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Background: This review identifies the predictors of late mortality and heart transplantation that remain relevant in the contemporary population of patients with a Fontan circulation, focusing on the potential impact of post-Fontan morbidities on the late outlook of these patients. Methods and Results: A total of 1561 patients who had survived the Fontan operation in Australia or New Zealand from 1975 to 2018 were included in this review. Over a median duration of 11.4 years, there was a total of 117 deaths (7%) and 32 heart transplantations (2%). Freedom from death and heart transplantation at 10, 20 and 35 years post Fontan surgery were 94% (95% CI 93–95%), 87% (95 %CI 85–90%) and 66% (95 %CI 57–78%) respectively. Being male, having an atriopulmonary Fontan, pre-Fontan atrioventricular valve intervention, or prolonged pleural effusions post Fontan were predictive of late death or heart transplantation. However, time-dependent variables such as the development of atrial arrhythmia, protein/losing enteropathy or late ventricular dysfunction were stronger predictors of the same outcome. Patients who developed a time-dependent risk factor had a freedom from death and heart transplantation rate of 54% (95 %CI 43–66) at 15 years and 44% (95 %CI 33–57) at 25 years post Fontan. However, 95% (95 %CI 91–99) of patients without any of the identified risk factors were free from death or heart transplantation rate at 25 years post Fontan. Conclusion: In conclusion, the occurrence of post-operative complications such as PLE, arrhythmia and ventricular dysfunction will likely precede the late demise of these patients.

The isolation and quantification of ethanolamine containing lipids from animal tissues may expose neutral lipid extracts to acidic or basic conditions during chromatographic separations or derivatization chemistry. While investigating the acid- and base-catalyzed production of anandamide in chromatographic fractions of rat brain extracts not containing anandamide, we observed that O,N-acyl migrations are facile. O,N-acyl migrations are well documented in synthetic organic chemistry literature, but are not well described or recognized with regard to methods in lipid isolation or lipid enzyme studies. We report here the synthesis and characterization of O- and N-acyl (palmitoyl- or arachidonoyl-)ethanolamines. Their rearrangements in base and acid are quantified by liquid chromatography–electrospray ionization mass spectrometry. The rearrangements proceed through a cyclic intermediate that is also formed during chemical reactions commonly used for derivatization of acylethanolamines for gas chromatography–mass spectrometry. The isolation and characterization of N- or O-acylethanolamines and their enzymatic formation requires awareness and consideration of the proclivity of these compounds to chemically rearrange.—Markey, S. P., T. Dudding, and T-C. L. Wang. Base- and acid-catalyzed interconversions of O-acyl- and N-acyl-ethanolamines: a cautionary note for lipid analyses. J. Lipid Res. 2000. 41: 657–662.

Background: Time is a valuable commodity that impacts hospital flow, patient experience and economic resources. This study aims to identify factors that affect daily treatment time over a course of radiation therapy (RT) in patients who underwent adjuvant breast RT., Methods: In all adjuvant breast/chestwall RT patients treated from October 2017 to May 2018, daily set-up, beam delivery time, and overall treatment times were collected. A multivariable linear regression analysis was conducted to identify significant predictive factors related to treatment time. A general linear regression model was used to determine whether there was a learning curve effect throughout the course of treatment that decreased treatment time as patient and staff familiarity with the treatment procedure increased., Results: A total of 567 patients were included with a median age of 61 years. The average overall treatment time for 2-field and 4-field RT was 8.3 (SD 2.4) and 13.1 (SD 5.6) minutes, respectively. Factors that significantly increased overall treatment times in patients prescribed 2-field RT were: bilateral techniques, breath-hold (BH) techniques, prone techniques (PR), reverse decubitus techniques (RD), wide tangents techniques, the use of bolus and number of segments delivered. (p < 0.05). Factors that significantly increased overall treatment times in patients who received 3-field and 4-field RT were: wide tangents volumes, a higher number of monitor units (MUs), bilateral techniques and BH techniques (p < 0.05). Older patients (≥60) who underwent 3-field and 4-field RT demonstrated a statistically significant increase in set-up time (p < 0.0001). Overall treatment time decreased from 10.0 to 9.3 min over the course of treatment, suggesting a minor learning curve (p = 0.009)., Conclusion: The use of bilateral RT, BH, PR, RD, wide tangents, bolus, increasing treatment volumes, and increasing plan complexity were associated with increased treatment times. Future research should quantify the impact of other factors (BMI, mobility, patient care assessments, and imaging protocols) and utility of technological tools (time-predicting models, machine learning tools, and operations research models) on treatment time to optimize RT scheduling and improve resource management., (Copyright © 2023. Published by Elsevier Inc.)

Recent technological advances continue to expand the universe of big data in biomedicine along the four axes of variety, veracity, volume, and velocity, fueling innovations in research and discovery while transforming care delivery. These advances allow quantitative capture of multimodal health, behavioral, social, and environmental data from n-of-all in near real-time to support the development of new therapies and personalization of treatment decisions for the n-of-one. Application of advanced analytical methods, including artificial intelligence and machine learning, to these modern data assets can greatly propel our understanding of health and disease, accelerating the development of safer and more effective anticancer therapies. In this perspective, we rationalize the creation of a universally accessible digital highway system as a foundational infrastructure to enable data fluidity in an equitable manner. An interoperable and integrated digital inter-state highway can facilitate efficient derivation of insights from biomedical big data to improve health outcomes and ensure that the U.S. remains at the leading-edge innovations in technology, advanced analytics, and precision medicine., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: To describe the clinical and epidemiological characteristics of children with coronavirus disease 2019 (COVID-19) in the state of Negeri Sembilan, Malaysia in the setting of mandatory hospital isolation and quarantine for all confirmed cases., Methods: A multi-centre, retrospective observational study was performed among children aged ≤12 years with laboratory-proven COVID-19 between 1 February and 31 December 2020., Results: In total, 261 children (48.7% males, 51.3% females) were included in this study. The median age was 6 years [interquartile range (IQR) 3-10 years]. One hundred and fifty-one children (57.9%) were asymptomatic on presentation. Among the symptomatic cases, fever was the most common presenting symptom. Two hundred and forty-one (92.3%) cases were close contacts of infected household or extended family members. Twenty-one (8.4%) cases had abnormal radiological findings. All cases were discharged alive without requiring supplemental oxygen therapy or any specific treatment during hospitalization. The median duration of hospitalization was 7 days (IQR 6-10 days). One (2.1%) of the uninfected guardians accompanying a child in quarantine tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) upon discharge., Conclusions: COVID-19 in children was associated with mild symptoms and a good prognosis. Familial clustering was an important epidemiologic feature in the outbreak in Negeri Sembilan. The risk of transmission of SARS-CoV-2 from children to guardians in hospital isolation was minimal despite close proximity., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The adoption of hypofractionated radiotherapy (HFRT) into clinical practice varies widely despite randomized trials and guidelines supporting its equivalence to conventional fractionated radiotherapy (CFRT) for certain patient populations. We assessed the use of HFRT at a single institution from 2011 to 2018, as well as time-savings calculations., Patients and Methods: A retrospective cohort study was conducted for patients with breast cancer receiving adjuvant radiotherapy by HFRT or CFRT. Trends in HFRT use (≤ 16 fractions) were stratified according to 4 subgroups: tangential breast RT, locoregional breast RT, tangential chest wall RT, and locoregional chest wall RT. Treatment time savings were approximated using the institutional median treatment time., Results: A total of 5190 patients were included. HFRT use in all subgroups increased from 2011 to 2018. Tangential breast HFRT alone increased from 62.2% in 2011 to 96.9% in 2018. Locoregional breast HFRT and tangential chest wall HFRT use increased from less than 10% in 2011 to 76.2% and 76.9% in 2018. In locoregional chest wall RT, HFRT use of 44.9% was observed in 2018. Increased use of locoregional HFRT was mainly due to institutional policy changes. Time-savings calculations showed that 4002 hours of treatment or an additional 1402 HFRT courses could have been administered if all patients received HFRT., Conclusion: The use of HFRT at our center increased in all patient subgroups. More evidence and guidelines for patients receiving chest wall or locoregional HFRT are required because the use of HFRT remains low in these patient cohorts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

While aerobic exercise training (AET) has generally been shown to improve 6-min walk test (6MWT) distance (6MWD) in patients with pulmonary hypertension (PH), a substantial number of patients appear to adapt differently, with minimal or even negative changes in 6MWT distance being reported., Purpose: To compare post-aerobic exercise training adaptations in cardiorespiratory functional capacity across three groups of patients with PH: those with high (HI), low (LI) and negative (NEG) post-training increases in 6MWD., Methods: Participants were 25 females (age 54 ± 11 years; BMI 31 ± 7 kg/m 2 ) who completed a vigorous, 10-week, thrice weekly, supervised treadmill walking exercise program. Cardiopulmonary exercise tests (CPET) and 6MWT were completed before and after training. Ten of the 25 participants were classified as HI (range = 47-143 m), 11 were classified as LI (range = 4-37 m) and 4 were classified as NEG (range = -17 to -53 m)., Results: Peak CPET duration, WR and time to anaerobic threshold (AT) were significantly higher (p < 0.05) after training in both the LI and HI groups but not in the NEG group. There was a significant improvement in VE/VCO 2 (p = 0.042), PETCO 2 (p = 0.011) and TV (p = 0.050) in the HI group after training, but not in the NEG or LI group., Conclusion: These findings suggest that sustained ventilatory inefficiency and restricted respiratory buffering may mediate exercise intolerance and impede the ability to adapt to exercise training in some patients with PH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Ventriculoperitoneal shunt infections are common and result in significant morbidity, mortality, and health care expenditure. The objective of this study was to create an evidence-based perioperative shunt infection prevention protocol and analyze its efficacy by comparing the incidence of shunt infection before and after implementation at one institution., Methods: A perioperative ventriculoperitoneal shunt surgery protocol was developed based on a systematic literature review with the goal of reducing infection rates. Patients undergoing shunt surgery at Upstate Medical University Hospital, from before and after implantation of the perioperative shunt surgery protocol, were retrospectively analyzed and compared. Retrospective data collection included shunt infection incidence as a primary outcome and clinical features of patients from both cohorts., Results: The pre-protocol and post-protocol cohorts included 226 and 285 patients, respectively. Twenty (8.8%) pre-protocol shunt infections and 16 (5.6%) post-protocol shunt infections were identified (P = 0.156). The relative risk of shunt infection between cohorts was 0.97 (95% confidence interval: 0.92-1.02)., Conclusions: Although shunt infection rates pre-protocol and post-protocol were not significantly different, a trend toward fewer shunt infections was observed with protocol implementation. Suboptimal compliance at our institution may have limited accurate assessment of protocol efficacy. Similar future studies may benefit from objectively assessing protocol compliance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The need for permanent pacing has been identified as a predictor of poor outcomes in the late survivors of Fontan surgery. However, it is not clear if the need for a pacemaker is a surrogate marker of a declining Fontan state, or if pacing is deleterious to the Fontan circulation., Objectives: We sought to compare the long-term outcomes of propensity-matched Fontan patients with and without a permanent pacemaker., Methods: Patients who have survived Fontan completion with a documented history of cardiac arrhythmia were identified from the Australia and New Zealand Fontan Registry. Pacemaker insertion details, cardiac function and electrophysiological data were obtained for the patients with a permanent pacemaker. Survival analysis was performed with propensity score matching to compare late survival and outcomes in patients with versus without a pacemaker., Results: There was a total of 310 patients with a history of cardiac arrhythmia, of which 126 (41%) had a permanent pacemaker. After propensity-score matching, 99 pairs were generated (n = 198). Patients with a permanent pacemaker had a higher risk of death (HR 3.32 95% CI 1.60-6.90, p = 0.001) and death or transplantation (HR 3.55 95% CI 1.87-6.73, p < 0.001). Patients who were only paced atrially were not at a significantly increased risk of death or transplantation. However, patients who were ventricular paced >50% of the time were much more likely to encounter late death or transplantation (HR 3.82 95% CI 1.64-8.95, p = 0.002)., Conclusions: Having a permanent pacemaker and needing ventricular pacing is likely associated with an increased risk of death and transplantation in patients with a Fontan circulation., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: Nearly 33,600 people die each year in the United States as a result of gunshot wounds (GSWs). Penetrating craniocerebral GSWs are often fatal with a nearly 70% death rate at the scene of the trauma. Overall combined mortality rate for patients who die at the scene or at the hospital is almost 91%. Poor outcome is associated with initial low Glasgow Coma Scale score and bihemispheric and transventricular gunshot trajectory. We summarize current understanding in management, prognostic factors, and survival outcomes in patients with a penetrating GSWs to the head. We report a patient with return to full function despite bihemispheric, multilobar involvement. Full function is defined here as ability to return to previous work and perform activities of daily living., Case Description: A 33-year-old man sustained a GSW to the head under unknown circumstances. On initial presentation, he had a Glasgow Coma Scale score of 15. He was verbalizing and communicating but was amnestic for the event. From a left frontal entry wound, the bullet traversed both frontal lobes of the brain reaching the right frontal-parietal junction. Physical examination and vital signs were normal. Appropriate surgical and medical management resulted in complete recovery., Conclusions: Craniocerebral GSWs have a high mortality rate and usually require aggressive management. Evaluation of most GSWs requires appropriate imaging studies followed by proactive treatment against infection, seizure, and increased intracranial pressure. Surgical intervention is often necessary and ranges from local wound débridement to craniectomy, decompression, and wound exploration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Radiation oncology Care Plans are predefined procedures that outline a patient's radiation therapy (RT) path of care. Care Plans allow for standardization of centre-specific procedures and workflows, thereby laying the foundation for autoforwarding of RT tasks and mandatory information capture via assessment forms. However, the integration of Care Plans at a large centre with established workflows is challenging and requires a redesign of numerous processes across all disciplines and site groups in an electronic data management system. Here, we describe the development and implementation experience of IQ Script enabled MOSAIQ Care Plans at the Odette Cancer Centre between summer 2014 and summer 2016., Methods: A core Care Plan development group was formed that included membership from key stakeholders in RT, oncology, and physics. Care Plan pre-development planning was performed in three phases that included (1) collection and organization of all site and technique-specific protocols and procedures, (2) creation of workflow process maps and intimate discussions with potential stakeholders regarding automation and information capture, and (3) integration of design concepts into the IQ Script enabled Care Plans authoring framework. Following pre-planning, IQ Script enabled Care Plans authoring was performed on a test server with standardized naming conventions and tracking sheets for all IQ scripting triggers and events. Care Plan workflows were tested, and a senior therapist transferred individual Care Plans to the production server. Care Plans were then released gradually over a 1-year period, starting with pilot sites with the highest site group member buy-in. A post-implementation survey was performed to assess end-user feedback., Summary and Conclusions: IQ Script enabled Care Plans resulted in standardization of clinical processes including patient booking, autoforwarding of RT tasks, and mandatory information capture. Survey results indicated stakeholder satisfaction with the implementation process. Comments for improving Care Plans included changes to computed tomography simulation assessment forms for more robust capture of dose prescription and fractionation. Overall, the transition to Care Plans allowed our center to enhance information documentation, streamline our RT workflow, and ultimately improve the accuracy and efficiency of patient care. For the radiation oncologist, the use of Care Plans has also eliminated the use of another software system in which to request planning., (Copyright © 2018. Published by Elsevier Inc.)

Background: The HexaPOD has been developed to correct for errors in six degrees of freedom (6DOF), which enables it with the potential to improve setup accuracy. This is critical in hypofractionated head and neck (H&N) stereotactic body radiation therapy (SBRT) plans, which have highly conformal dose distributions and close proximity of critical normal structures., Purpose: The purpose of the study was to investigate whether using the HexaPOD to correct for error in 6DOF will increase setup accuracy for H&N SBRT patients., Methods and Materials: For each of the 20 SBRT H&N patients in this study, two sets of global computed tomography scans and cone beam computed tomography matches were performed for the first and last fraction of each patient's treatment. One of the global matches included corrections for rotations and the other did not. Next, sub-regions of interest, based on bony landmarks, were identified for each patient and local registrations were performed to match these sub-regions of interest to determine local sub-region errors in the global registration. The differences in local error, with and without rotations, were examined to determine whether the residual local setup errors were significantly different., Results: T-test results demonstrate a statistically significant difference in local error when correcting for rotations vs. not, in all 6DOF. When examining the actual magnitude of residual error reduction using three-dimensional vectors of the average translational differences, an average reduction of 0.9 mm is observed when 6DOF corrections are applied., Conclusions: Residual setup errors in each of the 6DOF were statistically significant; however, the magnitude depicts a very small reduction in residual error <1 mm. Clinically, this makes a very small difference because the planning target volume (PTV) presumably covers an expansion of 3-5 mm., (Copyright © 2017 Canadian Association of Medical Radiation Technologists. Published by Elsevier Inc. All rights reserved.)

Central nervous system mucormycosis is an aggressive fungal infection often ending in fatality. The usual circumstance is an immunocompromised individual presenting with rapidly progressive rhinocerebral involvement. An extremely rare variant of central nervous system mucormycosis isolated to the basal ganglia in an immunocompetent intravenous drug user is detailed in this manuscript. The patient was aggressively treated with aspiration of the fungal abscess and long-term intravenous antifungal agents., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Penetrating traumatic brain injuries (TBIs), with the exception of gunshot wounds, are relatively rare occurrences and affect all ages. Clinical presentation varies depending on the mechanism of the injury. Prompt surgical treatment is often indicated and is influenced by patient clinical examination, anatomic trajectory, and the penetrating object's size, shape, and velocity., Methods: We present 3 cases of penetrating TBI. Their similarities and differences affecting operative and medical management are compared. We relate our experience with management of penetrating intracranial foreign bodies in general and discuss the relevant literature., Results: Our first case was a 12-year-old male who presented with a self-inflicted transfacial transcranial injury by a crossbow. The arrow passed through the left sphenoid and cavernous sinus and exited through the parietal calvarium. Our second case was a 37-year-old man with a transoral intracranial stab wound by a knife. In our third case, we present a 46-year-old male who accidentally fired a nail gun into his right ear. The nail traversed the posterior wall of the external auditory canal into the posterior fossa, ending in the cerebellar vermis. Each case was treated with craniotomy and foreign body removal. All resulted in good outcomes after surgical treatment., Conclusion: Surgery in penetrating TBI is the treatment of choice. Our cases demonstrate how certain principles applied to individual patient scenarios may optimize clinical results. Severity of the injury and operative approach are among the most important considerations to achieve the best patient outcomes., (Published by Elsevier Inc.)

Dermoid cysts are rare, benign intracranial lesions commonly located in the posterior fossa. We describe a uniquely located dermoid cyst in the foreman ovale resected via a combined pterional and transzygomatic approach., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Tissue stiffness is tightly controlled under normal conditions, but changes with disease. In cancer, tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the cells themselves soften. Within the past decade, and particularly in the last few years, there is increasing evidence that the stiffness of the extracellular matrix modulates cancer and stromal cell mechanics and function, influencing such disease hallmarks as angiogenesis, migration, and metastasis. This review briefly summarizes recent studies that investigate how cancer cells and fibrosis-relevant stromal cells respond to ECM stiffness, the possible sensing appendages and signaling mechanisms involved, and the emergence of novel substrates - including substrates with scar-like fractal heterogeneity - that mimic the in vivo mechanical environment of the cancer cell.

Background: DNase (Pulmozyme) effectiveness in cystic fibrosis treatment is in some cases limited by its inability to access DNA trapped within bundles in highly viscous fluids that also contain actin. Dissociating DNA-containing bundles using actin depolymerizing agents and polyanions has potential to increase DNase efficacy., Methods: Fluorescence measurements of YOYO-1 and a rheological creep-recovery test quantified DNA content and viscoelasticity in 150 sputum samples from adult CF patients and their susceptibility to fluidization by DNase1, alone and in combination with gelsolin and poly-aspartate (p-Asp). Fluidization of sputum by these agents is compared to their capacity to increase antibacterial activity in sputum, measured using a luminescent Pseudomonas aeruginosa strain and a bacterial killing assay., Results: The polyanion p-Asp (1-50 μg/g of sputum), the actin severing protein gelsolin (10-90 μg/g) and their combination enhance the ability of DNase 1 to increase the abnormally low mechanical compliance of CF sputum and to promote bacterial killing in sputum by colistin and tobramycin, two antibiotics commonly used to treat CF., Conclusions: Addition of low concentrations of p-ASP or gelsolin can increase the therapeutic value of Pulmozyme (DNase 1)., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to describe the effectiveness of local vascularized flaps for the repair of various skull base defects., Methods: We analyzed a cohort of 138 patients undergoing skull base surgery in a retrospective review of all head and neck surgical oncology cases done at a major tertiary care center between 2005 and 2008., Results: Eighteen patients met our inclusion criteria, requiring local vascularized flap or free graft reconstruction. The mean age of our patients was 39.7 years, with an equal distribution of men and women. The mean follow-up was 16.4 months. Neoplastic causes accounted for the majority of skull base lesions (11/18 cases), followed by traumatic lesions (5/18 cases). Other causes of lesions in our study included encephalocele (1 case), and infection (1 case). The most common location for skull base defects in our study was the anterior skull base (14/18 cases). Other locations included the infratemporal fossa (1 case). The mean size of defect repaired was 4.46 cm, and the mean area was 12.85 cm(2). Repair with local vascularized tissue flaps resulted in a success rate of 87.5%. Moreover, our meningitis and cerebrospinal fluid leak rate was only 11.1% after repair., Conclusion: Local vascularized flap utilization in open reconstruction of the skull base has an excellent success rate, with no second donor site morbidity. The success is comparable to free tissue transplant reconstruction and should be in the armamentarium of every neurosurgeon and skull base surgeon. Appropriate incision planning and preoperative evaluation and selection is essential for the success of this type of reconstructive technique., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: In vivo electronic portal imaging device (EPID) dosimetry is an advanced imaging technique that can obtain patient-specific dose data for quality assurance purposes. However, clinical integration of this technique remains a challenge. This study evaluates the impact of implementing an in vivo EPID technique into the treatment delivery workflow for head and neck cancer (HNC) patients in a large cancer centre setting., Materials/methods: Intensity-modulated radiation therapy treatment delivery was simulated on a phantom for 10 HNC cases with and without in vivo EPID dosimetry. Investigators performed the EPID technique by using a preliminary protocol written by medical physicists. Process maps were created to illustrate changes in treatment delivery workflow., Results: Treatment delivery times increased by an average of 2.34 minutes (P = .0006) when the EPID technique was used. Factors that increased treatment times included the time for storing captured EPID data, adjustment of the imaging panel position as a function of field size, and an inability to use automatic field sequencing when acquiring images., Conclusions: The involvement of stakeholders in protocol development allows for the identification of usability issues and staff training needs. Findings from this study have identified limitations of the in vivo EPID technique that may negatively impact treatment delivery workflow. Efficiencies within in vivo EPID dosimetry systems can be improved by enabling automatic field sequencing with automatic image-saving capabilities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation.

To further unravel the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), we performed high-resolution array comparative genomic hybridization on diagnostic specimens from 47 children with T-ALL and identified monoallelic or biallelic LEF1 microdeletions in 11% (5 of 47) of these primary samples. An additional 7% (3 of 44) of the cases harbored nonsynonymous sequence alterations of LEF1, 2 of which produced premature stop codons. Gene expression microarrays showed increased expression of MYC and MYC targets in cases with LEF1 inactivation, as well as differentiation arrest at an early cortical stage of thymocyte development characterized by expression of CD1B, CD1E, and CD8, with absent CD34 expression. LEF1 inactivation was associated with a younger age at the time of T-ALL diagnosis, as well as activating NOTCH1 mutations, biallelic INK4a/ARF deletions, and PTEN loss-of-function mutations or activating mutations of PI3K or AKT genes. These cases generally lacked overexpression of the TAL1, HOX11, HOX11L2, or the HOXA cluster genes, which have been used to define separate molecular pathways leading to T-ALL. Our findings suggest that LEF1 inactivation is an important step in the molecular pathogenesis of T-ALL in a subset of young children.

Elderly fall has become an issue of great public health concern and typically important to the aging population in Hong Kong because it carries a great burden to the individuals and the society. More accurate information about environmental risk factors to falls among the elderly could alleviate if not overcome the situation. Conventional approaches to elderly falls were mainly conducted using statistical methods and clinical tests on falls. This study employs ecological and associative analysis using the geographic information systems (GIS) technology to visualize spatial association of falls and environmental factors. The study identified eleven hot spots of elderly falls with unique environmental characteristics. Amongst various environmental attributes, busy streets and junctions, outdoor markets, and refuse collection points, exhibit a strong spatial relationship with the hot spots. The results have demonstrated that GIS can offer an excellent synergic platform to explore the role of space and pattern in fall occurrences.

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with poorly characterized genetics. We performed high resolution comparative genomic hybridization on 25 MCC specimens using a high-density oligonucleotide microarray. Tumors frequently carried extra copies of chromosomes 1, 3q, 5p, and 6 and lost chromosomes 3p, 4, 5q, 7, 10, and 13. MCC tumors with less genomic aberration were associated with improved survival (P=0.04). Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions. Three regions of genomic alteration were of particular interest: a deletion of 5q12-21 occurred in 26% of tumors, a deletion of 13q14-21 was recurrent in 26% of tumors and contains the well-characterized tumor suppressor RB1, and a previously unreported focal amplification at 1p34 was present in 39% of tumors and centers on L-Myc (MYCL1). L-Myc is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in the closely related small cell lung cancer. Normal skin showed no L-Myc expression, whereas 4/4 MCC specimens tested expressed L-Myc RNA in relative proportion to the DNA copy number gain. These findings suggest several genes that may contribute to MCC pathogenesis, most notably L-Myc.

The shortage of cadaveric donors for simultaneous pancreas-kidney transplantation has prompted the use of cadaveric organs from pediatric donors. The long-term outcome and its impact on overall long-term survival are unknown. A total of 680 recipients receiving cadaver Simultaneous pancreas-kidney (SPK) transplantation from pediatric and adult donors between July 1986 and September 2001 were analyzed and compared. Ten-year kidney and pancreas graft survival for SPK transplantation from donors aged <18 years (n = 142) were 80% and 72%, respectively, compared to 61% pancreas and kidney graft survival from donors > or =18 years of age (n = 538; p = 0.03 and 0.05, respectively). Five years post-transplant, blood glucose, HbA1c and creatinine clearance were significantly better in recipients from pediatric donors (85.3 +/- 13 mg/dL, 5.5 +/- 3.5% and 65.6 +/- 16 mL/min, respectively), compared to recipients from adult donors (95.1 +/- 29 mg/dL, 5.9 +/- 3.5% and 58.3 +/- 17 mL/min; p = 0.001, 0.01 and 0.002, respectively). Causes of graft failure for kidney and pancreas transplants were similar between the two groups. No statistically significant difference was observed in patient survival between recipients from pediatric donors compared to adult donors (85% vs. 76%, p = 0.29). When recipients of SPK from pediatric donors were stratified according to age (3-11 years and 12-17 years) and compared, no difference in kidney or pancreas graft survival was observed (kidney 76.4% vs. 81.3%, p = 0.15; pancreas 75% vs. 76%, p = 0.10, respectively). Pediatric donors represent a valuable source of organs, providing excellent short- and long-term outcomes. Wide utilization of pediatric organs will substantially increase the donor pool.

Owing to the shortage of organ donors, there is renewed interest in donation after cardiac death (DCD), formerly referred to as nonheart-beating donation. From January 1984 until August 2000, 382 renal transplants were performed from DCD donors. These were compared with 1089 renal transplants performed from donation after brain death (DBD) donors. The mean warm ischemic time in DCD donors was 16.5 min. There was no statistical difference in cold ischemic time, rate of primary nonfunction, or graft loss in the first 30 days after transplantation. The rate of delayed graft function (DGF) was higher for DCD donors (27.5% vs. 21.3%; p = 0.016) and discharge creatinine was higher in DCD donors (1.92 mg/dL vs. 1.71 mg/dL; p = 0.001). There was no statistical difference in the 5-, 10-, or 15-year allograft survival when DCD donors were compared with DBD donors (64.8%, 44.8%, 27.8% vs. 71.3%, 48.3%, 33.8%; p = 0.054). Likewise, no statistical difference in the rate of technical complications was seen. Our long-term data indicate that the results of renal transplantation from DCD donors are equivalent to long-term allograft survival from DBD donors despite an increase in the rate of DGF. Organ procurement organizations, transplant centers, and hospitals should work to expand the implementation of DCD policies., (Copyright 2004 Blackwell Munksgaard)

Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.

We analyzed the expression of high in normal-1 (HIN-1), a putative breast tumor suppressor gene, and uteroglobin related protein-1 (UGRP-1), a homologue of HIN-1, in adult and developing mouse tissues. Highest HIN-1 and UGRP-1 expression is detected in the lung, while lower level HIN-1 expression is also detected in the stomach, heart, small intestine, uterine and mammary glands. The expression of both genes was detected only at E17.5-18.5 and the HIN-1 messenger RNA was localized to the epithelia of the trachea, bronchi, and uterine glands. The expression of HIN-1 is up-regulated during retinoic acid induced differentiation of bronchial epithelial cells. We also identified two putative Drosophila HIN-1 homologues. The expression of HIN-1 is restricted to terminally differentiated airway epithelial cells in vivo and in vitro implicating HIN-1 in the acquisition or maintenance of terminally differentiated epithelial phenotype., (Copyright 2002 Elsevier Science Ireland Ltd.)

It is well known that cardiovascular risk factors and dyslipidemia along with obesity can be identified early in life. Serum lipids and lipoproteins influence skin vessel reactivity in adults. The purpose of this study was to investigate the cutaneous microcirculation and its correlation to dyslipidemia in obese children. Thirty-four obese children and an equal number of age- and sex-matched healthy children were enrolled in this study. Laser Doppler flowmetry and dynamic capillaroscopy were performed to measure total cutaneous blood flow and nutritional blood flow, respectively. A significantly higher cutaneous baseline flow and peak flow after a 1-min arterial occlusion was noticed in obese group as compared to normal control. Results of dynamic capillaroscopy revealed values of resting capillary blood cell velocity that did not differ from controls but a significantly lower peak CBV after a 1-min arterial occlusion in obesity. Plasma lipids examination showed a high triglycerides and low high density lipoprotein cholesterol levels in obesity. Pearson analysis detected no significant correlations between pCBV, baseline flow and peak flow and dyslipidemia in obesity. These results may be explained by the fact that the duration of dyslipidemia in our study population was not long enough to cause vascular damage or the dyslipidemia was not pronounced enough to have an impact on skin vessel activity tests. It is also possible, that the combination of methods used in the present study was not sensitive enough to detect an existing correlations between flow values and high triglycerides/low HDL-cholesterol values in the obese group. Our results suggest that all the responses of the cutaneous microcirculation were mainly due to physiological compensatory rather than pathological reactions in young obese children. The results of cutaneous microcirculatory assessment in obese children provide follow-up parameters for assessing the risk of cardiovascular diseases later in life.

Myc family oncoproteins function as sequence-specific transcription factors that are believed to regulate the expression of genes governing cellular growth, differentiation, and programmed cell death. Activities of Myc are countered by those of Mad and Mxi1, two related members of the Myc superfamily. Mad and Mxi1 compete with Myc for common elements and interact with putative transcriptional repressors. While the precise role of the Myc superfamily in cutaneous biology remains to be determined, findings from a number of organ systems suggest that the regulated expression and function of its members are intimately correlated with proper development and physiology. Reviewed here are current data on Myc superfamily function with references where relevant to cutaneous processes with the ultimate goal of providing a framework upon which these proteins can be exploited in gene therapeutic approaches for diseases of the skin, including neoplasia.

A selective reproducible high-performance liquid chromatographic assay for the simultaneous quantitative determination of the antimalarial compound artemether (ARM), dihydroartemisinin (DQHS) and artemisinin (QHS), as internal standard, is described. After extraction from plasma, ARM and DQHS were analysed using a Lichrocart/Lichrosphere 100 CN stainless-steel column and a mobile phase of acetonitrile-0.05 M acetic acid (15:85, v/v) adjusted to pH 5.0, and electrochemical detection in the reductive mode. The mean recovery of ARM and DQHS over a concentration range of 30-120 ng/ml was 81.6% and 93.4%, respectively. The within-day coefficients of variation were 0.89-7.01% for ARM and 3.45-8.11% for DQHS. The day-to-day coefficients of variation were 2.06-8.43% and 3.22-6.33%, respectively. The minimum detectable concentration for ARM and DQHS in plasma was 2.5 and 1.25 ng/ml for both compounds. The method was found to be suitable for use in clinical pharmacological studies.

Delta-9-Tetrahydrocannabinol (delta-9-THC) in doses of 0.01, 0.05, 0.1, 0.5, and 1.0 mg/kg, i.v. was administered to adult rabbits previously adapted to the testing chamber. Additionally, a group of rabbits not adapted to any part of the testing regimen was administered 1.0 mg/kg delta-9-THC. Cortical and hippocampal electroencephalographs as well as postural and activity behaviors of the unrestrained animals were recorded. In the adapted rabbits, there were dose-related increased in cortical voltage output, disruption of hippocampal theta rhythm and cortical polyspike bursts. Behaviorally, there was a dose-related tendency for standing and exploration to decrease, and at 0.5 and 1.0 mg/lh, delta-9-THC produced sprawling. In the nonadapted rabbits, administration of 1.0 mg/kh of the drug caused EEG and behavioral stimulation followed by depression of both, The results suggest that the bahavioral actions of cannabinols are largely dependent upon the animal's existing state of arousal.