Lhermitte-Duclos Disease in Pediatric Population: Report of 2 Cases.

INTRODUCTION: Lhermitte-Duclos disease (LDD), also known as dysplastic cerebellar gangliocytoma, is an uncommon disorder in children, characterized by being a slow-growing lesion of the posterior fossa, which mainly affects the granular cell layer of the cerebellar parenchyma and may be associated with other multiple hereditary hamartomas and neoplasms. CASE PRESENTATION: We report 2 cases of LDD in pediatric patients and describe clinical symptoms and radiological and histopathological characteristics. In addition, we analyzed the relation to Cowden Syndrome based on the International Cowden Syndrome Consortium Operational Criteria and the most updated guidelines by the National Comprehensive Cancer Network (NCCN Guidelines Version 1.2020). CONCLUSION: LDD is a very rare disease in childhood but should be considered in the differential diagnosis of posterior fossa lesions. LDD can mimic low-grade glial tumors or infectious diseases. Patients develop late clinical manifestations due to the slow-growing pattern, and conservative treatment with outpatient follow-up may be an option in asymptomatic children.

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions.

RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.

Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions.

miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.

Amount of Sleep, Daytime Sleepiness, Hazardous Driving, and Quality of Life of Second Year Medical Students.

OBJECTIVE: The authors describe the sleep habits of second year medical students and look for associations between reported sleep duration and depression, burnout, overall quality of life, self-reported academic success, and falling asleep while driving. METHODS: The authors conducted a cross-sectional descriptive study of two consecutive cohorts of second year medical students at a large public university in the USA. Participants completed an anonymous survey about their sleep habits, daytime sleepiness (Epworth sleepiness scale), burnout (Maslach burnout inventory), depression (PRIME MD), and perceived stress (perceived stress scale). Categorical and continuous variables were compared using chi square tests and t tests, respectively. RESULTS: Sixty-eight percent of the students responded. Many (34.3%) reported fewer than 7 h of sleep on typical weeknights, including 6.5% who typically sleep less than 6 h. Twenty-five students (8.4%) reported nodding off while driving during the current academic year. Low typical weeknight sleep (fewer than 6 h vs 6-6.9 h vs 7 or more hours) was associated with (1) higher Epworth sleepiness scale scores, (2) nodding off while driving, (3) symptoms of burnout or depression, (4) decreased satisfaction with quality of life, and (5) lower perceived academic success (all p values ≤0.01). Students reporting under 6 h of sleep were four times more likely to nod off while driving than those reporting 7 h or more. CONCLUSION: Educational, behavioral, and curricular interventions should be explored to help pre-clinical medical students obtain at least 7 h of sleep most on weeknights.

PREFABL: predictors of failure of antibiotic locks for the treatment of catheter-related bacteraemia.

BACKGROUND: Antibiotic lock (ABL) solutions can effectively treat catheter-related bacteraemia (CRB) without the need for catheter exchange. This approach does not increase secondary infectious complications. We evaluated the risk factors that contribute to failure when CRB is treated with ABLs and systemic antibiotics in paediatric haemodialysis patients. METHODS: A retrospective chart review of 72 children on haemodialysis between January 2004 and June 2006 was performed. We evaluated risk factors for ABL treatment using patients' characteristics, CRB/catheter characteristics and patients' biochemical profiles. The first CRB of each catheter was included in the statistical analysis. Our end points were outcome at 2 weeks of treatment and at 6 weeks following treatment. Compound symmetry covariance structure was employed for statistical analysis. RESULTS: We treated 149 CRB in 50 patients. The incidence was 3.4 CRB/1000 catheter days. Thirty CRB failed to be cleared with the use of ABL and systemic antibiotics at 2 weeks of treatment (30/149, 20 vs 80%, P < 0.001). Twenty-four of these catheters required exchange. Thirty-nine of the treated catheters got re-infected within the next 6 weeks (39/125, 31 vs 69%, P < 0.001). CRB aetiology was the only statistically significant independent variable for 2-week outcome (P = 0.033). Coagulase-negative Staphylococcus CRB had higher odds of being cleared at 2 weeks compared with other CRB aetiologies. For the 6-week outcome, the statistically significant independent variables in the final model included age (P = 0.048) and serum phosphorous level (P < 0.001). Younger age and higher serum phosphorous levels were independent risk factors for failure at 6 weeks with re-infection. Area under the receiver operating characteristic (ROC) curve for the model of the 2-week outcome was 0.736 with the percentage of correct predictions at 81.2%. Area under the ROC curve for the model of the 6-week outcome was 0.689 with the percentage of correct predictions at 75.5%. CONCLUSIONS: CRB can effectively be treated with ABLs and systemic antibiotics. CRB aetiology is the only independent variable of early treatment failure. Younger age and higher serum phosphorous levels are independent risk factors for re-infection at 6 weeks.

Characterization of Laminins in Healthy Human Aortic Valves and a Modified Decellularized Rat Scaffold.

Aortic valve stenosis is one of the most common cardiovascular diseases in western countries and can only be treated by replacement with a prosthetic valve. Tissue engineering is an emerging and promising treatment option, but in-depth knowledge about the microstructure of native heart valves is lacking, making the development of tissue-engineered heart valves challenging. Specifically, the basement membrane (BM) of heart valves remains incompletely characterized, and decellularization protocols that preserve BM components are necessary to advance the field. This study aims to characterize laminin isoforms expressed in healthy human aortic valves and establish a small animal decellularized aortic valve scaffold for future studies of the BM in tissue engineering. Laminin isoforms were assessed by immunohistochemistry with antibodies specific for individual α, ß, and γ chains. The results indicated that LN-411, LN-421, LN-511, and LN-521 are expressed in human aortic valves (n = 3), forming a continuous monolayer in the endothelial BM, whereas sparsely found in the interstitium. Similar results were seen in rat aortic valves (n = 3). Retention of laminin and other BM components, concomitantly with effective removal of cells and residual DNA, was achieved through 3 h exposure to 1% sodium dodecyl sulfate and 30 min exposure to 1% Triton X-100, followed by nuclease processing in rat aortic valves (n = 3). Our results provide crucial data on the microenvironment of valvular cells relevant for research in both tissue engineering and heart valve biology. We also describe a decellularized rat aortic valve scaffold useful for mechanistic studies on the role of the BM in heart valve regeneration.

Extension of ovarian tissue into the infundibulopelvic ligament beyond visual margins.

OBJECTIVE: The purpose of our study was to identify microscopic margins of the ovary and possible extension of the ovarian tissue beyond visual margins into the infundibulopelvic (IP) tissue to formulate recommendations for adequate salpingo-oophorectomy. METHODS: An observational study was conducted with thirty female patients who underwent bilateral salpingo-oophorectomy (BSO) as part of their procedure at Bethesda North Hospital between September 2007 and May 2008. RESULTS: Thirty patients underwent BSO as part of their primary procedure. Two ovaries were excluded from the study because of multiple adhesions to the pelvic wall and distortion of the IP ligaments resulting in fifty-eight ovaries accepted for study. Microscopic extension of the ovarian stroma into IP ligament beyond gross visual margins was found in eight ovaries (13.8%), five left ovaries and three right ovaries. The range of the extension was from 0.2 cm to 1.4 cm (four ovaries 0.2 cm, one 0.4 cm, two 0.8 cm and one 1.4 cm). CONCLUSION: Our study demonstrates that ovarian stroma can extend beyond grossly visual margins. To prevent residual ovarian tissue following oophorectomy surgeons need to ligate the IP ligament at or more than 2 cm proximal to the visual ovarian margins. Similar surgical principals need to be applied during oophorectomy by abdominal, laparoscopic and vaginal approach.

Prophylaxis of catheter-related bacteremia using tissue plasminogen activator-tobramycin locks.

This retrospective study was designed to investigate the effectiveness of tissue plasminogen activator-tobramycin antibiotic lock solutions (TPA/tobra ABLs) for prophylaxis of catheter-related bacteremia (CRB) in high-risk children on long-term hemodialysis. During the first 6 months (Era 1), the high-risk group was defined. These patients received TPA/tobra ABL prophylaxis after every hemodialysis treatment for the next 6 months (Era 2). The prophylaxis regimen was applied once a week for the third 6-months period (Era 3). Primary endpoints were CRB and infection-free catheter survival. There were 16,412 catheter days, and 95 cases of CRB in 43 children. The incidence of CRB was 5.8/1,000 catheter days. Significant decrease in the incidence of CRB was observed when prophylactic TPA/tobra ABL was used in the high-risk group (P = 0.0201). There was a tendency for less CRB when prophylactic ABL was applied after every hemodialysis session compared with once a week (P = 0.0947). The catheters in the high-risk group had shorter survival times than those in the average-risk group in Era 1 (P < 0.0001). However, both the overall and infection-free survival of the catheters in the high-risk group significantly improved while the patients were receiving TPA/tobra ABL prophylaxis, becoming similar to the outcomes of the catheters in the average-risk group and exhibiting statistically non-significant differences (P = 0.5571 and P = 0.9711, respectively). In conclusion, the TPA/tobra ABLs may effectively reduce the rate of CRB, and this may prolong both the overall and infection-free survival times of the catheters in the high-risk group.

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve.

Thoracic aortic aneurysm (TAA) is the progressive enlargement of the aorta due to destructive changes in the connective tissue of the aortic wall. Aneurysm development is silent and often first manifested by the drastic events of aortic dissection or rupture. As yet, therapeutic agents that halt or reverse the process of aortic wall deterioration are absent, and the only available therapeutic recommendation is elective prophylactic surgical intervention. Being born with a bicuspid instead of the normal tricuspid aortic valve (TAV) is a major risk factor for developing aneurysm in the ascending aorta later in life. Although the pathophysiology of the increased aneurysm susceptibility is not known, recent studies are suggestive of a transformation of aortic endothelium into a more mesenchymal state i.e., an endothelial-to-mesenchymal transition in these individuals. This process involves the loss of endothelial cell features, resulting in junction instability and enhanced vascular permeability of the ascending aorta that may lay the ground for increased aneurysm susceptibility. This finding differentiates and further emphasizes the specific characteristics of aneurysm development in individuals with a bicuspid aortic valve (BAV). This review discusses the possibility of a developmental fate shared between the aortic endothelium and aortic valves. It further speculates about the impact of aortic endothelium phenotypic shift on aneurysm development in individuals with a BAV and revisits previous studies in the light of the new findings.

miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its targets pentraxin-3 and dipeptidyl-peptidase 4. In vitro and in vivo, we showed that miR-29b overexpression therapy, through inhibition of pentraxin-3 and dipeptidyl-peptidase 4, could dampen the vascular inflammatory response.

Comparison of tissue plasminogen activator-antibiotic locks with heparin-antibiotic locks in children with catheter-related bacteraemia.

BACKGROUND: An accepted pathogenesis of catheter-related bacteraemia (CRB) is the seeding of microorganisms from the intraluminal biofilm of central venous catheters. Antibiotic locks (ABL) are solutions containing high concentrations of antimicrobials with or without anticoagulants that aim to destroy the biofilm. METHODS: In this study, two different ABL solutions, tissue plasminogen activator (TPA)-based and heparin-based ABL, used in conjunction with systemic antibiotics, were prospectively compared in the treatment of CRB. RESULTS: A total of 42 children on chronic haemodialysis with 11,016 catheter-days were observed for signs and symptoms of CRB over a period of 10 months. Twenty-four CRBs were diagnosed in 18 children (2.2 CRB/1000 catheter-days) and were treated with the protocol. Symptoms of CRB resolved in 83% within 48 h of treatment. None of the infected catheters required early emergent exchange or removal for poorly controlled CRB. Six children had recurrence of CRB within 6 weeks, of which four required catheter exchange. There was no specific microorganism or type of CRB that predisposed to higher recurrence rates. The mean infection-free survival of the catheters following TPA-ABL treatment was shorter than that following heparin-ABL treatment, but was not statistically significant by the log-rank test (126.8 +/- 81.6 days versus 154.5 +/- 70.4 days). CONCLUSION: Both TPA-ABL and heparin-ABL used in conjunction with systemic antibiotics can effectively clear CRB without significant late recurrence at 6 weeks. Early use of ABL for management of CRB can potentially decrease the need for catheter removal, thus salvaging vascular access sites.

Antibiotic lock solutions allow less systemic antibiotic exposure and less catheter malfunction without adversely affecting antimicrobial resistance patterns.

There are current concerns that antibiotic lock solutions (ABL) can induce antimicrobial resistance in long-term hemodialysis patients. Retrospective chart review of 157 children on hemodialysis between January 1997 and June 2006 was performed. In ERA I, only systemic antibiotics were used. In ERA II, ABL were added to systemic antibiotics when needed. In ERA III, ABL were used for treatment of all cases of catheter-related bacteremia (CRB) and for CRB prophylaxis in high-risk patients. The study includes 111,325 catheter days. The CRB incidence was 3.9 CRB/1000 catheter days. There was significant decrease for the total systemic antibiotic exposure (P = 0.0484) and the percentage of catheters lost to malfunction (P = 0.001) in ERA III. Protocol ABL exposure was associated with a trend to increased tobramycin-gentamicin resistance for gram-positive CRBs (P = 0.2586) but with improved tobramycin-gentamicin resistance for gram-negative (P = 0.0949) and polymicrobial CRBs (P = 0.1776) and improved vancomycin resistance for gram-positive CRBs (P = 0.0985). This retrospective analysis does not support the premise that ABL use will promote antimicrobial resistance in the hemodialysis population. The decreased exposure to systemic antibiotics by vigorous ABL use may even improve the antimicrobial resistance patterns in this population in the long term.

Comparison of early versus late use of antibiotic locks in the treatment of catheter-related bacteremia.

BACKGROUND AND OBJECTIVES: This retrospective study compared the effectiveness of the timing of the antibiotic locks to clear catheter-related bacteremia in children on chronic hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The early antibiotic lock group received antibiotic locks along with systemic antibiotics from the very beginning of catheter-related bacteremia. The late antibiotic lock group was given only systemic antibiotics initially, and antibiotic locks were used late in the infection if the catheter-related bacteremia could not be cleared after resolution of symptoms. RESULTS: There were 264 catheter-related bacteremias in 79 children during 6 yr of observation. Early antibiotic locks were able to clear catheter-related bacteremia and resolve the symptoms more effectively without the need for catheter exchange when compared with late antibiotic locks. A total of 84 catheter-related bacteremias required wire-guided exchange of the catheters. Late antibiotic locks required wire-guided catheter exchange more frequently than the early antibiotic locks. The post-catheter-related bacteremia infection-free survival of the catheters after wire-guided exchange were significantly longer than those of both antibiotic lock groups. Recurrence of catheter-related bacteremia within 45 d after wire-guided exchange occurred at similar rates compared with the antibiotic lock groups. CONCLUSION: Antibiotic locks are significantly more effective in clearing catheter-related bacteremia when used early in infection, diminishing the need for catheter exchange. Wire-guided exchange has a late-onset advantage for infection-free survival compared with catheter in situ treatment. The recurrence rates in the first 45 d after catheter-related bacteremia are similar regardless of the treatment strategy.

Treatment of catheter-related bacteremia with tissue plasminogen activator antibiotic locks.

This retrospective study was completed to investigate the effectiveness of tissue plasminogen activator (TPA) antibiotic locks (ABL) along with systemic antibiotics (AB) to clear catheter-related bacteremia (CRB) in children on chronic hemodialysis. There were 76 CRBs in 37 children. CRBs were successfully cleared with AB/ABL in 63/76 (83%) cases. Ten of 76 (13%) CRBs were symptomatic at 48 h of treatment. These were seven polymicrobial, two gram-negative, and one Candida CRB. 13/76 (17%) episodes required catheter exchange, and all were wire-guided exchanges. TPA-ABL/AB cleared gram-positive and gram-negative CRBs significantly better than polymicrobial CRBs (p < 0.01). The infection-free survival and the rate of recurrence at 45 days was not statistically different between the TPA-ABL/AB group and the catheter-exchange group. If CRB was symptomatic at 48 h of treatment, recurrence at 6 weeks was more frequent with persistent use of TPA-ABL/AB (p < 0.05). There were no episodes of metastatic infections, catheter malfunction from occlusion, or catheter breakdown during the course of TPA-ABL treatments. In conclusion, TPA-ABL can be safely and effectively used in the management of CRB, increasing the probability of catheter survival and preserving the vascular access site. With the exception of polymicrobial CRB, there is no disadvantage in using TPA-ABL/AB over catheter exchange, as the infection-free survival and the rate of recurrence are comparable.

Prevention of catheter-related bacteremia in pediatric intestinal transplantation/short gut syndrome children with long-term central venous catheters.

Catheter-related bacteremia (CRB), along with liver failure is the leading cause of mortality and morbidity in parenteral nutrition dependent children. Immunosuppressant therapy following transplantation increases the risk of CRB. Previous reports in pediatric cancer patients have described the use of antibiotic lock solutions (ABL) for prophylaxis of CRB. In our institution, we evaluated five children (ages between one and four yr old), three with intestinal transplantation and two with short gut syndrome, who were high risk for recurrent CRB defined by their incidence of bacteremias in the observation period (>2 CRB/six months or life-threatening CRB). These children received the prophylactic ABL protocol with tobramycin-tissue plasminogen activator, four h per day, on alternating ports for six to eight months. Each patient was his/her own historical control. We observed decreased incidence of CRB's (p < 0.05), days of hospitalization due to CRB's (p < 0.0001), the days of intensive care admissions due to CRB (p < 0.0001), as well as the total days of systemic antibiotic exposure (p < 0.001). Catheter survival during the ABL era was longer but not reaching statistical significance. There was no advantage in removing and later replacing the catheter to wire-guided exchange while on systemic antibiotics. One patient presented with break-through bacteremia, septic shock and died. None of the catheters were lost to occlusion/malfunction. ABL did not induce an increased resistance to tobramycin. These preliminary findings suggest that ABL can be used safely and effectively in parenteral nutrition dependent children with long-term central venous catheters.

Pielonefritis enfisematosa: reporte de dos casos y revisión de la literatura / Emphysematous pyelonephitis: report of two cases and review

Presentamos dos pacientes mujeres diabéticas con Pielonefritis enfisematosa bilateral atendidas en nuestro hospital. Ambas tenían más de 50 años de edad. El diagnóstico se realizó por la presencia de gas a nivel de amos riñones, en la tomografía axial computarizada (TAC) abdominal. Una de las pacientes fue sometida a nefrectomía bilateral y la otra a nefrectomía derecha. Ambas pacientes tuvieron mala evolución pese al tratamiento antibiótico y quirúrgico. Debido a su alta mortalidad hacemos énfasis en el diagnóstico y tratamiento precoz.

Hiperoxaluria primaria con pancitopenia: a propósito de un caso / Primary hyperoxaluria and pancitopenia: A case report

Se presenta el caso de un varón, de 15 años de edad, con diagnóstico de litiasis renal desde la infancia que evolucionó a Insuficiencia Renal Crónica, requiriendo hemodiálisis. Seis meses antes del reporte se agregan dolores articulares, con signos flogósicos en rodilla derecha, compromiso progresivo del estado general, pérdida de peso y anemia. Al examen físico se encuentra a un paciente emaciado, pálido, con múltiples adenopatías cervicales, y presencia de hepato-esplenomegalia. Se realizan exámenes evidenciándose: pancitopenia, con mayor compromiso de la serie roja (hemoglobina 7,3mg/dL, leucocitos 2600/uL, y plaquetas 123 000/uL). Los valores de transaminasas y bilirrubinas fueron normales así como los dosajes de Fierro, Transferrina, Acido Fólico y Vitamina B12. La ecografía abdominal revela riñones calcificados y atróficos y los Rx de abdómen demuestran nefrocalcinosis y litiasis renal. La biopsia de medula ósea evidenció un extenso depósito de cristales de oxalato de calcio, dispuestos en forma radiada, con casi completa obliteración de la medula ósea con un número variable de células multinucleadas y fibrosis moderada. El aspirado de medula ósea no mostró cristales de oxalato de calcio. este reporte hace una revisión sobre hiperoxaluria primaria, y resalta la importancia de reconocer la enfermedad como causa de falla renal en un paciente con historia clínica de litiasis renal y nefrocalcinosis.