precipitation with ethanol. The optimum pH and temperature for laccase activity were 5.5 and 40°C, respectively, with syringaldazine as the substrate.

The apoprotein(a) [apo(a)] gene encodes a protein component of the circulating lipoprotein(a) [Lp(a)]. The apo(a) gene is highly homologous to the plasminogen gene. It encodes one of the most polymorphic human proteins, due to variability in the number of repetitions of structures called kringles. In addition, Lp(a) levels vary among individuals by more than two orders of magnitude, the high levels being highly correlated with predisposition to early atherosclerotic disease. To better understand the genetics and function of the apo(a) gene, we have cloned in yeast artificial chromosome vectors DNA fragments comprising the linked apo(a) and plasminogen genes and other members of the plasminogen family. By a combination of pulsed-field gel electrophoresis and genome walking experiments, we have identified the 5' portion and flanking regions of the apo(a) gene.

Plasma concentrations of the atherogenic lipoprotein(a) (Lp(a)) are predominantly determined by inherited sequences within or closely linked to the apolipoprotein(a) gene locus. Much of the interindividual variability in Lp(a) levels is likely to originate at the level of apo(a) gene transcription. However, the liver-specific apo(a) basal promoter is extremely weak and does not exhibit common functional variations that affect plasma Lp(a) concentrations. In a search for additional apo(a) gene control elements, we have identified two fragments with enhancer activity within the 40-kilobase pair apo(a)-plasminogen intergenic region that coincide with DNase I-hypersensitive sites (DHII and DHIII) observed in liver chromatin of mice expressing a human apo(a) transgene. Neither enhancer exhibits tissue specificity. DHIII activity was mapped to a 600-base pair fragment containing nine DNase I-protected elements (footprints) that stimulates luciferase expression from the apo(a) promoter 10–15-fold in HepG2 cells. Binding of the ubiquitous transcription factor Sp1 plays a major role in the function of this enhancer, but no single site was indispensable for activity. DHIII comprises part of the regulatory region of an inactive long interspersed nucleotide element 1 retrotransposon, raising the possibility that retrotransposon insertion can influence the regulation of adjacent genes. DHII enhancer activity was localized to a 180-base pair fragment that stimulates transcription from the apo(a) promoter 4–8-fold in HepG2 cells. Mutations within an Sp1 site or either of two elements composed of direct repeats of the nuclear hormone receptor half-site AGGTCA in this sequence completely abolished enhancer function. Both nuclear hormone receptor elements were shown to bind peroxisome proliferator-activated receptors and other members of the nuclear receptor family, suggesting that this enhancer may mediate drug and hormone responsiveness.