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1.
Pediatr Blood Cancer ; : e31217, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39039777

RESUMO

Germ cell tumors (GCT) are a complex, heterogeneous collection of tumors that may present in either gonadal or extragonadal sites. They consist of a variety of benign and malignant histologies that can occur at several locations throughout the body. An important component of treatment is surgical resection, and while the key components of resection are site specific, the universal goals of GCT resection include the complete resection of tumor without violating the tumor capsule, while preserving function of surrounding organs, minimizing morbidity, and assessing for regional spread.

2.
Pediatr Surg Int ; 40(1): 58, 2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38400936

RESUMO

PURPOSE: A robotic-assisted laparoscopic approach to appendicostomy offers the benefits of a minimally invasive approach to patients who would typically necessitate an open procedure, those with a larger body habitus, and those requiring combined complex colorectal and urologic reconstructive procedures. We present our experience performing robotic-assisted appendicostomies with a focus on patient selection, perioperative factors, and functional outcomes. METHODS: A retrospective review of patients who underwent a robotic-assisted appendicostomy/neoappendicostomy at our institution was performed. RESULTS: Twelve patients underwent robotic-assisted appendicostomy (n = 8) and neoappendicostomy (n = 4) at a range of 8.8-25.8 years. Five patients had a weight percentile > 50% for their age. Seven patients underwent combined procedures. Median operative time for appendicostomy/neoappendicostomy only was 185.0 min. Complications included surgical site infection (n = 3), stricture requiring minor operative revision (n = 2), conversion to an open procedure due to inadequate appendiceal length (prior to developing our technique for robotic neoappendicostomies; n = 1), and granuloma (n = 1). At a median follow-up of 10.8 months (range 1.7-74.3 months), 91.7% of patients were consistently clean with antegrade enemas. DISCUSSION: Robotic-assisted laparoscopic appendicostomy and neoappendicostomy with cecal flap is a safe and effective operative approach. A robotic approach can potentially overcome the technical difficulties encountered in obese patients and can aid in patients requiring both a Malone and a Mitrofanoff in a single, combined minimally invasive procedure.


Assuntos
Incontinência Fecal , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Incontinência Fecal/cirurgia , Colostomia , Laparoscopia/métodos , Enema/métodos , Estudos Retrospectivos
3.
PLoS Pathog ; 17(10): e1009994, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34662366

RESUMO

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are also utilized to treat a wide range of disorders including muscle spasm, overactive bladder, and pain. BoNTs' ability to target neurons determines their specificity, potency, and therapeutic efficacy. Homologous synaptic vesicle membrane proteins synaptotagmin-1 (Syt1) and synaptotagmin-2 (Syt2) have been identified as receptors for BoNT family members including BoNT/B, DC, and G, but their contributions at physiologically relevant toxin concentrations in vivo have yet to be validated and established. Here we generated two knockin mutant mouse models containing three designed point-mutations that specifically disrupt BoNT binding in endogenous Syt1 or Syt2, respectively. Utilizing digit abduction score assay by injecting toxins into the leg muscle, we found that Syt1 mutant mice showed similar sensitivity as the wild type mice, whereas Syt2 mutant mice showed reduced sensitivity to BoNT/B, DC, and G, demonstrating that Syt2 is the dominant receptor at skeletal neuromuscular junctions. We further developed an in vivo bladder injection assay for analyzing BoNT action on bladder tissues and demonstrated that Syt1 is the dominant toxin receptor in autonomic nerves controlling bladder tissues. These findings establish the critical role of protein receptors for the potency and specificity of BoNTs in vivo and demonstrate the differential contributions of Syt1 and Syt2 in two sets of clinically relevant target tissues.


Assuntos
Toxinas Botulínicas/metabolismo , Sinaptotagmina II/metabolismo , Sinaptotagmina I/metabolismo , Animais , Técnicas de Introdução de Genes , Camundongos , Modelos Animais
4.
Curr Opin Urol ; 31(2): 140-146, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33394765

RESUMO

PURPOSE OF REVIEW: Botulinum neurotoxin A (BoNT/A), or Botox, is a popular option for overactive bladder (OAB) and neurogenic bladder (NGB) with or without incontinence. This review aims to discuss the clinical outcomes of BoNT in adult and pediatric bladder conditions, and introduces the potential benefit of novel, engineered neurotoxins beyond BoNT/A. RECENT FINDINGS: A large volume of evidence supports the use of Botox for OAB (to reduce urgency, frequency and incontinence episodes), and for NGB (to decrease incontinence and improve bladder capacity and detrusor pressures). Botox is now also Food & Drug Administration (FDA)-approved for pediatric neurogenic detrusor overactivity. However, urinary retention, diminished response over time and treatment failures are prevalent issues with Botox. Modifying natural BoNTs or forming chimeric toxins are alternatives to BoNT/A that may have higher efficacy and lower side-effect profile. One example is BoNT/BMY-WW. This novel engineered toxin binds to a more commonly expressed synaptotagmin receptor, with potentially more potent paralytic effect and less capacity for systemic diffusion. SUMMARY: Novel engineered neurotoxins may be the next frontier in OAB and NGB therapy.


Assuntos
Toxinas Botulínicas Tipo A , Bloqueio Nervoso , Fármacos Neuromusculares , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Adulto , Toxinas Botulínicas Tipo A/efeitos adversos , Toxinas Botulínicas Tipo A/uso terapêutico , Criança , Humanos , Bloqueio Nervoso/métodos , Fármacos Neuromusculares/efeitos adversos , Fármacos Neuromusculares/uso terapêutico , Resultado do Tratamento , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico
5.
Neurourol Urodyn ; 40(8): 1981-1988, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34486166

RESUMO

AIMS: We aimed to describe the effectiveness of Onabotulinumtoxin A (Botox) in children with neurogenic bladder (NGB) unresponsive to medical therapy to determine urodynamic parameters predictive of success. METHODS: Children receiving Botox for refractory NGB, between 2008 and 2019, from a single academic center, were included in this study. Botox success was defined as improvement of incontinence and/or urodynamic parameters. RESULTS: Of 34 patients who received Botox, 13 (38.2%) had a positive response from their first injection, with improvement in capacity by a median of 35% of expected capacity for age compared to only a 9% increase in those who did not respond clinically. When patients were divided into groups by baseline urodynamic parameters, high-pressure (Pdetmax > 20 cm H2 O) patients had significantly greater improvement in compliance compared with low-pressure patients (p = 0.017). Low compliance patients (<10 ml/cm H2 O) had a dramatic improvement of 3.08 ml/cm H2 O in their compliance compared with minimal change in the high compliance group (p = 0.003). Finally, low-capacity (<50% of expected CC) patients had significant improvement in capacity and compliance when compared with high-capacity patients (p = 0.004 and p = 0.036, respectively). Improvement in detrusor overactivity (DO) was noted in both the clinical responders and non-responders. CONCLUSION: In our series, 38% had clinical success with intradetrusor Botox injections for refractory neurogenic bladder. When successful, improvement in capacity and compliance, DO, and/or incontinence was consistent with prior literature. While we could not determine which parameters predicted success, subdividing patients into categories based on baseline urodynamic parameters identified who would benefit from Botox treatment based on differential improvements in capacity and compliance. At least 1 injection of Botox should be considered for a subset of children with refractory NGB, before undertaking more invasive treatments.


Assuntos
Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Toxinas Botulínicas Tipo A/uso terapêutico , Criança , Humanos , Fármacos Neuromusculares/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Urodinâmica
6.
Can J Urol ; 26(1): 9654-9659, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30797248

RESUMO

INTRODUCTION: To evaluate the reasons leading to an extended hospital stay (EHS) in patients undergoing radical cystectomy (RC) with postoperative enhanced recovery after surgery (ERAS) protocol. MATERIALS AND METHODS: A total of 509 patients underwent RC and urinary diversion with ERAS between May 2012 and March 2017. The protocol includes no bowel preparation, early feeding, predominantly non-narcotic pain control and µ opioid antagonists. Non-consenting/lost to follow up patients, and those with non-urothelial carcinoma were excluded. We defined EHS as ≥ 5 postoperative days and compared the cohort to those with a LOS of ≤ 4 days. Demographics including modifiable and non-modifiable factors as well as in-house complications as possible contributing factors to EHS was reviewed. RESULTS: There were 279/509 (54.8%) patients had an EHS. Median age was 73 years, 82.4% were male, and 36.6% had a Charlson comorbidity index (CCI) of > 2. Univariate analysis demonstrated that age > 65 years, CCI > 2, increased operative time, anemia requiring transfusion and non-orthotopic diversion were associated with EHS. On multivariate analysis, advanced age, operative time, postop transfusion, CCI > 2 as well as surgeon specific preferences was associated with EHS. Within EHS patients, 86% stayed due to an in-house complication; ileus (34.3%), anemia requiring transfusion (9.8%), UTIs (9.4%) and atrial fibrillation (8.5%). CONCLUSIONS: Advanced age, operative time, postop transfusion, CCI > 2 and surgeon-specific preferences are associated with an EHS following RC with ERAS. The common causes of EHS are in-house complications, mainly ileus.


Assuntos
Cistectomia , Recuperação Pós-Cirúrgica Melhorada , Tempo de Internação/estatística & dados numéricos , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Protocolos Clínicos , Cistectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derivação Urinária
8.
Proc Natl Acad Sci U S A ; 110(10): 4003-8, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23431178

RESUMO

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34(+) hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34(+) grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Mesenquimais , Regeneração/fisiologia , Disrafismo Espinal/fisiopatologia , Disrafismo Espinal/cirurgia , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Urinaria Neurogênica/cirurgia , Bexiga Urinária/fisiopatologia , Bexiga Urinária/cirurgia , Adolescente , Animais , Criança , Citratos/química , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Regeneração Nervosa/fisiologia , Polímeros/química , Ratos , Ratos Nus , Disrafismo Espinal/complicações , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Bexiga Urinária/irrigação sanguínea , Bexiga Urinaria Neurogênica/etiologia
9.
J Pediatr Urol ; 20(4): 692.e1-692.e6, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38951046

RESUMO

BACKGROUND: Urethrocutaneous fistula (UCF) formation is a known complication following hypospadias repair, affecting between 5 and 70% of cases. Moreover, approximately 30% of patients experience refistulization after UCF repair. The use of extracellular matrices, such as AmnioCord, a dehydrated human umbilical cord allograft manufactured by MiMedx®, may mitigate high rates of refistulization. OBJECTIVE: To determine whether the use of AmnioCord during UCF repair is associated with reduced incidence of subsequent UCFs among pediatric patients. DESIGN, SETTING, AND PARTICIPANTS: Electronic medical records were retrospectively reviewed among 60 patients who underwent at least one UCF repair at a pediatric hospital in a large urban setting in the U.S. between January 2012-June 2018. Patients were followed through January 2024. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusted generalized estimating equation regression models were used to assess the association between AmnioCord use and rates of refistulization, while controlling for confounding variables. RESULTS: The number of fistula presentations per patient ranged from one to four; 53.3% had one fistula, 30.0% had two, and 16.6% had three or more. Overall fistula repair success rate was 56.8% but significantly differed by AmnioCord use in adjusted modelling; 69.4% of cases that received AmnioCord were successfully repaired, compared to 47.2% of cases that did not receive AmnioCord. In adjusted models, patients who received AmnioCord had 2.66 times greater odds of surgical success than patients who did not receive AmnioCord (95% CI:1.13-6.24; p = 0.02). CONCLUSIONS: This study demonstrates a positive association between AmnioCord use and successful UCF closure among pediatric patients.


Assuntos
Fístula Cutânea , Hipospadia , Complicações Pós-Operatórias , Cordão Umbilical , Doenças Uretrais , Fístula Urinária , Humanos , Masculino , Estudos Retrospectivos , Fístula Urinária/etiologia , Fístula Urinária/cirurgia , Fístula Urinária/epidemiologia , Fístula Cutânea/etiologia , Fístula Cutânea/cirurgia , Fístula Cutânea/epidemiologia , Pré-Escolar , Hipospadia/cirurgia , Doenças Uretrais/cirurgia , Doenças Uretrais/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Cordão Umbilical/cirurgia , Lactente , Resultado do Tratamento , Criança , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Aloenxertos
10.
J Kidney Cancer VHL ; 11(3): 33-39, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39148862

RESUMO

Although rare in adults, Wilms tumor is the most common pediatric renal tumor. Treatment typically involves radical nephrectomy followed by adjuvant chemotherapy or radiation, although outcomes differ between children and adults which may be due to challenges in accurately diagnosing these patients. In this article, we present a case report of an adult patient with Jeune syndrome and multiple urologic abnormalities who underwent radical nephrectomy for a large renal mass and was subsequently diagnosed with an epithelial predominant Wilms tumor. Epithelial predominant Wilms tumor may have distinct origins from other Wilms tumor histological subtypes and may incur better outcomes. Herein, we discuss the literature surrounding this rare entity as well as the anticipated treatment course.

11.
BMC Med ; 11: 160, 2013 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-23837842

RESUMO

BACKGROUND: The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. METHODS: In an open-label, phase 1/phase 2 study, patients (N=36) with long-standing T2D were divided into three groups (Group A, oral medications, n=18; Group B, oral medications+insulin injections, n=11; Group C having impaired ß-cell function with oral medications+insulin injections, n=7). All patients received one treatment with the Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient's circulation. RESULTS: Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61%±1.12 at baseline to 7.25%±0.58 at 12 weeks (P=2.62E-06), and 7.33%±1.02 at one year post-treatment (P=0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. CONCLUSIONS: Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01415726.


Assuntos
Diabetes Mellitus Tipo 2/cirurgia , Sangue Fetal/transplante , Imunomodulação , Resistência à Insulina , Terapia de Alvo Molecular/métodos , Células-Tronco Multipotentes/transplante , Transplante de Células-Tronco/métodos , Adulto , Idoso , Técnicas de Cocultura , Diabetes Mellitus Tipo 2/imunologia , Feminino , Sangue Fetal/imunologia , Seguimentos , Humanos , Hipoglicemiantes/administração & dosagem , Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Resistência à Insulina/imunologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/imunologia , Transplante Autólogo
12.
Bioengineering (Basel) ; 10(7)2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37508840

RESUMO

Recent advances in targeted cancer therapy hold great promise for both research and clinical applications and push the boundaries in finding new treatments for various currently incurable cancers. However, these therapies require specific cell-targeting mechanisms for the efficient delivery of drug cargo across the cell membrane to reach intracellular targets and avoid diffusion to unwanted tissues. Traditional drug delivery systems suffer from a limited ability to travel across the barriers posed by cell membranes and, therefore, there is a need for high doses, which are associated with adverse reactions and safety concerns. Bacterial toxins have evolved naturally to specifically target cell subtypes via their receptor binding module, penetrating the cell membrane efficiently through the membrane translocation process and then successfully delivering the toxic cargo into the host cytosol. They have, thus, been harnessed for the delivery of various drugs. In this review, we focus on bacterial toxin translocation mechanisms and recent progress in the targeted delivery systems of cancer therapy drugs that have been inspired by the receptor binding and membrane translocation processes of the anthrax toxin protective antigen, diphtheria toxin, and Pseudomonas exotoxin A. We also discuss the challenges and limitations of these studies that should be addressed before bacterial toxin-based drug delivery systems can become a viable new generation of drug delivery approaches in clinical translation.

13.
Sci Rep ; 13(1): 19520, 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37945675

RESUMO

Neurogenic bladder (NB) affects people of all ages. Electric impedance myography (EIM) assesses localized muscle abnormalities. Here, we sought to investigate whether unique detrusor EIM signatures are present in NB due to spinal cord injury (SCI). Twenty-eight, 8-10 weeks old, C57BL/6J female mice were studied. Twenty underwent spinal cord transection; 8 served as controls. Cohorts were euthanized at 4 and 6 weeks after spinal cord transection. Each bladder was measured in-situ with EIM with applied frequencies of 1 kHz to 10 MHz, and then processed for molecular and histologic study. SCI mice had greater bladder-to-body weight ratio (p < 0.0001), greater collagen deposition (p = 0.009), and greater smooth-muscle-myosin-heavy-chain isoform A/B ratio (p < 0.0001). Compared with the control group, the SCI group was associated with lower phase, reactance, and resistance values (p < 0.01). Significant correlations (p < 0.001) between bladder-to-body weight ratios and EIM measurements were observed across the entire frequency spectrum. A severely hypertrophied phenotype was characterized by even greater bladder-to-body weight ratios and more depressed EIM values. Our study demonstrated distinct EIM alterations in the detrusor muscle of mice with NB due to SCI. With further refinement, EIM may offer a potential point-of-care tool for the assessment of NB and its response to treatment.


Assuntos
Traumatismos da Medula Espinal , Bexiga Urinaria Neurogênica , Humanos , Camundongos , Feminino , Animais , Músculo Esquelético/fisiologia , Impedância Elétrica , Bexiga Urinaria Neurogênica/etiologia , Camundongos Endogâmicos C57BL , Miografia , Fenótipo , Peso Corporal
14.
bioRxiv ; 2023 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-38106029

RESUMO

Spinal cord injury (SCI) evokes profound bladder dysfunction. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed systemic inosine treatment improved bladder function following SCI in rats. Here, we applied multi-omics analysis to explore molecular alterations in the bladder and their sensitivity to inosine following SCI. Canonical pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator analysis identified MYC as a key regulator, whereas causal network analysis predicted multiple regulators of DNA damage response signaling following injury, including PARP-1. Staining for both DNA damage (γH2AX) and PARP activity (poly-ADP-ribose) markers in the bladder was increased following SCI, and attenuated in inosine-treated tissues. Proteomics analysis suggested that SCI induced changes in protein synthesis-, neuroplasticity-, and oxidative stress-associated pathways, a subset of which were shown in transcriptomics data to be inosine-sensitive. These findings provide novel insights into the molecular landscape of the bladder following SCI, and highlight a potential role for PARP inhibition to treat neurogenic bladder dysfunction.

15.
Toxins (Basel) ; 15(1)2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36668830

RESUMO

Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (STEC-HUS) is a clinical syndrome involving hemolytic anemia (with fragmented red blood cells), low levels of platelets in the blood (thrombocytopenia), and acute kidney injury (AKI). It is the major infectious cause of AKI in children. In severe cases, neurological complications and even death may occur. Treating STEC-HUS is challenging, as patients often already have organ injuries when they seek medical treatment. Early diagnosis is of great significance for improving prognosis and reducing mortality and sequelae. In this review, we first briefly summarize the diagnostics for STEC-HUS, including history taking, clinical manifestations, fecal and serological detection methods for STEC, and complement activation monitoring. We also summarize preventive and therapeutic strategies for STEC-HUS, such as vaccines, volume expansion, renal replacement therapy (RRT), antibiotics, plasma exchange, antibodies and inhibitors that interfere with receptor binding, and the intracellular trafficking of the Shiga toxin.


Assuntos
Injúria Renal Aguda , Infecções por Escherichia coli , Síndrome Hemolítico-Urêmica , Escherichia coli Shiga Toxigênica , Criança , Humanos , Escherichia coli Shiga Toxigênica/metabolismo , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/terapia , Infecções por Escherichia coli/complicações , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/terapia , Antibacterianos/uso terapêutico , Antibacterianos/metabolismo , Injúria Renal Aguda/etiologia
16.
Toxins (Basel) ; 13(3)2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803852

RESUMO

Shiga toxins (Stxs) are classic bacterial toxins and major virulence factors of toxigenic Shigella dysenteriae and enterohemorrhagic Escherichia coli (EHEC). These toxins recognize a glycosphingolipid globotriaosylceramide (Gb3/CD77) as their receptor and inhibit protein synthesis in cells by cleaving 28S ribosomal RNA. They are the major cause of life-threatening complications such as hemolytic uremic syndrome (HUS), associated with severe cases of EHEC infection, which is the leading cause of acute kidney injury in children. The threat of Stxs is exacerbated by the lack of toxin inhibitors and effective treatment for HUS. Here, we briefly summarize the Stx structure, subtypes, in vitro and in vivo models, Gb3 expression and HUS, and then introduce recent studies using CRISPR-Cas9-mediated genome-wide screens to identify the host cell factors required for Stx action. We also summarize the latest progress in utilizing and engineering Stx components for biomedical applications.


Assuntos
Infecções por Escherichia coli/metabolismo , Síndrome Hemolítico-Urêmica/metabolismo , Toxinas Shiga/metabolismo , Escherichia coli Shiga Toxigênica/metabolismo , Triexosilceramidas/metabolismo , Animais , Sistemas CRISPR-Cas , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/microbiologia , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Imunotoxinas/uso terapêutico , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Conformação Proteica , Toxinas Shiga/química , Toxinas Shiga/genética , Toxinas Shiga/uso terapêutico , Escherichia coli Shiga Toxigênica/genética , Relação Estrutura-Atividade
17.
Nat Commun ; 12(1): 3748, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145250

RESUMO

C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for TcdB, but its pathophysiological relevance and the molecular details that govern recognition remain unknown. Here, we determine the cryo-EM structure of a TcdB-CSPG4 complex, revealing a unique binding site spatially composed of multiple discontinuous regions across TcdB. Mutations that selectively disrupt CSPG4 binding reduce TcdB toxicity in mice, while CSPG4-knockout mice show reduced damage to colonic tissues during C. difficile infections. We further show that bezlotoxumab, the only FDA approved anti-TcdB antibody, blocks CSPG4 binding via an allosteric mechanism, but it displays low neutralizing potency on many TcdB variants from epidemic hypervirulent strains due to sequence variations in its epitopes. In contrast, a CSPG4-mimicking decoy neutralizes major TcdB variants, suggesting a strategy to develop broad-spectrum therapeutics against TcdB.


Assuntos
Antígenos/metabolismo , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Clostridioides difficile/patogenicidade , Enterocolite Pseudomembranosa/patologia , Proteoglicanas/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Antígenos/genética , Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Sítios de Ligação/fisiologia , Anticorpos Amplamente Neutralizantes/farmacologia , Microscopia Crioeletrônica , Enterocolite Pseudomembranosa/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Proteoglicanas/genética
18.
J Pediatr Urol ; 16(6): 807-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32861587

RESUMO

INTRODUCTION: Although the consequences of testicular torsion (TT) have been recognized for centuries, little progress has been made to improve outcomes beyond those seen with timely scrotal exploration. Even with testicular salvage, ischemia/reperfusion injury cause significant atrophy and functional impairment. Recent efforts have sought to identify adjuvant pharmacological or surgical interventions that may attenuate these consequences. In this review, we assess the evidence supporting clinical use of these nascent interventions. METHODS: We conducted a review of the literature published from 2000 to 2020, using the search terms "torsion", "testicular", "reperfusion", "ischemia", and "injury". Clinical and laboratory research focused on adjuvant pharmacological and surgical techniques mitigating torsion-associated injury in animal models and humans were identified. We recorded intervention timing/dose/route, and outcome timing/category through biomarkers of reperfusion injury, histology, and hormonal/reproductive function. RESULTS: Fifty-four FDA-approved agents, plus 52 herbal/investigational drugs, were reported in animal TT models. In every study, the investigated agents showed beneficial effects on measured endpoints compared to controls. Despite these universally promising animal findings, no pharmacological trials in humans were reported. Surgical techniques studied in animal models included decompression (tunica albuginea incision, TAI), "ischemic conditioning", and hypothermia. Only three human studies on surgical adjuvant maneuvers have been reported, all involving TAI; these showed potential benefit, but the level of evidence is low. CONCLUSION: There is preliminary evidence that adjuvant treatments may mitigate the effects of ischemia/reperfusion injury. However, the pool of investigated pharmacological agents is wide, yet remarkably shallow; most compounds have been reported in a single animal study. To advance this field, a mechanism-based approach should be used to select promising agents that can be tested systematically. This will determine treatment parameters that maximize safety, efficacy, and tolerability. Only then is it possible to move toward human trials. Adjuvant surgical methods such as TAI show promise in humans but require more robust clinical evaluation.


Assuntos
Traumatismo por Reperfusão , Torção do Cordão Espermático , Animais , Atrofia/patologia , Humanos , Isquemia , Masculino , Traumatismo por Reperfusão/prevenção & controle , Torção do Cordão Espermático/tratamento farmacológico , Torção do Cordão Espermático/patologia , Torção do Cordão Espermático/cirurgia , Testículo/patologia
19.
World J Mens Health ; 38(1): 115-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385468

RESUMO

PURPOSE: Men take testosterone (T) boosting supplements to naturally improve T levels. We evaluated the composition and advertised claims of "T boosting" supplements, and supporting published evidence. MATERIALS AND METHODS: Fifty "T booster" supplements were evaluated for active ingredients and product claims, discovered via Google search. PubMed was reviewed for any literature supporting the claims, followed by review of Recommended Daily Allowance (RDA) and upper tolerable intake level (UL) for each component. RESULTS: Ninety percent of supplements claimed to "boost T", 50% "improve libido", and 48% "feel stronger". One-hundred nine unique components were found, with a mean number of 8.3 per product. On PubMed, 24.8% of supplements had data showing an increase in T with supplementation, 10.1% had data showing a decrease in T, and 18.3% had data showing no change in T. No data were found on 61.5% of supplements on their effect on T. Supplements contained a median 1,291% of the RDA for vitamin B12, 807.6% for vitamin B6, 272% of zinc, 200% of vitamin B5, and 187.5% of vitamin B3. Thirteen products exceeded the US Food and Drug Administration UL of ingredients (zinc, vitamin B3, and magnesium). CONCLUSIONS: Ninety percent of "T booster" supplements claimed to boost T. However, only 24.8% of these had data to support these claims. A total of 10.1% contained components with data suggesting a negative effect on T. Many had supra-therapeutic doses of vitamins and minerals, occasionally over the UL. Patients should be informed that "T booster" supplements may not have ingredients to support their claims.

20.
F S Rep ; 1(1): 15-20, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34223207

RESUMO

OBJECTIVE: To determine if there has been a change in empirical medical therapy (EMT) practices since a 2010 American Urological Association survey reported that 25% of urologists treated infertile men who were pursuing a pregnancy with testosterone (T). DESIGN: Survey-based cohort study of AUA members. SETTING: Practice patterns were evaluated of urologists in academic and nonacademic hospital centers. PATIENTS: Practice patterns were evaluated in the treatment of men with idiopathic infertility. INTERVENTIONSS: None. MAIN OUTCOME MEASURES: Subgroup analysis by means of univariate analysis between means (Fisher exact test) and descriptive proportions was used to compare male infertility fellowship-trained urologists (RUs) to general urologists (non-RUs). RESULTS: A total of 191 urologists responded (4.7%). Excluding trainees, 164 responses (85.9%) were analyzed: 134 (82.3%) were from non-RUs and 29 from (17.7%) RUs. Over all, 65.9% treated male infertility with a combination of EMT and surgery (93.1% of RU vs. 60.4% of non-RUs). The most common medications used by RUs were clomiphene (100%), anastrozole (85.7%), and hCG/LH (82.1%). Non-RUs used these less frequently. Overall, 24.4% of the urologists reported that they would use T to treat male infertility: 14.4% (n = 4) of RUs and 24.4% (n = 30) of non-RUs. CONCLUSIONS: A total of 65.9% of urologists would treat male infertility with the use of EMT and surgery. The most common EMTs were clomiphene, anastrozole, and hCG/LH. Of concern, 24.4% of urologists considered T to treat male infertility, a medication with known contraceptive potential. This is unchanged from the 2010 survey, and confirms the need for reproductive medicine guidelines that include the topic of EMT use in infertile men.

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