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1.
J Pediatr Rehabil Med ; 15(4): 633-638, 2022.
Article in English | MEDLINE | ID: mdl-36314224

ABSTRACT

PURPOSE: Patients with neurogenic bladder (NB) often perform clean intermittent catheterization (CIC) and are predisposed to bladder colonization. Antibiotics are not routinely indicated in those with asymptomatic bacteriuria (ASB). The original purpose of this study was to compare patients that received antibiotics for ASB and those that did not. However, because the non-antibiotic group was very small, the final analysis evaluated treatment patterns of ASB in children with NB. METHODS: A retrospective chart review was completed, including patients who presented with urinary tract infection (UTI) and NB managed by CIC. Patients with symptoms of UTI were excluded. Basic demographics, urinalysis, culture results, and antibiotic prescriptions were collected. RESULTS: The sample included 272 patient encounters for 109 unique patients. Of these, 50.7% were female, and the median age was 10.25 years. More than half the urine cultures (56.2%) grew gram-negative organisms, and 31.3% contained 2 or more organisms. Nearly all encounters received treatment with antibiotics. Twenty-three encounters with no culture performed or the culture resulted in no growth received antibiotic therapy. CONCLUSIONS: Antibiotic resistance and antibiotic stewardship are primary concerns in healthcare today. This organization's current practice pattern shows high antibiotic use for ASB in patients with NB. Future studies are required to identify outcomes associated with treatment versus non-treatment in these patients.


Subject(s)
Bacteriuria , Urinary Bladder, Neurogenic , Urinary Tract Infections , Humans , Child , Female , Male , Bacteriuria/drug therapy , Bacteriuria/diagnosis , Bacteriuria/etiology , Anti-Bacterial Agents/therapeutic use , Urinary Bladder, Neurogenic/complications , Urinary Bladder, Neurogenic/drug therapy , Retrospective Studies , Urinary Tract Infections/complications , Urinary Tract Infections/drug therapy , Urinary Tract Infections/diagnosis
2.
Urology ; 130: 148-150, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30986487

ABSTRACT

Alveolar soft part sarcoma (ASPS) is a rare malignancy with high rates of metastasis at presentation, defined by an unclear cellular origin and a unique unbalanced ASPSCR1-TFE3 translocation (der(17)t(X:17)(p11:q25)).1 ASPS is insensitive to chemotherapy and has been reported to involve the bladder only twice in the pediatric literature; once as a primary malignancy,2 and once as a secondary malignancy after cytotoxic chemotherapy.3 Herein, we report the third case of pediatric bladder ASPS in a female patient who received cytotoxic chemotherapy for low-risk neuroblastoma. This would represent the second case of pediatric bladder ASPS as a secondary malignancy after prior chemotherapy.


Subject(s)
Antineoplastic Agents/adverse effects , Neoplasms, Second Primary/chemically induced , Sarcoma, Alveolar Soft Part/chemically induced , Urinary Bladder Neoplasms/chemically induced , Antineoplastic Agents/therapeutic use , Female , Humans , Male , Neuroblastoma/drug therapy
3.
J Urol ; 198(5): 1159-1167, 2017 11.
Article in English | MEDLINE | ID: mdl-28571679

ABSTRACT

PURPOSE: A nonrefluxing megaureter is a relatively common cause of antenatal hydronephrosis. Although nonoperative management is favored, surgical intervention is sometimes warranted. However, there is controversy regarding the best approach, particularly in young children. We describe our experience with nondismembered side-to-side refluxing ureterocystotomy as a simple option to address obstruction. MATERIALS AND METHODS: Between January 2012 and January 2017, 32 patients underwent ureterocystotomy at 4 referral centers in North America. Demographics, surgical indications, complications, need for further interventions and change in hydronephrosis were captured. Patients were monitored clinically and with serial ultrasounds. RESULTS: Mean age at surgery was 3.7 months (range 0 to 33) and 25 (78%) patients were male. Unilateral procedures were performed in 29 patients. All patients were initially identified based on the presence of antenatal hydronephrosis and symptoms developed in 10. The procedure was conducted for primary nonrefluxing megaureter in 27 patients and to address secondary obstruction in the remainder. Mean followup was 34.3 months (range 6 to 58). At the most recent evaluation most children demonstrated significant improvement in dilation (86%). To date, 6 patients have undergone further procedures, including a circumcision and 2 ureteral reimplantations for recurrent infections. CONCLUSIONS: Our results suggest that side-to-side refluxing ureterocystotomy is a straightforward, minimally invasive alternative for the surgical management of nonrefluxing megaureter. Despite the trade-off of relieving obstruction and creating reflux, it can be considered a potentially definitive procedure in patients who remain infection-free, particularly circumcised boys. Extended followup with close monitoring is critical to document long-term results with this intervention.


Subject(s)
Practice Guidelines as Topic , Ureter/abnormalities , Ureteral Obstruction/surgery , Ureterostomy/standards , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Kidney Pelvis , Male , Retrospective Studies , Treatment Outcome , Ultrasonography , Ureter/surgery , Ureteral Obstruction/congenital
4.
Can Urol Assoc J ; 11(3-4): E134-E137, 2017.
Article in English | MEDLINE | ID: mdl-28515816

ABSTRACT

INTRODUCTION: Advances in communication technology are shaping our medical practice. To date, there is no clear evidence that this mode of communication will have any effect on unnecessary postoperative emergency room (ER) visits. We aim to evaluate the effect of email and media communication with application of smartphone digital photography on post-hypospadias repair ER visit rates. METHODS: This prospective cohort study included all patients who underwent hypospadias repair performed by a single surgeon from October 2014 to November 2015. Patients were categorized into two groups: Group A consented for smartphone photography and email communication and Group B declined. Reason for ER visits within 30 days postoperatively was assessed by another physician, who was blinded of patient group assignment. The reasons were categorized as: unnecessary ER visit, indicated ER visit, or visit unrelated to hypospadias surgery. Chi-square test and T-test were used for statistical analysis. Relative risk (RR) and corresponding 95% confidence interval (CI) were also calculated. Statistical significance was set at p<0.05. RESULTS: Over a 14-month period, 96 patients underwent hypospadias repair (81 in Group A, 15 in Group B 5). No significant difference was noted between groups for overall ER return rate (RR 0.46, 95% CI 0.21, 1.0). However, the number of ER visits for wound check not requiring intervention was significantly lower in Group A than in Group B (RR 0.14, 95% CI 0.035, 0.56); likewise, a higher number of ER visits requiring intervention was noted in Group A compared with Group B, although statistically this was not significant (RR 1.67, 95% CI 0.23, 12.21). CONCLUSIONS: Email communication with the use of smartphone digital photography significantly reduced the number of unnecessary ER visits for post-hypospadias wound checks.

5.
J Urol ; 197(3 Pt 2): 951-956, 2017 03.
Article in English | MEDLINE | ID: mdl-27593475

ABSTRACT

PURPOSE: Voiding cystourethrogram involves radiation exposure and is invasive. Several guidelines, including the 2011 AAP (American Academy of Pediatrics) guidelines, no longer recommend routine voiding cystourethrogram after the initial urinary tract infection in children. The recent trend in voiding cystourethrogram use remains largely unknown. We examined practice patterns of voiding cystourethrogram use and explored the impact of these guidelines in a single payer system in the past 8 years. MATERIALS AND METHODS: We identified all voiding cystourethrograms performed at a large pediatric referral center between January 2008 and December 2015. Patients 2 to 24 months old who underwent an initial voiding cystourethrogram for the diagnosis of a urinary tract infection in the first 6 months of 2009 and 2014 were identified. Medical records were retrospectively reviewed. RESULTS: During the study period 8,422 voiding cystourethrograms were performed and the annual number declined over time. In the pre-AAP and post-AAP cohorts 233 and 95 initial voiding cystourethrograms were performed, respectively. While there was no statistically significant difference in the vesicoureteral reflux detection rate between 2009 and 2014 (37.3% vs 43.0%, p = 0.45), there was a threefold increase in high grade vesicoureteral reflux in 2014 (2.6% vs 8.4%, p = 0.03). CONCLUSIONS: A clear trend toward fewer voiding cystourethrograms was noted at our institution. This decrease started before 2011 and cannot be attributed to the AAP guidelines alone. While most detected vesicoureteral reflux remains low grade, there was a greater detection rate of high grade vesicoureteral reflux in 2014 compared to 2009. This may reflect a favorable impact of a more selective approach to obtaining voiding cystourethrograms.


Subject(s)
Cystography/statistics & numerical data , Practice Patterns, Physicians' , Procedures and Techniques Utilization/statistics & numerical data , Urethra/diagnostic imaging , Urinary Tract Infections/diagnostic imaging , Vesico-Ureteral Reflux/diagnostic imaging , Female , Humans , Infant , Male , Practice Guidelines as Topic , Retrospective Studies , Single-Payer System , Tertiary Care Centers , Urination , Urology/standards
6.
J Urol ; 197(3 Pt 1): 792-797, 2017 03.
Article in English | MEDLINE | ID: mdl-27765696

ABSTRACT

PURPOSE: Open dismembered pyeloplasty is the preferred repair for ureteropelvic junction obstruction. Minimally invasive techniques have been applied to the original open approach but no clear advantage has been demonstrated for these technological advances. We evaluate outcomes between transperitoneal laparoscopic and open pyeloplasty in children. MATERIALS AND METHODS: All children 1 to 18 years old with ureteropelvic junction obstruction requiring operative repair were offered enrollment in the study. Patients were prospectively randomized to either laparoscopic or open pyeloplasty through a flank incision. RESULTS: A total of 50 patients in the laparoscopic group and 48 in the open group were enrolled from 2005 to 2014. Mean followup was similar between the groups (13.7 months in the laparoscopic group vs 12.3 months in the open group, p = 0.54). The only significantly different outcomes were for mean operative time, which was 139.5 minutes (range 94 to 213) in the laparoscopic group and 122.5 minutes (83 to 239) in the open group (p <0.01), and mean length of stay, which was 25.9 hours (18 to 143) in the laparoscopic group and 28.2 hours (16 to 73) in the open group (p = 0.02). Analgesic usage, success rate, total charges and all parameters in children older than 11 years were similar between the groups. CONCLUSIONS: Open and laparoscopic dismembered pyeloplasty are comparable and effective methods for repair of ureteropelvic junction obstruction. Although operative time was statistically shorter in the open group and length of stay was shorter in the laparoscopic group, the clinical significance of these variables is questionable. The approach to repair may best be based on family preference for incision aesthetics and surgeon comfort with either approach, rather than more classically objective outcome measures.


Subject(s)
Kidney Pelvis/surgery , Laparoscopy , Ureteral Obstruction/surgery , Urologic Surgical Procedures/methods , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Prospective Studies , Treatment Outcome
7.
Surg Clin North Am ; 97(1): 161-172, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27894425

ABSTRACT

The pediatric patient presenting with acute scrotal pain requires prompt evaluation and management given the likelihood of testicular torsion as the underlying cause. Although other diagnoses can present with acute testicular pain, it is important to recognize the possibility of testicular torsion because the best chance of testicular preservation occurs with expeditious management. When testicular torsion is suspected, prompt surgical exploration is warranted. A delay in surgical management should not occur in an effort to obtain confirmatory imaging. When torsion is discovered, the contralateral testicle should undergo fixation to reduce the risk of asynchronous torsion.


Subject(s)
Disease Management , Spermatic Cord Torsion/surgery , Urologic Surgical Procedures, Male/methods , Acute Disease , Child , Humans , Male
8.
J Urol ; 196(3): 862-8, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27017936

ABSTRACT

PURPOSE: There is paucity of validated objective early imaging markers to help predict future renal deterioration in infants with posterior urethral valves. We evaluated the prognostic value of total renal parenchymal area, renal echogenicity and corticomedullary differentiation regarding future development of chronic kidney disease. MATERIALS AND METHODS: We analyzed initial postnatal ultrasonographic images from serial posterior urethral valve cases seen at a single tertiary referral center using National Institutes of Health sponsored image processing software. Echogenicity and corticomedullary differentiation were objectively measured as ratios relative to the adjacent liver or spleen and between cortex and medulla. The primary study outcome, renal function at last followup, was dichotomized based on glomerular filtration rate and/or need for renal replacement therapy (dialysis or renal transplantation, stage 5 chronic kidney disease). RESULTS: A total of 75 patients were evaluated, of whom 16 had progression to stage 5 chronic kidney disease after a mean ± SD followup of 64.2 ± 38.9 months. Mean renal parenchymal area was 21.41 cm(2) in patients without and 16 cm(2) in patients with stage 5 chronic kidney disease (p <0.001), and mean corticomedullary differentiation was 1.77 and 1.21, respectively (p <0.001). Bilateral echogenic kidneys were significantly associated with development of stage 5 chronic kidney disease (p = 0.004). The performance of corticomedullary differentiation in predicting stage 5 chronic kidney disease was statistically significant (AUROC 0.881, 95% CI 0.776-0.987, p <0.001). CONCLUSIONS: Estimates of renal parenchyma quantity (total renal parenchymal area) and quality (corticomedullary differentiation and renal echogenicity) measured on initial postnatal ultrasound carry prognostic value in determining future risk of stage 5 chronic kidney disease in patients with posterior urethral valves. These data are promising for developing tools to risk stratify patients, counsel parents and customize monitoring protocols.


Subject(s)
Glomerular Filtration Rate/physiology , Kidney/diagnostic imaging , Renal Insufficiency, Chronic/diagnosis , Ultrasonography/methods , Urethra/abnormalities , Urethral Diseases/complications , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Humans , Infant , Male , Prognosis , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/physiopathology , Retrospective Studies , Risk Factors , Time Factors , Urethra/diagnostic imaging , Urethral Diseases/congenital , Urethral Diseases/diagnosis
9.
J Urol ; 194(4): 1086-90, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25963187

ABSTRACT

PURPOSE: In children with congenital obstructive uropathy, including posterior urethral valves, lower urinary tract decompression is recommended pending definitive surgical intervention. Current options, which are limited to a feeding tube or Foley catheter, pose unappreciated constraints in luminal diameter and are associated with potential problems. We assess the impact of luminal diameter on the current draining options and present a novel alternative method, repurposing a widely available stent that optimizes drainage. MATERIALS AND METHODS: We retrospectively reviewed patients diagnosed with posterior urethral valves between January 2013 and December 2014. In all patients a 6Fr 12 cm Double-J ureteral stent was advanced over a guidewire in a retrograde fashion into the bladder. Luminal flow and cross-sectional areas were also assessed for each of 3 tubes for urinary drainage, ie 6Fr Double-J stent, 5Fr feeding tube and 6Fr Foley catheter. RESULTS: A total of 30 patients underwent uneventful bedside Double-J stent placement. Mean ± SD age at valve ablation was 28.5 ± 16.6 days. Mean ± SD peak serum creatinine was 2.23 ± 0.97 mg/dl after birth and 0.56 ± 0.22 mg/dl at the procedure. Urine output after stent placement was excellent in all patients. The Foley catheter and feeding tube drained approximately 18 and 6 times more slowly, respectively, and exhibited half the calculated cross-sectional luminal area compared to the Double-J stent. CONCLUSIONS: Use of Double-J stents in neonates with posterior urethral valves is a safe and effective alternative method for lower urinary tract decompression that optimizes the flow/lumen relationship compared to conventional drainage options.


Subject(s)
Drainage/instrumentation , Drainage/methods , Stents , Urinary Bladder Neck Obstruction/surgery , Urinary Catheterization , Humans , Infant, Newborn , Retrospective Studies
10.
Urol Clin North Am ; 42(1): 31-42, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25455170

ABSTRACT

The indication for use of laparoscopy, in the pediatric population, was initially for diagnostic purposes. As confidence with the technology and utility grew, it began to be applied for therapeutic indications. With equivalent surgical outcomes and decreased morbidity, the usefulness of a laparoscopic approach became more apparent, and today minimally invasive surgery is an indispensable tool in the management of many pediatric urologic conditions. The management of renal pathologies using laparoscopy is now currently the approach of choice for most pediatric renal maladies.


Subject(s)
Laparoscopy/methods , Nephrectomy/methods , Robotics/methods , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Child , Female , Follow-Up Studies , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Laparoscopy/adverse effects , Male , Minimally Invasive Surgical Procedures/adverse effects , Minimally Invasive Surgical Procedures/methods , Nephrectomy/instrumentation , Patient Positioning , Pediatrics , Peritoneum/surgery , Postoperative Complications/physiopathology , Retroperitoneal Space/surgery , Risk Assessment , Treatment Outcome , Umbilicus/surgery
11.
J Urol ; 193(2): 632-6, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25219697

ABSTRACT

PURPOSE: We examined the presentation, diagnosis and management of radiologically detected pediatric urachal anomalies and assessed the risk of malignant degeneration. MATERIALS AND METHODS: Our radiology database (2000 to 2012) was queried for all children younger than 18 years who were diagnosed with a urachal anomaly radiographically, and the operative database was used to determine those who underwent excision. Data collected included demographics, presenting symptoms, imaging modality and indication for excision. These data were compared to the Ontario Cancer Registry to determine the risk of malignancy. RESULTS: A total of 721 patients were radiographically diagnosed with a urachal anomaly (667 incidentally), yielding a prevalence of 1.03% of the general pediatric population. Diagnoses were urachal remnants (89% of cases), urachal cysts (9%) and patent urachus (1.5%). Ultrasonography was the most common imaging modality (92% of cases), followed by fluoroscopy/voiding cystourethrography (5%) and computerized tomography/magnetic resonance imaging (3%). A total of 61 patients (8.3%) underwent surgical excision. Indications for imaging and treatment were umbilical drainage (43% of patients), abdominal pain (28%), palpable mass (25%) and urinary tract infection (7%). Mean age at excision was 5.6 years and 64% of the patients were male. Based on provincial data, the number needed to be excised to prevent a single case of urachal adenocarcinoma was 5,721. CONCLUSIONS: Urachal anomalies are more common than previously reported. Children with asymptomatic lesions do not appear to benefit from prophylactic excision, as the risk of malignancy later in life is remote and a large number of urachal anomalies would need to be removed to prevent a single case of urachal adenocarcinoma.


Subject(s)
Adenocarcinoma/epidemiology , Urachus/abnormalities , Urinary Bladder Neoplasms/epidemiology , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Prognosis , Risk Assessment
12.
Ther Adv Urol ; 6(4): 165-76, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25083165

ABSTRACT

Advances in the management of Wilms' tumor have been dramatic over the past half century, not in small part due to the institution of multimodal therapy and the formation of collaborative study groups. While different opinions exist in the management of Wilms' tumors depending on where one lives and practices, survival rates have surpassed 90% across the board in Western societies. With more children surviving into adulthood, the concerns about morbidity have reached the forefront and now represent as much a consideration as oncologic outcomes these days. Innovations in treatment are on the horizon in the form of potential tumor markers, molecular biological means of testing for chemotherapeutic responsiveness, and advances in the delivery of chemotherapy for recurrent or recalcitrant tumors. Other technological innovations are being applied to childhood renal tumors, such as minimally invasive and nephron-sparing approaches. Risk stratification also allows for children to forego potentially unnecessary treatments and their associated morbidities. Wilms' tumor stands as a great example of the gains that can be made through protocol-driven therapy with strenuous outcomes analyses. These gains continue to spark interest in minimization of morbidity, while avoiding any compromise in oncologic efficacy. While excitement and innovation are important in the advancement of treatment delivery, we must continue to temper this enthusiasm and carefully evaluate options in order to continue to provide the highest standard of care in the management of this now highly curable disease.

13.
Can Urol Assoc J ; 7(7-8): E481-5, 2013.
Article in English | MEDLINE | ID: mdl-23914264

ABSTRACT

OBJECTIVE: We report the outcomes of an early loose closure of the scrotum with a modified U-stitch to minimize use of split thickens skin graft for patients with hemiscrotal tissue loss after surgical debridement. METHODS: From January 2006 to August 2011, 28 male patients presented with Fournier's gangrene, requiring major urological surgical care and scrotal debridement at Denver Health Medical Center. Surgical outcomes were compared between patients receiving a novel U-Stitch approximation and those treated by traditional management. RESULTS: The mean age of the patients was 47.1 ± 10.2 years. In total 8 patients (2.2%) developed bacteremia and 3 (0.1%) had methicillin-resistant staphylococcus aureus (MRSA) infection. There was conversion from the U-Stitch approximation patients to traditional management. U-stitch patients required less hospitalization than patients requiring split-thickness skin graft (STSG) due to loss of >50% of the total scrotal tissue (11 vs. 35 days, p = 0.081). The U-stitch demonstrated non-inferiority to traditional treatment. CONCLUSION: Immediate loose scrotal wound approximation with efficient surgical debridement for Fournier's gangrene may prevent testis exposure facilitating local wound treatment, decreasing the length of hospital stay in patients with Fournier's gangrene involving the scrotum. Future randomized trials may validate these findings.

14.
J Lab Clin Med ; 145(4): 204-11, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15962839

ABSTRACT

Individuals with sickle-cell disease (SCD) and transgenic sickle mice expressing human betaS globin exhibit enhanced reactive oxygen species (ROS) production, vascular inflammation, and episodic vasoocclusion. We hypothesize that reduction of ROS will reduce endothelial-cell activation and adhesion-molecule expression, thereby inhibiting vasoocclusion. To test this hypothesis, we measured endothelial-cell activation, adhesion-molecule expression, and vasoocclusion in sickle mice after administering i.v. polynitroxyl albumin (PNA), a superoxide dismutase and catalase mimetic. Untreated sickle mice, compared with normal mice, showed increased activation of nuclear factor-kappaB (NF-kappaB), an oxidant-sensitive transcription factor, in their lungs, livers, and skin. NF-kappaB activation was increased further in the livers and skin of sickle but not normal mice after hypoxia-reoxygenation. IV administration of PNA inhibited NF-kappaB activation by 60% (P < .01) in the lungs and by 33% (P < .05) in the livers of sickle mice after hypoxia-reoxygenation. PNA also reduced the expression of vascular cell-adhesion molecule-1 (VCAM-1) by 57% in lung (P < .05) and by 33% in liver (P < .05) and reduced the expression of intercellular-adhesion molecule-1 (ICAM-1) by 40% in lung (P < .05) and by 53% in liver (P < .05). PNA inhibited a hypoxia-reoxygenation-induced increase in leukocyte rolling (P < .01) and adhesion (P < .05) in venules of the dorsal skin. Most importantly, PNA completely inhibited hypoxia-reoxygenation-induced vasoocclusion (P < .001). Control albumin had no effect on NF-kappaB, VCAM-1, ICAM-1, rolling, adhesion, or vasoocclusion. We speculate that therapies to reduce oxidative stress will inhibit inflammation and vasoocclusion in SCD.


Subject(s)
Albumins/pharmacology , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/physiopathology , Antioxidants/pharmacology , Nitrogen Oxides/pharmacology , Anemia, Sickle Cell/complications , Animals , Female , Inflammation/drug therapy , Inflammation/etiology , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microcirculation/drug effects , Oxidative Stress , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology
15.
Am J Physiol Heart Circ Physiol ; 288(6): H2715-25, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15665055

ABSTRACT

Activation of vascular endothelium plays an essential role in vasoocclusion in sickle cell disease. The anti-inflammatory agents dexamethasone and adhesion molecule-blocking antibodies were used to inhibit endothelial cell activation and hypoxia-induced vasoocclusion. Transgenic sickle mice, expressing human alpha-, beta(S)-, and beta(S-Antilles)-globins, had an activated vascular endothelium in their liver, lungs, and skin, as exhibited by increased activation of NF-kappaB compared with normal mice. NF-kappaB activation increased further in the liver and skin after sickle mice were exposed to hypoxia. Sickle mice had decreases in red blood cell (RBC) velocities and developed vasoocclusions in subcutaneous venules in response to hypoxia. Dexamethasone pretreatment prevented decreases in RBC velocities and inhibited vasoocclusions and leukocyte-endothelium interactions in venules after hypoxia. Dexamethasone treatment inhibited NF-kappaB, VCAM-1, and ICAM-1 expression in the liver, lungs, and skin of sickle mice after hypoxia-reoxygenation. VCAM-1 or ICAM-1 blockade with monoclonal antibodies mimicked dexamethasone by inhibiting vasoocclusion and leukocyte adhesion in sickle mice, demonstrating that endothelial cell activation and VCAM-1 and ICAM-1 expression are necessary for hypoxia-induced vasoocclusion in sickle mice. VCAM-1, ICAM-1, and vasoocclusion increased significantly 3 days after dexamethasone discontinuation, possibly explaining rebounds in vasoocclusive crises observed after withdrawal of glucocorticosteroids in sickle patients. We conclude that anti-inflammatory treatments that inhibit endothelial cell activation and adhesion molecule expression can inhibit vasoocclusion in sickle cell disease. Rebounds in vasoocclusive crises after dexamethasone withdrawal are caused by rebounds in endothelial cell activation.


Subject(s)
Anemia, Sickle Cell/physiopathology , Endothelium, Vascular/physiopathology , Hemoglobin, Sickle/genetics , Hypoxia/physiopathology , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/genetics , Animals , Blood Flow Velocity/drug effects , Dexamethasone/therapeutic use , Heart Rate/drug effects , Humans , Intercellular Adhesion Molecule-1/genetics , Mice , Mice, Transgenic , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Skin/blood supply , Vascular Cell Adhesion Molecule-1/genetics , Venules/drug effects , Venules/physiopathology
16.
Blood ; 101(10): 3953-9, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12543857

ABSTRACT

Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human alpha- and sickle beta-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-S(Antilles), NY-S/S(Antilles) (NY-S x Berk-S(Antilles)), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P

Subject(s)
Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/pathology , Endothelium, Vascular/pathology , Anemia, Sickle Cell/blood , Animals , C-Reactive Protein/genetics , Cell Adhesion Molecules/genetics , Crosses, Genetic , Cytokines/genetics , Disease Models, Animal , Humans , Inflammation/blood , Inflammation/pathology , Inflammation/physiopathology , Lipopolysaccharides/toxicity , Mice , Mice, Transgenic , RNA, Messenger/genetics , Serum Amyloid P-Component/genetics
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