Evaluating Safety of Ring Versus Clamp Devices in Neonatal Circumcision: A Meta-Analysis.

BACKGROUND: While device-based circumcision is considered non-inferior to traditional dissection, there is no consensus on the efficacy and safety of ring devices in comparison with clamp devices. We aimed to compare the safety outcomes of ring-based versus clamp-based circumcision techniques in neonates. METHODS: MEDLINE, EMBASE, Scopus, and CINAHL were searched following the Cochrane collaboration (PRISMA guidelines), without language restrictions, to identify relevant randomized controlled trials. Adverse events, bleeding events, infection events, and procedure time were extracted and analyzed from the selected studies. RESULTS: From 1661 citations, seven trials were included, encompassing 3390 patients. These studies compared ring-based to clamp-based circumcision devices in neonates. No significant difference was found in overall adverse events between the two groups. However, ring devices showed significantly fewer bleeding events compared to clamp devices. Infection events and procedure time were similar for both groups. CONCLUSIONS: Both ring and clamp devices have similar safety profiles, with ring devices potentially offering a reduced risk of bleeding. A comprehensive understanding of ring-specific complications and cosmetic outcomes is necessary for a more complete evaluation of these circumcision techniques. Our analysis is limited from a lack of detailed examination of ring-specific complications and their impact on cosmetic results. The included studies varied in quality, and some exhibited a risk of bias. LEVEL OF EVIDENCE: Level IV Treatment Study.

Bladder embryonal rhabdomyosarcoma presenting in the perinatal period: Report of two consecutive cases.

Bladder embryonal rhabdomyosarcomas (ERMS) are malignant soft tissue tumors that rarely present in the perinatal period. Herein, we report two cases that were diagnosed in the newborn period (one with concomitant posterior urethral valves [PUV]), managed with chemotherapy and surgical resection to minimize the need for radiation.

Febrile ulceronecrotic Mucha-Habermann disease - a case and treatment review.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of pityriasis lichenoides, characterized by sudden onset of generalized ulceronecrotic papules that rapidly coalesce into ulcers associated with high fever. Systemic manifestations such as intravascular disseminated coagulation and pulmonary, cardiac, gastrointestinal, and central nervous system involvement are common. Treatment is based on oral corticosteroids, immunosuppressive drugs such as methotrexate, and general supportive treatment. The present case describes a stepwise approach to a patient with Mucha-Habermann disease with insufficient response to methotrexate.

Assessment and validation of the pet-owner relationship scale for Brazil.

Introduction: This study aimed to perform a cross-cultural adaptation of the cat-owner/dog-owner relationship scales. The method involved several stages: conceptual, item, semantic, operational, measurement, and functional equivalence. Procedures included translation, synthesis of translations, back-translation, consensus on the English versions, external evaluation by the original authors, expert committee evaluation, and pre-tests. Methods: The study surveyed 234 pet owners across Brazil using a 20-item questionnaire. Data analysis utilized confirmatory factor analysis, covariance-based modeling, and multigroup analysis. Results: The study confirmed the content and construct validity of the model, demonstrating good convergent validity. Hypotheses testing revealed significant inverse relationships between Perceived Cost and Perceived Emotional Closeness, and between Perceived Cost and Pet-Owner Interactions. A positive correlation was found between Perceived Emotional Closeness and Pet-Owner Interactions, with Perceived Emotional Closeness also mediating the relationship between Perceived Cost and Pet-Owner Interactions. No significant differences were found across different pet owner groups, indicating the scale's invariance and reliability across various demographics. Discussion: The study significantly expands understanding of the complex dynamics in pet-owner relationships and emphasizes the interplay between emotional and practical factors. It offers valuable insights for future research and practices in animal and human welfare.

A Cohort Study to Evaluate the Evolution of the Optic Nerve Head Parameters and Inner Retinal Thickness During Childhood.

PURPOSE: To compare children's stereometric optic disc parameters and inner retinal thickness measured by optical coherence tomography (OCT) in two different moments in life in the same children and to establish a correlation between the optic nerve head (ONH) area and the difference of these parameters in the two observations. METHODS: In this observational cohort, children were evaluated on two occasions: at 6.7 ± 1.6 and 13.2 ± 0.7 years of age. Cup volume, neuroretinal rim (NRR) area, average cup-to-disc ratio, peripapillary retinal nerve fiber layer (pRNFL), and ganglion cell inner plexiform layer (GCIPL) were measured by the Cirrus HD-OCT (Carl Zeiss Meditec AG). RESULTS: A total of 175 children were included, 89 boys (50.9%) and 86 girls (49.1%). There was a significant decrease of the NRR area (P < .001) and increase of the cup volume (P < .001) on the second observation. The pRNFL thickness and GCIPL thickness also decreased (P < .001 and P = .002, respectively). There was a positive correlation between the ONH area and the difference of the cup volume (P = .047; r = 0.102) and a negative correlation with the difference of the NRR area (P < .001; r = 0.237). CONCLUSIONS: During childhood, there is an increase of the cup volume, a decrease of the NRR area, and a decrease of inner retinal layer thickness (more significant in the superior and inferior quadrants) measured by OCT. This study demonstrates that in children with large discs the enlargement of the cup and decrease of the NRR is more evident. Considering these changes, the physiological enlargement of the cup in a child with a large disc can be misinterpreted as the development of a glaucomatous lesion. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XXX-XXX.].

Intradetrusor Versus Suburothelial Onabotulinum Toxin A in Adults with Neurogenic and Non-neurogenic Overactive Bladder Syndrome: A Meta-Analysis.

PURPOSE: This systematic review and meta-analysis aimed to compare the effectiveness and safety of submucosal injection of onabotulinum toxin A (OnabotA) with intradetrusor injection for overactive bladder syndrome (OAB). METHODS: This systematic review is registered with PROSPERO (CRD42021237964). A licensed librarian surveyed Medline, EMBASE, Scopus, and Google Scholar databases to conduct a comprehensive search. Studies comparing suburothelial and intradetrusor techniques of OnabotA injection for OAB were included, along with clinical and urodynamic variables and complications. The studies were assessed for quality on the basis of Cochrane Collaboration guidelines and evaluated using statistical analysis via a random-effect model and I2 statistic. Data extraction and analysis were conducted using Covidence systematic review platform and Review Manager software. RESULTS: Six studies with 299 patients were included in the systematic review, with four reporting that suburothelial injection of OnabotA was as effective as intradetrusor injection and two reporting intradetrusor injection to be more effective. The meta-analysis found no significant difference between the suburothelial and intradetrusor groups for mean daily catheter or voiding frequency (mean difference: 2.12 [95% confidence interval (CI): -1.61, 5.84]) and the mean number of urgency/urge incontinence episodes (mean difference: 0.08 [95% CI: -1.42, 1.57]). However, a significant heterogeneity was found among the studies. Only the mean volume at first detrusor contraction showed a significant difference, being higher for suburothelial injection (mean difference: 33.39 [95% CI: 0.16, 66.63]). No significant difference was noted for mean compliance, mean bladder capacity, and mean maximum detrusor pressure. Urinary tract infections (UTIs) (p = 0.24) and acute urinary retention (p = 0.92) showed no significant difference between the two groups. The risk of bias varied among the studies. CONCLUSIONS: Suburothelial injection of OnabotA is as effective as intradetrusor injection in improving OAB symptoms, and it has similar complication rates. A higher mean volume of the first detrusor contraction was found in a urodynamic study with suburothelial injection.

The impact of posterior urethral valves on pediatric quality of life and family function: Prospective analysis of serial patients managed in a dedicated multidisciplinary clinic.

INTRODUCTION: Posterior urethral valves (PUV) is a chronic condition that can adversely impact child and family health related quality of life (HRQOL). Surprisingly, to date, the impact of this condition on the QOL of children with PUV has not been studied. Thus, our aim is to evaluate this important aspect of care using validated questionnaires in our institutional PUV clinic. METHODS: From December 2022 to January 2024, the PedsQL Inventory and associated family impact module was distributed in our PUV clinic. Higher scores reflect better HRQoL and less impact on family. Children >8 years old completed the tool themselves, otherwise parents completed the tools on behalf of the child. We compared PUV scores against reported psychometric data from healthy children and other chronic illnesses. RESULTS: A total of 112 families completed the questionnaires. The total HRQoL score was 80 ± 13. Overall, we noted that the domains reflecting psychosocial impact were significantly lower than those of physical well-being (76 ± 16 vs. 89 ± 15 for psychosocial and physical impact, respectively; p < 0.01). There was a significant difference in the psychosocial emotional impact for children managed with clean intermittent catheterization (CIC) compared to those who were not (69 ± 21 vs. 81 ± 16; p = 0.005) (Table 2). In addition, we noted that children with PUV scored similar to healthy controls, but higher than children with other chronic illnesses. With respect to the impact on family, overall, parent, and family impacts were 76 ± 19, 78 ± 21, and 81 ± 21, respectively. DISCUSSION: Chronic illness has been associated with a negative impact on HRQoL in both adults and children. We noted similar findings the present study, particularly for young children and those who are maintained on CIC. To our knowledge, this is the first study to evaluate the impact of PUV on a child's HRQoL as well as the impact on the family, and to document a negative psychosocial impact of CIC in this population. However, there are some important limitations to be addressed including relying on families to complete questionnaires accurately during busy clinic visits and the lack of controls from the same environment. CONCLUSION: When compared to healthy controls, PUV patients score similarly in HRQoL assessment. In addition, children <3years of age report a negative impact on physical well being, and CIC negatively impacts the emotional well-being. These data can be used to advocate for better mental health supports and social work for these children.

The Role of Secondary Conservative Management Strategies in Bladder and Bowel Dysfunction: A Systematic Review and Meta-analysis.

OBJECTIVE: We sought to determine the effect of secondary management strategies in addition to urotherapy on bowel bladder dysfunction outcomes. STUDY DESIGN: The review protocol was prospectively registered (CRD42023422168). MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus (database initiation until June 2023) were searched. Comparative studies of secondary management strategies vs conventional urotherapy alone were included. Two authors independently screened titles, abstracts, and reviewed full-text articles. Two authors extracted data related to study characteristics, methodology, subjects, and results. RESULTS: In this systematic review and meta-analysis of 18 studies and 1228 children, secondary management strategies (home-based education, biofeedback, and physical therapy) were associated with reduced symptom burden, fewer recurrent urinary tract infections, and improved uroflowmetry findings than children treated solely with urotherapy for conservative management. CONCLUSIONS: Although there is significant reporting heterogeneity, secondary conservative management strategies such as home education, biofeedback or cognitive behavioral therapy, and physiotherapy-based education are associated with less urinary incontinence, fewer infections, and fewer abnormal uroflowmetry findings.

Assessing safety and tolerability of super selective alpha-1 adrenergic blockers in infants under 3 years: Insights from a single-center study on lower urinary tract obstruction (LUTO).

BACKGROUND: Little is known about alpha blocker use in young children, particularly in those with lower urinary tract obstruction (LUTO). Therefore, we aimed to assess the safety and tolerability of selective alpha-blockers in children under 3 years of age with LUTO. METHODS: A prospectively-collected database captured 93 patients born between 12/2005 and 01/2023. Assessed data included baseline characteristics, ultrasound features, blood pressure (BP), side effects and creatinine values. Primary outcome was side effects or discontinuation of alpha-blockers. Secondary outcomes were BP parameters, growth, and kidney function. Data are shown as median with interquartile range (IQR), Odds Ratio (OR) with 95% CI and mean value with standard deviation (SD). RESULTS: A total of 33 patients less than 3 years of age were started on alpha-blockers at 16.8 ± 11.8 months and followed for 48.9 ± 40.5 months. At last follow-up, no significant effect on systolic/diastolic BP percentiles (p > 0.9 and p > 0.9), creatinine levels (p > 0.9). Weight percentiles increased to the last follow-up (37.8 ± 33.2 vs. 53.6 ± 32.9, p = 0.0133) while height percentiles increased from 28 to 100 days to last follow-up (12.9 ± 18.3 vs. 39.6 ± 35.2, p=0.001). Four patients discontinued alpha-blockers; however, no side-effects were reported during the study period. CONCLUSIONS: No severe clinical or systemic side effects were observed, demonstrating safety and tolerability in young children with LUTO. Although alpha-blockers did not significantly improve kidney function in short term follow-up, and failure to thrive was not observed in these children. Additional studies with more patients are required to assess the optimal dosing and timing leading to maximal benefits for these infants.

Pediatric Urology Providers' Perceptions and Attitudes on Transitional Urologic Care in a Single-Payer Health Care System.

INTRODUCTION: Advances in health care have improved outcomes for pediatric patients with congenital neurourological conditions, highlighting the need for an effective transition from pediatric to adult care. This study investigates Canada's transitional urologic care within its single-payer health care system, focusing on the active members of Pediatric Urologists of Canada and their practices, perceptions, and attitudes toward transitional urologic care. METHODS: A survey was distributed to 35 Pediatric Urologists of Canada members from July 2023 to January 2024, which collected data on transitional care practices and available transitional urology clinics. It also focused on a service overview, covering aspects such as the responder's geographic and institutional affiliations, clinical practice characteristics involving transitional care, perceived challenges, and strategies for care enhancement. RESULTS: Nationwide engagement emphasized a commitment to improving transitional care, with a significant proportion of respondents (64%) having over 10 years of practice, reflecting substantial experience in addressing transitional care challenges. The survey identified 4 dedicated transitional care clinics, 3 of which are active, pointing to concerted efforts toward specialized service provision. The major challenges identified include the lack of adult transitional care initiatives and governmental support. Recommendations for improvement should focus on standardizing transition protocols and boosting patient education. The survey also underscored the necessity of protocolized care for spina bifida-neurogenic bladder and complex urogenital conditions. CONCLUSIONS: This study highlights the active efforts and existing challenges within Canada's transitional urologic care system, particularly emphasizing operational transitional care clinics as a crucial step forward in catering to transitioning patients' needs.

Toxicity mechanisms of plastic nanoparticles in three terrestrial species: antioxidant system imbalance and neurotoxicity.

The detrimental impacts of plastic nanoparticles (PNPs) are a worldwide concern, although knowledge is still limited, in particular for soil mesofauna. This study investigates the biochemical impact of 44 nm polystyrene PNPs on three soil models-Enchytraeus crypticus (Oligochaeta), Folsomia candida (Collembola) and Porcellionides pruinosus (Isopoda). Exposure durations of 3, 7 and 14 days (d) were implemented at two concentrations (1.5 and 300 mg kg-1 PNPs). Results revealed PNPs impact on the activities of the glutathione-dependent antioxidative enzyme, glutathione S-transferase (GST) and on the neurotransmitter acetylcholinesterase (AChE) for all three species. Catalase (CAT) played a minor role, primarily evident in F. candida at 300 mg kg-1 PNPs (CAT and GST response after 14 d), with no lipid peroxidation (LPO) increase. Even with the antioxidant defence, P. pruinosus was the most sensitive species for lipid oxidative damage (LPO levels increased after 7 d exposure to 300 mg kg-1 PNPs). Significant AChE inhibitions were measured already after 3 d to both PNP concentrations in F. candida and E. crypticus, respectively. Significant AChE inhibitions were also found in P. pruinosus but later (7 d). Overall, the toxicity mechanisms of PNPs involved antioxidant imbalance, being (mostly) the glutathione-associated metabolism part of that defence system. Neurotoxicity, linked to AChE activities, was evident across all species. Sensitivity to PNPs varied: P. pruinosus > F. candida ≅ E. crypticus. This pioneering study on PNPs toxicity in soil invertebrates underscores its environmental relevance, shedding light on altered biochemical responses, that may compromise ecological roles and soil ecosystem fitness.

Potential effects of the discharge of wastewater treatment plant (WWTP) effluents in benthic communities: evidence from three distinct WWTP systems.

Wastewater treatment plant (WWTP) effluents can be sources of environmental contamination. In this study, we aimed to understand whether effluents of three different WWTPs may have ecological effects in riverine recipient ecosystems. To achieve this, we assessed benthic phytobenthos and macroinvertebrate communities at three different locations relative to the effluent discharge: immediately upstream, immediately downstream and 500-m downstream the effluent discharge. Two approaches were employed: the ecological status classification as defined in the Water Framework Directive (WFD) based on biological indicators; constrained multivariate analysis to disentangle the environmental drivers (physicochemical variables and contaminants, namely metals, polycyclic aromatic hydrocarbons, pharmaceuticals, and personal care products) of ecological changes across the study sites. The results showed inconsistencies between the WFD approach and the multivariate approach, as well as between the responses of macroinvertebrates and diatoms. The WWTP effluents impacted benthic communities in a single case: macroinvertebrates were negatively affected by one of the WWTP effluents, likely by the transported pharmaceuticals (other stressors are essentially homogeneous among sites). Given the findings and the scarcity of consistent evidence on ecological impacts that WWTP effluents may have in recipient ecosystems, further research is needed towards more sustainable regulation and linked environmental protection measures.

Adipose tissue rearrangement in cancer cachexia: The involvement of ß3-adrenergic receptor associated pathways.

Cancer-associated cachexia (CAC) is a complex multiple organ syndrome that significantly contributes to reduced quality of life and increased mortality among many cancer patients. Its multifactorial nature makes its early diagnosis and effective therapeutic interventions challenging. Adipose tissue is particularly impacted by cachexia, typically through increased lipolysis, browning and thermogenesis, mainly at the onset of the disease. These processes lead to depletion of fat mass and contribute to the dysfunction of other organs. The ß-adrenergic signalling pathways are classical players in the regulation of adipose tissue metabolism. They are activated upon sympathetic stimulation inducing lipolysis, browning and thermogenesis, therefore contributing to energy expenditure. Despite accumulating evidence suggesting that ß3-adrenergic receptor stimulation may be crucial to the adipose tissue remodelling during cachexia, the literature remains controversial. Moreover, there is limited knowledge regarding sexual dimorphism of adipose tissue in the context of cachexia. This review paper aims to present the current knowledge regarding adipose tissue wasting during CAC, with a specific focus on the role of the ß3-adrenergic receptor, placing it as a potential therapeutic target against cachexia.

Should a Refluxing Internal Diversion Be Considered a Temporizing Procedure? Extended Follow-up and Outcomes After Side-to-Side Ureterovesicostomy for Primary Obstructive Megaureter in Young Children.

PURPOSE: We describe long-term outcomes, including UTIs and need for reimplantation, after ureterovesicostomy (UV) as a lasting surgical procedure for children with primary obstructive megaureter (POM). MATERIALS AND METHODS: Children referred to our institution between 2016 and 2023 who underwent refluxing UV were analyzed. POM was defined as hydroureteronephrosis with distal ureteral dilatation > 7 mm and a negative workup for other etiologies of hydronephrosis. We assessed for surgical outcomes, complications, rate of UTI, and improvement in upper tract dilatation. Statistical analyses assessed for change in hydronephrosis metrics over follow-up. RESULTS: Among 183 patients diagnosed with POM, 47 (24%) underwent UV. Median age of presentation, surgery, and follow-up was 2, 9, and 43 months, respectively. A total of 7 patients developed 30-day complications: Clavien-Dindo grade 1 in 2 (transient urinary retention) and grade 2 in 5 (UTIs). During monitoring 14 (30%) developed UTIs and 7 (15%) required ureteral reimplant or UV takedown. After surgery there was a significant decrease in the proportion of patients with high-grade hydronephrosis, anteroposterior renal pelvis diameter, and maximum ureteral dilatation. CONCLUSIONS: Refluxing UV is a safe alternative to cutaneous diversion in POM. Most patients had improvement in upper tract dilatation with an acceptable short-term complication rate and need for reoperation (in comparison to routine later reimplantation). Our experience suggests that monitoring alone after UV is feasible, and that selective subsequent reconstruction is a reasonable strategy.

Knowledge about cervical cancer in young Portuguese women: a cross-sectional study.

Introduction: Health literacy is crucial to adherence to medical interventions in therapeutics, prevention, and diagnosis. The basis for literacy is knowledge. To accomplish the goals for the elimination of cervical cancer, one of the most prevalent and preventable cancers, we must understand the determinants of non-adherence and address them specifically to ensure patients' active participation. Aim: To determine women's knowledge regarding the manifestations of cervical cancer and its prevention. Materials and methods: We conducted a cross-sectional study in an urban population from northern Portugal. Women aged 18 to 30 years were randomly assigned to answer the Cervical Cancer Awareness Measure questionnaire, including questions of knowledge about the causes and symptoms of cervical cancer, prospecting for individual and social-related determinants. Results: The total number of participants was 270, with a mean age of 24.7 years. Knowledge about symptoms scored 5.4 ± 2.6, with a maximum of 12 points, and knowledge about the causes scored 5.7 ± 1.9, with a maximum of 11 points. The correlation between both was 0.334. High education, high socio-economic status, self-perception of one's capacity to recognize symptoms, and knowledge about the HPV vaccine were associated with better knowledge. Discussion: Portuguese women present low knowledge about cervical cancer, potentially affecting their health through exposure to risk situations and non-adherence to routine screening.

Development of a loop-mediated isothermal amplification assay for the rapid detection of Styphnolobium japonicum (L.) Schott as an adulterant of Ginkgo biloba (L.).

BACKGROUND: Species adulteration is a concern in herbal products, especially when plant substitutes of lower economic value replace valuable botanicals. Styphnolobium japonicum is well known as a potential adulterant of Ginkgo biloba, which is one of the most demanded medicinal plants due to its wide use in pharmaceuticals, food supplements, and traditional medicine. Despite bearing some resemblance to ginkgo's flavonol composition, S. japonicum lacks many of G. biloba's desired therapeutic properties. To prevent adulteration practices, it is crucial to implement rigorous quality control measures, including fast and simple diagnostic tools that can be used on-field. PURPOSE: This study aims to develop for the first time a species-specific loop-mediated isothermal amplification (LAMP) method for the fast identification of S. japonicum in ginkgo-containing products. METHODS: A set of four specific primers (SjF3, SjB3, SjFIP, and SjBIP) and loop primers (SjLF and SjLB) were designed for a LAMP based assay using the 5.8S partial sequence and the internal transcribed spacer 2 of nuclear ribosomal DNA of S. japonicum. RESULTS: The successful amplification of the LAMP assay was inspected through visual detection, with the highest intensity recorded at the optimal conditions set at 68 °C for 40 min. The primers showed high specificity and were able to accurately discriminate S. japonicum from G. biloba and 49 other species of medicinal plants. Furthermore, the proposed LAMP assay proved to be fast, selective, and highly sensitive, as demonstrated by the absolute and relative limits of detection, which were reached at 0.5 pg for S. japonicum DNA and 0.01 % S. japonicum in G. biloba, respectively. CONCLUSIONS: This novel approach allows easy identification and discrimination of S. japonicum as a potential adulterant of G. biloba, thus being a useful tool for quality control. Compared to chromatographic or PCR-based methods, the assay proved to be fast, sensitive and did not require expensive equipment, thus offering the possibly usage in field analysis.

Advancing Precision Medicine: A Review of Innovative In Silico Approaches for Drug Development, Clinical Pharmacology and Personalized Healthcare.

The landscape of medical treatments is undergoing a transformative shift. Precision medicine has ushered in a revolutionary era in healthcare by individualizing diagnostics and treatments according to each patient's uniquely evolving health status. This groundbreaking method of tailoring disease prevention and treatment considers individual variations in genes, environments, and lifestyles. The goal of precision medicine is to target the "five rights": the right patient, the right drug, the right time, the right dose, and the right route. In this pursuit, in silico techniques have emerged as an anchor, driving precision medicine forward and making this a realistic and promising avenue for personalized therapies. With the advancements in high-throughput DNA sequencing technologies, genomic data, including genetic variants and their interactions with each other and the environment, can be incorporated into clinical decision-making. Pharmacometrics, gathering pharmacokinetic (PK) and pharmacodynamic (PD) data, and mathematical models further contribute to drug optimization, drug behavior prediction, and drug-drug interaction identification. Digital health, wearables, and computational tools offer continuous monitoring and real-time data collection, enabling treatment adjustments. Furthermore, the incorporation of extensive datasets in computational tools, such as electronic health records (EHRs) and omics data, is also another pathway to acquire meaningful information in this field. Although they are fairly new, machine learning (ML) algorithms and artificial intelligence (AI) techniques are also resources researchers use to analyze big data and develop predictive models. This review explores the interplay of these multiple in silico approaches in advancing precision medicine and fostering individual healthcare. Despite intrinsic challenges, such as ethical considerations, data protection, and the need for more comprehensive research, this marks a new era of patient-centered healthcare. Innovative in silico techniques hold the potential to reshape the future of medicine for generations to come.

Structural characterization of the ACDC domain from ApiAP2 proteins of the malaria parasite.

The Apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in the malaria parasite. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins and no other functional domains have been extensively characterized. One protein domain, which is present in a subset of the ApiAP2 proteins, is the conserved AP2-coincident domain mostly at the C-terminus (ACDC domain). Here we solved for the first time the crystal structure of the ACDC domain from two distinct Plasmodium falciparum ApiAP2 proteins and one orthologue from P. vivax , revealing a non-canonical four-helix bundle. Despite little sequence conservation between the ACDC domains from the two proteins, the structures are remarkably similar and do not resemble that of any other known protein domains. Due to their unique protein architecture and lack of homologues in the human genome, we performed in silico docking calculations against a library of known antimalarial compounds and we identified a small molecule that can potentially bind to any Apicomplexan ACDC domain within a pocket highly conserved amongst ApiAP2 proteins. Inhibitors based on this compound would disrupt the function of the ACDC domain and thus of the ApiAP2 proteins containing it, providing a new therapeutic window for targeting the malaria parasite and other Apicomplexans.