A microfluidic opto-caloric switch for sorting of particles by using 3D-hydrodynamic focusing based on SLE fabrication capabilities.

In a miniaturised flow switch fluid flows are controlled by reducing the local viscosity via absorption of laser radiation. Through this, the local flow rates are increased to switch the outlet port of a fluid flow carrying the analyte. The microfluidic chip is fabricated using Selective Laser-Induced Etching (SLE). SLE allows novel 3D-hydrodynamic focusing, realising circular shaped channel cross-sections and adapting interaction volume geometries to the profile of the laser radiation for optimised absorption. The performance of the switch is validated experimentally with a dyed analyte and video image processing. The ability to sort particles like cells is demonstrated at 8 Hz using polystyrene beads having a diameter of 8 µm.

Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer.

BACKGROUND: Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. METHODS: Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. RESULTS: In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response. CONCLUSION: Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia.

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.

Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series.

MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report, we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one yr and/or three yr post-liver transplantation. Findings show either no significant change (n=8) or improvement (n=5) in IQ scores pre- to post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced no significant change (n=8) in adaptive scores. In general, findings indicate that liver transplantation minimizes the likelihood of additional central nervous system damage, providing an opportunity for possible stabilization or improvement in neurocognitive functioning.

Friendships and social interactions of school-aged children with migraine.

We set out to evaluate the friendships and social behaviour of school-aged children with migraine. Concern exists regarding the impact of paediatric migraine on daily activities and quality of life. We hypothesized that children with migraine would have fewer friends and be identified as more socially sensitive and isolated than comparison peers. Sixty-nine children with migraine participated in a school-based study of social functioning. A comparison sample without migraine included classmates matched for gender, race and age. Children with migraine had fewer friends at school; however, this effect was limited to those in elementary school. Behavioural difficulties were not found. Middle-school students with migraine were identified by peers as displaying higher levels of leadership and popularity than comparison peers. Concern may be warranted about the social functioning of pre-adolescent children with migraine; however, older children with migraine may function as well as or better than their peers.

Quadrupole ion traps and trap arrays: geometry, material, scale, performance.

Quadrupole ion traps are reviewed, emphasizing recent developments, especially the investigation of new geometries, guided by multiple particle simulations such as the ITSIM program. These geometries include linear ion traps (LITs) and the simplified rectilinear ion trap (RIT). Various methods of fabrication are described, including the use of rapid prototyping apparatus (RPA), in which 3D objects are generated through point-by-point laser polymerization. Fabrication in silicon using multilayer semi-conductor fabrication techniques has been used to construct arrays of micro-traps. The performance of instruments containing individual traps as well as arrays of traps of various sizes and geometries is reviewed. Two types of array are differentiated. In the first type, trap arrays constitute fully multiplexed mass spectrometers in which multiple samples are examined using multiple sources, analyzers and detectors, to achieve high throughput analysis. In the second, an array of individual traps acts collectively as a composite trap to increase trapping capacity and performance for a single sample. Much progress has been made in building miniaturized mass spectrometers; a specific example is a 10 kg hand-held tandem mass spectrometer based on the RIT mass analyzer. The performance of this instrument in air and water analysis, using membrane sampling, is described.

Staged informed consent for a randomized clinical trial in childhood leukemia: impact on the consent process.

BACKGROUND: Children Cancer Group (CCG) 1991 is the first childhood acute lymphoblastic leukemia trial within CCG that allowed the utilization of a staged approach to the consent process. METHODS: One hundred and forty subjects participated in the Project on Informed Consent which compared the primary outcome measures in the consent process of patients enrolled in CCG-1991 with those enrolled in other CCG leukemia studies. RESULTS: The parents' trust scores were higher for the CCG-1991 compared with other protocols. Eighty percent of parents enrolled in CCG-1991 understood the distinction between the randomized clinical trial and the standard treatment arm, compared with 62.5% in the other studies, P = 0.05. Multiple other outcome measures suggested a positive impact from staged informed consent. CONCLUSIONS: Our results suggest that a consent process with a staged approach can help investigators obtain a more truly informed consent. Future research is needed to confirm the benefits of the staged approach to the informed consent process.

Slag analysis with laser-induced breakdown spectrometry.

Laser-induced breakdown spectrometry (LIBS) has been applied for multi-elemental analysis of slag samples from a steel plant. In order to avoid the time-consuming step of sample preparation, the liquid slag material can be filled in special probes. After cooling of the liquid slag and solidification, the samples can be analyzed with LIBS. Chemical analysis of slag is an essential input parameter used for numerical simulations to control liquid steel processing. The relative variation range of element concentrations in slag samples from steel production can amount to up to 30%. A multivariate calibration model is used to take into account matrix effects caused by these varying concentrations. By optimizing the measuring parameters as well as the calibration models, an agreement between the standard X-ray fluorescence (XRF) analysis and LIBS analysis in terms of the coefficient of determination r2 of 0.99 for the main analytes CaO, SiO2, and Fetot of converter slag samples was achieved. The average repeatability of the LIBS measurement for these elements in terms of the relative standard deviation of the determined concentration is improved to less than 1.0%. With these results, the basis is established for future on-line applications of LIBS in the steel-making industry for slag analysis.

Fluoroscopy-assisted dual-catheter thromboembolectomy: a new technique useful in patients with embolization to arteries of disproportionate diameters.

Distal embolization is a complication of aortoiliac aneurysm repair. Fluoroscopy-assisted catheter thromboembolectomy is useful in removing popliteal and tibial emboli from the femoral approach. Concomitant presence of aortoiliac and popliteal aneurysms, a known association, may present a difficult challenge to embolus extraction. Currently available embolectomy catheters large enough for thrombus extraction from a popliteal aneurysm are too large for safe tibial artery cannulation, and tibial balloon catheters cannot be enlarged sufficiently to transfer the thrombus through the aneurysmal popliteal segment. We treated a patient who embolized to his popliteal aneurysm and distal tibial circulation following aortoiliac aneurysm repair. A fluoroscopy-assisted dual-catheter technique was used to extract the thrombus through the femoral approach, eliminating the need for direct popliteal or tibial exploration. This technique uses two balloon catheters of graduated size, maneuvered concurrently under fluoroscopic guidance into the tibial and popliteal circulation. The smaller tibial catheter is inflated, and thrombus is withdrawn into the popliteal segment. The larger popliteal balloon catheter is then inflated distal to the smaller catheter, and both catheters are withdrawn simultaneously to deliver the clot through the femoral arteriotomy. This technique can be useful for successful balloon catheter extraction of thrombus via remote access, in an arterial system with variable diameter, eliminating the need for direct popliteal or tibial exploration.

Sibling adjustment to pediatric traumatic brain injury: a case-controlled pilot study.

OBJECTIVE: To assess depressive symptoms, self-concept, and behavior in non-affected siblings of children with severe pediatric traumatic brain injury (TBI). DESIGN: Cross-sectional study with case controls. SETTING: Children's hospital tertiary care center. PARTICIPANTS: Twelve siblings of children consecutively admitted to an inpatient rehabilitation unit after a severe TBI. Case controls were randomly selected from the sibling's classmates. MAIN OUTCOME MEASURES: The Child Behavior Checklist (CBCL), the Teacher's Report Form of the CBCL (TRF-CBCL), the Self-Perception Profile for Children and the Children's Depression Inventory (CDI). RESULTS: No statistical differences were found in depressive symptoms, self-concept, or behavior between the siblings and their classmates 3 to 18 months after injury. Poorer functional outcomes in the child with a TBI were found to correlate significantly with lower self-concept and more symptoms of depression in the siblings. CONCLUSIONS: Further research is needed to evaluate the potential impact on sibling adjustment after pediatric TBI.

Neuropsychological functioning of youths with sickle cell disease: comparison with non-chronically ill peers.

OBJECTIVE: To compare the neuropsychological functioning of children with sickle cell disease (SCD) with no evidence of overt clinical stroke to that of classmates without a chronic illness matched on gender, race, and age. We examined both overall level of performance and patterns of performance utilizing empirically derived construct scores of key domains of neurocognitive functioning. METHODS: An abbreviated neuropsychological battery of tests was given to 31 children with SCD and 31 case controls. Empirically derived construct scores were developed for primary analyses. RESULTS: Children with SCD had significantly lower scores on three level-of-performance construct scores: total, verbal, and attention/memory. Mean scores for children with SCD were lower than those for case controls on every level-of-performance construct score and every standardized test score. However, pattern-of-performance construct scores were not significantly different. CONCLUSIONS: Children with SCD without overt stroke demonstrate significant deficits in neurocognitive functioning compared to classroom case controls. These findings highlight the impact of SCD on general neurocognitive functioning and suggest that routine screening of cognitive functioning should be a requisite element of comprehensive care for children with SCD. Within the context of documented physical limitations, we conclude that children with SCD are at very high risk for impaired psychosocial outcomes.

Aggression, antisocial behavior, and substance abuse in survivors of pediatric cancer: possible protective effects of cancer and its treatment.

OBJECTIVE: To examine aggression, antisocial behavior, and substance abuse in young adult survivors of pediatric cancer (PCS) relative to case control peers (CC). METHODS: We obtained self-reports of current aggression, antisocial behavior, and lifetime substance use from 26 PCS (time off-treatment, M: = 56 months) and 26 CC using the Antisocial Behavior Checklist and the Drinking and Drug History. A report of current aggression and antisocial behavior also was obtained from primary caregivers using the Child Behavior Checklist. RESULTS: PCS self-reported significantly less illegal drug use and experimentation than CC. No significant differences emerged between groups for use of alcohol and tobacco nor for aggression and antisocial behavior. CONCLUSIONS: PCS are functioning as well as, or better than, CC in terms of aggression, antisocial behavior, and substance abuse. However, given the compromised health status of survivors, efforts should focus on further reduction of drug-related risk behaviors that may amplify organ damage or increase risk for further malignancies in this population.

Social, emotional, and behavioral functioning of children with juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the hypothesis that children with juvenile rheumatoid arthritis (JRA) would have more social and emotional problems than case-control classmates. METHODS: Using a case-control design, children with JRA (n = 74), ages 8-14, were compared with case-control classmates (n = 74). Peer relationships, emotional well-being, and behavior, based on peer-, teacher-, parent-, and self-report scores on common measures, were compared using analysis of variance. RESULTS: Relative to case-control classmates, children with JRA were similar on all measures of social functioning and behavior. Mothers reported more internalizing symptoms in the child with JRA, but child self reports and father reports showed no differences. Scores on all standardized measures were in the normal range for both the JRA and the case-control groups. CONCLUSION: Children with JRA were remarkably similar to case-control children on measures of social functioning, emotional well-being, and behavior. These findings are not supportive of disability/stress models of chronic illness in childhood and suggest considerable psychological hardiness among children with JRA.

Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters.

The substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters was determined using brush border membrane vesicles and CHO cell lines permanently expressing the Na(+)/bile acid cotransporters from rabbit ileum or rabbit liver. The hepatic transporter showed a remarkably broad specificity for interaction with cholephilic compounds in contrast to the ileal system. The anion transport inhibitor diisothiocyanostilbene disulfonate (DIDS) is a strong inhibitor of the hepatic Na(+)/bile acid cotransporter, but does not show any affinity to its ileal counterpart. Inhibition studies and uptake measurements with about 40 different bile acid analogues differing in the number, position, and stereochemistry of the hydroxyl groups at the steroid nucleus resulted in clear structure;-activity relationships for the ileal and hepatic bile acid transporters. The affinity to the ileal and hepatic Na(+)/bile acid cotransport systems and the uptake rates by cell lines expressing those transporters as well as rabbit ileal brush border membrane vesicles is primarily determined by the substituents on the steroid nucleus. Two hydroxy groups at position 3, 7, or 12 are optimal whereas the presence of three hydroxy groups decreased affinity. Vicinal hydroxy groups at positions 6 and 7 or a shift of the 7-hydroxy group to the 6-position significantly decreased the affinity to the ileal transporter in contrast to the hepatic system. 6-Hydroxylated bile acid derivatives are preferred substrates of the hepatic Na(+)/bile acid cotransporter. Surprisingly, the 3alpha-hydroxy group being present in all natural bile acids is not essential for high affinity interaction with the ileal and the hepatic bile acid transporter. The 3alpha-hydroxy group seems to be necessary for optimal transport of a bile acid across the hepatocyte canalicular membrane. A modification of bile acids at the 3-position therefore conserves the bile acid character thus determining the 3-position of bile acids as the ideal position for drug targeting strategies using bile acid transport pathways.

Psychosocial adjustment of children with chronic illness: an evaluation of three models.

This study was designed to assess social, emotional, and behavioral functioning of children with chronic illness and to evaluate three models addressing the impact of chronic illness on psychosocial functioning: discrete disease, noncategorical, and mixed. Families of children with cancer, sickle cell disease, hemophilia, and juvenile rheumatoid arthritis participated, along with families of classroom comparison peers without a chronic illness who had the closest date of birth and were of the same race and gender (COMPs). Mothers, fathers, and children provided information regarding current functioning of the child with chronic illness or the COMP child. Child Behavior Checklist and Children's Depression Inventory scores were examined. Results provided support for the noncategorical model. Thus, the mixed model evaluated in this study requires modifications before its effectiveness as a classification system can be demonstrated.

Social, emotional, and behavioral functioning of children with cancer.

OBJECTIVE: It was hypothesized that children with cancer would have more social problems and difficulties with emotional well-being than case control, same race/gender, similarly aged classmates. STUDY DESIGN: Using a case controlled design, children with any type of cancer requiring chemotherapy except brain tumors (n = 76), currently receiving chemotherapy, ages 8 to 15, were compared with case control classroom peers (n = 76). Peer relationships, emotional well-being, and behavior were evaluated based on peer, teacher, parent, and self-report, and were compared using analysis of variance and structural equation modeling. RESULTS: Relative to case controls, children with cancer were perceived by teachers as being more sociable; by teachers and peers as being less aggressive; and by peers as having greater social acceptance. Measures of depression, anxiety, loneliness, and self-concept showed no significant differences, except children with cancer reported significantly lower satisfaction with current athletic competence. There were also no significant differences in mother or father perceptions of behavioral problems, emotional well-being, or social functioning. Scores on all standardized measures were in the normal range for both groups. Comparisons of the correlation matrices of children with cancer and to the correlation matrix of the comparison children using structural equation modeling suggested they were not significantly different. CONCLUSIONS: Children with cancer currently receiving chemotherapy were remarkably similar to case controls on measures of emotional well-being and better on several dimensions of social functioning. These findings are not supportive of disability/stress models of childhood chronic illness and suggest considerable psychologic hardiness.

A controlled study of peer relationships of children surviving brain tumors: teacher, peer, and self ratings.

OBJECTIVE: Evaluate the behavioral reputation and peer acceptance of children diagnosed and treated for brain tumors. METHOD: Twenty-eight children surviving brain tumors (8-18 years of age) were compared to 28 nonchronically ill, same classroom, same gender comparison peers (COMP). Peer, teacher, and self-report data were collected. RESULTS: Relative to COMP, children who had been diagnosed with brain tumors received fewer friendship nominations from clasmates and were described by peer, teacher, and self-report as socially isolated. Although they were no longer receiving therapy for their disease, peers perceived brain tumor survivors as being sick, more fatigued, and often absent from school. CONCLUSIONS: These data suggest that children surviving brain tumors are at risk for social difficulties even after treatment ends, although the specific cause(s) for this vulnerability were not investigated in the current study.

Informed consent in the Childrens Cancer Group: results of preliminary research.

BACKGROUND: Informed consent is critical to the ethical conduct of pediatric cancer clinical research. Research regarding such consent has been limited. METHODS: After conducting a background survey of institutional practice from principal investigators (PIs) at 113 Childrens Cancer Group (CCG) centers, the authors obtained more detailed data regarding informed consent from 23 parents of children recently enrolled in CCG research trials and from 23 clinician-investigators at 5 CCG institutions. RESULTS: Approximately 73% of PIs responded to the background survey, providing context in which to interpret the more detailed information. Parents reported that they found the informed consent process helpful, although somewhat confusing. Satisfaction with informed consent was not related to ethnicity or education level. Parents found discussion with staff more helpful than the consent document, and the majority reported that the amount of information conveyed was appropriate. Although only 3 parents (13%) reported that too much information was given, nearly 50% of the investigators believed too much information usually is provided. All investigators believed that patients benefit from participation in CCG studies; the majority recommend that the child be enrolled on study, and the majority believe the major obstacle to good informed consent is parents' "state of shock." CONCLUSIONS: Parents expressed general satisfaction with the consent process. By contrast, clinician responses indicate dissatisfaction with the informed consent process. Future research must include more centers and larger numbers of parents of children who we enrolled as well as those who declined to participate in CCG studies, examine consent in minority subgroups, and further investigate the role of clinician-investigators and their interaction with parents and children during the informed consent process.