Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.

ABSTRACT: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition.

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.

Inhibiting PI3K-AKT-mTOR Signaling in Multiple Myeloma-Associated Mesenchymal Stem Cells Impedes the Proliferation of Multiple Myeloma Cells.

The microenvironment of cancer cells is receiving increasing attention as an important factor influencing the progression and prognosis of tumor diseases. In multiple myeloma (MM), a hematological cancer of plasma cells, mesenchymal stem cells (MSCs) represent an integral part of the bone marrow niche and tumor microenvironment. It has been described that MM cells alter MSCs in a way that MM-associated MSCs promote the proliferation and survival of MM cells. Yet, our understanding of the molecular mechanisms governing the interaction between MM cells and MSCs and whether this can be targeted for therapeutic interventions is limited. To identify potential molecular targets, we examined MSCs by RNA sequencing and Western blot analysis. We report that MSCs from MM patients with active disease (MM-Act-MSCs) show a distinct gene expression profile as compared with MSCs from patients with other (non-) malignant diseases (CTR-MSCs). Of note, we detected a significant enrichment of the PI3K-AKT-mTOR hallmark gene set in MM-Act-MSCs and further confirmed the increased levels of related proteins in these MSCs. Pictilisib, a pan-PI3K inhibitor, selectively reduced the proliferation of MM-Act-MSCs as compared with CTR-MSCs. Furthermore, pictilisib treatment impaired the MM-promoting function of MM-Act-MSCs. Our data thus provide a deeper insight into the molecular signature and function of MSCs associated with MM and show that targeting PI3K-AKT-mTOR signaling in MSCs may represent an additional therapeutic pathway in the treatment of MM patients.

Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells.

Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing chemotherapy-induced apoptosis. This encouraged us to investigate leukaemia-BM niche-associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells' proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients.

Kelch 13-propeller polymorphisms in Plasmodium falciparum from Jazan region, southwest Saudi Arabia.

BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended at the initial phase for treatment of Plasmodium falciparum, to reduce morbidity and mortality in all countries where malaria is endemic. Polymorphism in portions of P. falciparum gene encoding kelch (K13)-propeller domains is associated with delayed parasite clearance after ACT. Of about 124 different non-synonymous mutations, 46 have been identified in Southeast Asia (SEA), 62 in sub-Saharan Africa (SSA) and 16 in both the regions. This is the first study designed to analyse the prevalence of polymorphism in the P. falciparum k13-propeller domain in the Jazan region of southwest Saudi Arabia, where malaria is endemic. METHODS: One-hundred and forty P. falciparum samples were collected from Jazan region of southwest Saudi Arabia at three different times: 20 samples in 2011, 40 samples in 2016 and 80 samples in 2020 after the implementation of ACT. Plasmodium falciparum kelch13 (k13) gene DNA was extracted, amplified, sequenced, and analysed using a basic local alignment search tool (BLAST). RESULTS: This study obtained 51 non-synonymous (NS) mutations in three time groups, divided as follows: 6 single nucleotide polymorphisms (SNPs) '11.8%' in samples collected in 2011 only, 3 (5.9%) in 2011and 2016, 5 (9.8%) in 2011 and 2020, 5 (9.8%) in 2016 only, 8 (15.7%) in 2016 and 2020, 14 (27.5%) in 2020 and 10 (19.6%) in all the groups. The BLAST revealed that the 2011 isolates were genetically closer to African isolates (53.3%) than Asian ones (46.7%). Interestingly, this proportion changed completely in 2020, to become closer to Asian isolates (81.6%) than to African ones (18.4%). CONCLUSIONS: Despite the diversity of the identified mutations in the k13-propeller gene, these data did not report widespread artemisinin-resistant polymorphisms in the Jazan region where these samples were collected. Such a process would be expected to increase frequencies of mutations associated with the resistance of ACT.

Visceral leishmaniasis in Saudi Arabia: From hundreds of cases to zero.

The kingdom of Saudi Arabia (KSA) has succeeded in bringing the reported numbers of Visceral leishmaniasis (VL) cases from hundreds during the 1980s and 1990s to zero case in 2019. The endemicity of VL has been confined mainly to the Southwest regions, namely Jazan and Aseer regions. Leishmania donovani species have been identified as the causative species of VL, while L. infantum have been isolated only from dogs in the endemic areas. Many species of sand flies were caught in Southwest, but P. orientalis is the probable transmitter of the disease. The black rat (Rattus ratus) was found to be contributing to maintenance of the parasite life cycle. VL is primarily a disease of children, and 80% of cases were Saudi's, while cases from Yeminis nationality represent the majority of non- Saudi patients. The common clinical presentation consist of chronic fever, abdominal distention, weight loss, anemia and hepatosplenomegaly. Laboratory findings include: anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hyperproteinaemia and hypergammaglobulinemia, low serum iron, and abnormal liver enzymes. Occurrence of jaundice has been identified as a bad prognostic sign. Diagnosis relying on direct smears from bone marrow aspirates was the commonest tool used, and also is advocated by the National Leishmaniasis Control Program (NLCP). Sodium stibogluconate (SSG) is the main drug used to treat VL cases, while Ambisome is preserved for complicated cases. Chemical control of sand flies using indoor residual spraying (IRS) with synthetic pyrethroids has been the most effective measure applied to prevent vector-human contact and disease transmission. The geographical overlap of VL and Malaria has facilitated the adoption and implementation of integrated vector control strategies. After reaching a zero case in 2019, the Ministry of Health (MoH) has a new commitment and facing a great challenge which are maintenance of current situation and elimination of VL. Through the support of stakeholders, encouragement of community participation, preparedness and readiness of leishmaniasis personnel, the new mission of the NLCP now is elimination of the scourge of VL from the country.

Biomechanical Assessment of Restored Mandibular Molar by Endocrown in Comparison to a Glass Fiber Post-Retained Conventional Crown: 3D Finite Element Analysis.

PURPOSE: To compare equivalent and contact stresses in a mandibular molar restored by all-ceramic crowns through two methods: ceramic endocrowns and ceramic crowns supported by fiber-reinforced composite (FRC) posts and core, by using 3D finite element analysis during normal masticatory load. MATERIALS AND METHODS: Three 3D models of a mandibular first molar were made and labeled as such: intact molar with no restoration (A); ceramic endocrown-restored molar (B); ceramic crown supported by FRC posts and core restored molar (C). By using 3D FE analysis with contact components, normal masticatory load was simulated. The mvM stresses in all models were calculated. Maximal mvM stresses in the ceramic of restorations, dentin, and luting cement were contrasted among models and to values of materials' strength. Contact shear and tensile stresses in the restoration/tooth interface around restorations were also calculated. RESULTS: The highest mvM stress levels in the enamel and dentin for the tooth restored by ceramic endocrown were lower in the crown ceramic than in tooth restored with FRC posts and all-ceramic crowns; however, in the resin adhesive cement interface it was lower for ceramic crown supported by FRC posts than the in ceramic endocrown restoration. The maximum contact shear and tensile stress values along the restoration/tooth interface of ceramic endocrowns were lower than those with ceramic crowns supported by FRC posts. CONCLUSIONS: Ceramic endocrown restorations presented a lower mvM stress level in dentin than the conventional ceramic crowns supported by FRC posts and core. Ceramic endocrown restorations in molars are less susceptible to damage than those with conventional ceramic crowns retained by FRC posts. Ceramic endocrowns properly cemented in molars must not be fractured or loosen during normal masticatory load. Therefore, ceramic endocrowns are advised as practicable, minimally invasive, and esthetic restorations for root canal treated mandibular molars.

Stability analysis of a steady state of a model describing Alzheimer's disease and interactions with prion proteins.

Alzheimer's disease (AD) is a neuro-degenerative disease affecting more than 46 million people worldwide in 2015. AD is in part caused by the accumulation of A[Formula: see text] peptides inside the brain. These can aggregate to form insoluble oligomers or fibrils. Oligomers have the capacity to interact with neurons via membrane receptors such as prion proteins ([Formula: see text]). This interaction leads [Formula: see text] to be misfolded in oligomeric prion proteins ([Formula: see text]), transmitting a death signal to neurons. In the present work, we aim to describe the dynamics of A[Formula: see text] assemblies and the accumulation of toxic oligomeric species in the brain, by bringing together the fibrillation pathway of A[Formula: see text] peptides in one hand, and in the other hand A[Formula: see text] oligomerization process and their interaction with cellular prions, which has been reported to be involved in a cell-death signal transduction. The model is based on Becker-Döring equations for the polymerization process, with delayed differential equations accounting for structural rearrangement of the different reactants. We analyse the well-posedness of the model and show existence, uniqueness and non-negativity of solutions. Moreover, we demonstrate that this model admits a non-trivial steady state, which is found to be globally stable thanks to a Lyapunov function. We finally present numerical simulations and discuss the impact of model parameters on the whole dynamics, which could constitute the main targets for pharmaceutical industry.

Seroprevalence of dengue fever and the associated sociodemographic, clinical, and environmental factors in Makkah, Madinah, Jeddah, and Jizan, Kingdom of Saudi Arabia.

This study aimed to estimate the seroprevalence of anti-dengue IgG antibodies in Makkah, Al Madinah, Jeddah, and Jizan; and to identify the associated demographic, clinical, and environmental independent risk factors. A community-based household serosurvey conducted between September 20, 2016 and January 31, 2017. A multi-stage stratified cluster sampling was used to select 6596 participants from Makkah, Madinah, Jeddah, and Jizan. Blood samples were drawn from all participants to detect anti-dengue IgG antibodies. A semi-structured questionnaire was used to collect information on demographic, clinical, and environmental data. Multivariate logistic regression was carried out to identify independent risk factors of dengue seropositivity. The dengue seroprevalence (95% confidence intervalI) was 26.7% (25.6%, 27.8%), with the highest (33.6%) and lowest (14.8%) rates in Jizan and Madinah, respectively, and reaching 50% or more in several districts of the four cities. Demographic predictors of seroprevalence included: dwelling in Makkah (odds ratio [OR] = 2.19, p < 0.001) or Jizan (OR = 2.17, p < 0.001); older age (OR = 3.91, p < 0.001 for age>30 years); housing type (OR = 1.84 and 1.82, p < 0.001 for popular and social houses, respectively); and number of household occupants (OR = 0.86 and 0.71 for 6-10 [p = 0.042] and 11-20 [p = 0.002] occupants, respectively). Environmental predictors included the absence of pest control works in residency area (OR = 1.39, p = 0.002), presence of mosquitoes in the home (OR = 1.39, p = 0.001), and absence of awareness campaigns (OR = 1.97, p < 0.001). One in four inhabitants of the Western region of Saudi Arabia was seropositive for the dengue virus. Implementation of behavior-based educational programs is recommended, involving the population in the identification and eradication of vector sources and promoting appropriate behaviors that prevent the spread.

Perceived Barriers to Breast Cancer Screening among Saudi Women at Primary Care Setting

Background: Screening for breast cancer (BC) is of low rate in Saudi Arabia; although it is provided in the country free of charge to the population. This cross-sectional study aimed at investigating the perceived barriers towards BC screening in Al Hassa, Saudi Arabia. It is crucial for increasing the rate of utilization of screening to identify the possible barriers for seeking BC screening in order to enhance early diagnosis and improve outcome. Materials and Methods: A total of 816 adult Saudi women aged ≥ 30 years attending for routine primary health services or accompanying patients at the selected primary health care centers (PHCs) were randomly selected from 12 PHCs (8 urban and four rural) using multi-stage sampling method. Participants were invited to personal interview using semi-structured data collection instrument including inquiries about socio-demographics, reproductive history, previous histories of diagnosed breast lesions and breast cancer. The perceived individual barriers towards screening, their attitudes, the reasons for not attending previously held screening campaigns in Al Hassa, were also included. Results: Low utilization of BC screening has being significantly associated with woman's age (OR=2.55; 95% CI= 1.71-3.83), higher educational status (OR=2.98; 95% CI=2.05-4.34), higher family income (OR=1.96; 95% CI=1.31-2.93), using hormonal contraception (OR=1.46; 95% CI=0.99-2.13) and positive history of previous breast (OR=12.16; 95% CI=6.89-21.46), as shown by the results of the logistic regression model. Exploratory factor analysis showed that personal fears (especially fear of doctors/ examiners, fear of hospitals and health facilities and fear of consequences/results) were the major factors that hinder women from utilizing the free of charge BC screening with high loading eigenvalue of 3.335, explaining 30.4% of the barriers. Conclusion: Educational interventions aim at improving breast cancer knowledge and addressing barriers should be incorporated as core component of the screening program in Saudi Arabia.

Impaired steroidogenesis and apoptosis of granulosa-luteal cells in primary culture induced by cis-platinum.

OBJECTIVE: The purpose of this study was to test the hypothesis that the cytotoxic drug cis-platinum (CP) induces premature ovarian failure by reducing the viability of human granulosa cells. STUDY DESIGN: We incubated cultured human granulosa-luteal cells (GLCs) with varying concentrations of CP for 48 hours. Steroidogenesis and apoptosis were assessed by progesterone and estradiol, annexin V/propidium iodide, phase contrast, and transmission electron microscopy. RESULTS: CP caused impaired production of progesterone and estradiol in a dose- and a time-dependent fashion. The estradiol production was more pronounced than progesterone for each concentration of CP that was studied. The phase contrast microscopy of CP-treated GLCs showed loss of cell number with condensed nuclei. CP-induced apoptosis was maximum at 20 µg/mL compared with a 10-µg/mL concentration (79.9% ± 4.6% vs 58.3% ± 3.9%; P < .01). The hallmark of apoptosis (ie, nuclear condensation, cell size shrinkage) was seen in CP-treated cells by transmission electron microscopy. CONCLUSION: CP induces apoptosis of human GLCs in culture with impaired steroidogenesis, which may be one mechanism by which a CP-containing regime induces premature ovarian failure.

HDQ, a potent inhibitor of Plasmodium falciparum proliferation, binds to the quinone reduction site of the cytochrome bc1 complex.

The mitochondrial bc(1) complex is a multisubunit enzyme that catalyzes the transfer of electrons from ubiquinol to cytochrome c coupled to the vectorial translocation of protons across the inner mitochondrial membrane. The complex contains two distinct quinone-binding sites, the quinol oxidation site of the bc(1) complex (Q(o)) and the quinone reduction site (Q(i)), located on opposite sides of the membrane within cytochrome b. Inhibitors of the Q(o) site such as atovaquone, active against the bc(1) complex of Plasmodium falciparum, have been developed and formulated as antimalarial drugs. Unfortunately, single point mutations in the Q(o) site can rapidly render atovaquone ineffective. The development of drugs that could circumvent cross-resistance with atovaquone is needed. Here, we report on the mode of action of a potent inhibitor of P. falciparum proliferation, 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ). We show that the parasite bc(1) complex--from both control and atovaquone-resistant strains--is inhibited by submicromolar concentrations of HDQ, indicating that the two drugs have different targets within the complex. The binding site of HDQ was then determined by using a yeast model. Introduction of point mutations into the Q(i) site, namely, G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition. In contrast, known inhibitor resistance mutations at the Q(o) site did not cause HDQ resistance. This study, using HDQ as a proof-of-principle inhibitor, indicates that the Q(i) site of the bc(1) complex is a viable target for antimalarial drug development.

Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression.

Atovaquone is an anti-malarial drug used in combination with proguanil (e.g. Malarone(TM)) for the curative and prophylactic treatment of malaria. Atovaquone, a 2-hydroxynaphthoquinone, is a competitive inhibitor of the quinol oxidation (Q(o)) site of the mitochondrial cytochrome bc(1) complex. Inhibition of this enzyme results in the collapse of the mitochondrial membrane potential, disruption of pyrimidine biosynthesis, and subsequent parasite death. Resistance to atovaquone in the field is associated with point mutations in the Q(o) pocket of cytochrome b, most notably near the conserved Pro(260)-Glu(261)-Trp(262)-Tyr(263) (PEWY) region in the ef loop). The effect of this mutation has been extensively studied in model organisms but hitherto not in the parasite itself. Here, we have performed a molecular and biochemical characterization of an atovaquone-resistant field isolate, TM902CB. Molecular analysis of this strain reveals the presence of the Y268S mutation in cytochrome b. The Y268S mutation is shown to confer a 270-fold shift of the inhibitory constant (K(i)) for atovaquone with a concomitant reduction in the V(max) of the bc(1) complex of ∼40% and a 3-fold increase in the observed K(m) for decylubiquinol. Western blotting analyses reveal a reduced iron-sulfur protein content in Y268S bc(1) suggestive of a weakened interaction between this subunit and cytochrome b. Gene expression analysis of the TM902CB strain reveals higher levels of expression, compared with the 3D7 (atovaquone-sensitive) control strain in bc(1) and cytochrome c oxidase genes. It is hypothesized that the observed differential expression of these and other key genes offsets the fitness cost resulting from reduced bc(1) activity.

Glycerol: an unexpected major metabolite of energy metabolism by the human malaria parasite.

BACKGROUND: Malaria is a global health emergency, and yet our understanding of the energy metabolism of the principle causative agent of this devastating disease, Plasmodium falciparum, remains rather basic. Glucose was shown to be an essential nutritional requirement nearly 100 years ago and since this original observation, much of the current knowledge of Plasmodium energy metabolism is based on early biochemical work, performed using basic analytical techniques (e.g. paper chromatography), carried out almost exclusively on avian and rodent malaria. Data derived from malaria parasite genome and transcriptome studies suggest that the energy metabolism of the parasite may be more complex than hitherto anticipated. This study was undertaken in order to further characterize the fate of glucose catabolism in the human malaria parasite, P. falciparum. METHODS: Products of glucose catabolism were determined by incubating erythrocyte-freed parasites with D-[1-13C] glucose under controlled conditions and metabolites were identified using 13C-NMR spectroscopy. RESULTS: Following a 2 h incubation of freed-P. falciparum parasites with 25 mM D-[1-13C] glucose (n = 4), the major metabolites identified included; [3-13C] lactate, [1,3-13C] glycerol, [3-13C] pyruvate, [3-13C] alanine and [3-13C] glycerol-3-phosphate. Control experiments performed with uninfected erythrocytes incubated under identical conditions did not show any metabolism of D-[1-13C] glucose to glycerol or glycerol-3-phosphate. DISCUSSION: The identification of glycerol as a major glucose metabolite confirms the view that energy metabolism in this parasite is more complex than previously proposed. It is hypothesized here that glycerol production by the malaria parasite is the result of a metabolic adaptation to growth in O2-limited (and CO2 elevated) conditions by the operation of a glycerol-3-phosphate shuttle for the re-oxidation of assimilatory NADH. Similar metabolic adaptations have been reported previously for other microaerobic/anaerobic organisms, such as yeast, rumen protozoa and human parasitic protozoa. CONCLUSION: These data highlight the need to re-evaluate the carbon and redox balance of this important human pathogen, ultimately leading to a better understanding of how the parasite is able to adapt to the variable environments encountered during parasite development and disease progression.

Urinary incontinence after continent urinary diversion using cecal wrap or plicated ileum: a patient questionnaire review.

OBJECTIVES: To evaluate the clinical and urodynamic results of a tapered-cecal wrap (TCW) versus a tapered-plicated ileal (TPI) anti-incontinence mechanism. METHODS: Of 54 consecutive patients who had undergone continent urinary diversions, 33 (17 with TCW and 16 with TPI) were evaluated. The primary disease that prompted diversion included bladder cancer (84%), neurogenic bladder (12%), and interstitial cystitis (3%). All patients were evaluated using a telephone questionnaire regarding ease of catheterization, degree of continence, occurrence of postoperative complications, and overall satisfaction in relation to their stoma. In addition, 6 patients in the TPI group and 5 in the TCW group underwent enterocystometry and outlet pressure recording. The mean follow-up was 30 months for the TCW group and 48 months for the TPI group. RESULTS: The overall functional continence rate was 100% for the TCW group and 81.3% for the TPI group. Transient difficulty with catheterization occurred in 35.3% of the TCW group and 18.7% of the TPI group. No differences were observed in the occurrence of postoperative complications. Urodynamics demonstrated a statistically significant increase in maximal outlet pressure with the reservoir full in the TCW group that was not noted in the TPI group. CONCLUSIONS: The addition of a cecal wrap to the efferent limb results in significantly improved continence. This was supported urodynamically with demonstration of an increase in maximal outlet pressure with the reservoir full in the TCW group. No difference in the surgical complication rate or long-term difficulty with catheterization was observed.