Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease.

Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.

Perceptions and behaviors of learner engagement with virtual educational platforms.

BACKGROUND: The COVID-19 pandemic has increased utilization of educational technology for surgical education. Our aim was to determine attitudes and behaviors of surgical education champions towards virtual educational platforms and learner engagement. METHODS: An electronic survey was distributed to all Association of Surgical Education members addressing i) methods of engagement in virtual learning ii) ways to improve engagement and iii) what influences engagement. Stratified analysis was used to evaluate differences in responses by age, gender, level of training and specialty. RESULTS: 154 ASE members completed the survey (13% response rate). 88% respondents accessed virtual learning events at home. Most (87%) had joined a virtual learning event and then participated in another activity. 1 in 5 who did this did so "always" or "often". Female respondents were more likely than males to join audio and then participate in another activity (62.3% v 37.7%, p = 0.04). CONCLUSIONS: Virtual platforms do not automatically translate into increased learner engagement. Careful design of educational strategies is essential to increase and maintain learner engagement when utilizing virtual surgical education.

Assessing learner engagement with virtual educational events: Development of the Virtual In-Class Engagement Measure (VIEM).

BACKGROUND: The COVID-19 pandemic has necessitated virtual education, but effects on learner engagement are unknown. We developed a virtual in-class engagement measure (VIEM) to assess learner engagement in online surgical education events. METHODS: Using the STROBE, an observer collected tool to document student engagement, as a template an ASE committee workgroup developed the VIEM. The VIEM had two parts: observer assessment and learner self-assessment of engagement. Trained observers collected engagement data from two institutions using the VIEM. Surgical attendings, fellows and residents were observed during virtual learning events. Educator attitudes towards online teaching were also assessed via survey. RESULTS: 22 events with 839 learners were observed. VIEM distinguished between sessions with low and high engagement. 20% of learners pretended to participate. Half of instructors were comfortable with virtual teaching, but only 1/3 believed was as effective as in-person. 2/3 of teachers believed video learners were more engaged than audio learners. CONCLUSIONS: Virtual platforms do not automatically translate into increased engagement. Standard tools such as VIEM may help with assessment of engagement during virtual education.

Understanding auditory verbal hallucinations: a systematic review of current evidence.

OBJECTIVE: Auditory verbal hallucinations (AVHs) are core features of psychotic illness and remain significant in predicting poor outcome and risk. There has been a wide range of approaches to understanding these experiences. METHOD: A systematic literature review summarizing different methods of investigation and their results; phenomenology, descriptive psychopathology, psychological, cognitive neurobiology, and neuroimaging. RESULTS: A number of 764 papers and texts were screened and 113 reviewed. Phenomenological studies are comparably few in number, and psychopathology remains based on concepts defined in the early 20th century. Psychological models focus on voice content and emotional reaction, and suggest a continuum of AVHs from normal experience. Neuropsychological models include AVHs as misattribution of inner speech, whilst functional neuroimaging studies focus on the spontaneous activity and connectivity of auditory networks. CONCLUSION: There has been a large growth in research on AVHs in recent decades dominated by neurobiological and neuroimaging studies. Future research should include focus on phenomenological aspects and AVHs change over the course of developing illness. Integration between branches of enquiry is needed, and the risk is that without this, models are proposed and investigated that bear scant relevance to the symptom itself.

A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans.

Gene-by-environment interactions are thought to underlie the majority of idiopathic cases of neurodegenerative disease. Recently, we reported that an environmental metabolite extracted from Streptomyces venezuelae increases ROS and damages mitochondria, leading to eventual neurodegeneration of C. elegans dopaminergic neurons. Here we link those data to idiopathic disease models that predict loss of protein handling as a component of disorder progression. We demonstrate that the bacterial metabolite leads to proteostatic disruption in multiple protein-misfolding models and has the potential to synergistically enhance the toxicity of aggregate-prone proteins. Genetically, this metabolite is epistatically regulated by loss-of-function to pink-1, the C. elegans PARK6 homolog responsible for mitochondrial maintenance and autophagy in other animal systems. In addition, the metabolite works through a genetic pathway analogous to loss-of-function in the ubiquitin proteasome system (UPS), which we find is also epistatically regulated by loss of PINK-1 homeostasis. To determine remitting counter agents, we investigated several established antioxidants and found that glutathione (GSH) can significantly protect against metabolite-induced proteostasis disruption. In addition, GSH protects against the toxicity of MG132 and can compensate for the combined loss of both pink-1 and the E3 ligase pdr-1, a Parkin homolog. In assessing the impact of this metabolite on mitochondrial maintenance, we observe that it causes fragmentation of mitochondria that is attenuated by GSH and an initial surge in PINK-1-dependent autophagy. These studies mechanistically advance our understanding of a putative environmental contributor to neurodegeneration and factors influencing in vivo neurotoxicity.

Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial.

AIMS: To evaluate safety, efficacy and glucose turnover during closed-loop with meal announcement using reduced prandial insulin boluses in adolescents with type 1 diabetes (T1D). METHODS: We conducted a randomized crossover study comparing closed-loop therapy with standard prandial insulin boluses versus closed-loop therapy with prandial boluses reduced by 25%. Eight adolescents with T1D [3 males; mean (standard deviation) age 15.9 (1.5) years, glycated haemoglobin 74 (17) mmol/mol; median (interquartile range) total daily dose 0.9 (0.7, 1.1) IU/kg/day] were studied on two 36-h-long visits. In random order, subjects received closed-loop therapy with either standard or reduced insulin boluses administered with main meals (50-80 g carbohydrates) but not with snacks (15-30 g carbohydrates). Stable-label tracer dilution methodology measured total glucose appearance (Ra_total) and glucose disposal (Rd). RESULTS: The median (interquartile range) time spent in target (3.9-10 mmol/l) was similar between the two interventions [74 (66, 84)% vs 80 (65, 96)%; p = 0.87] as was time spent above 10 mmol/l [21.8 (16.3, 33.5)% vs 18.0 (4.1, 34.2)%; p = 0.87] and below 3.9 mmol/l [0 (0, 1.5)% vs 0 (0, 1.8)%; p = 0.88]. Mean plasma glucose was identical during the two interventions [8.4 (0.9) mmol/l; p = 0.98]. Hypoglycaemia occurred once 1.5 h post-meal during closed-loop therapy with standard bolus. Overall insulin delivery was lower with reduced prandial boluses [61.9 (55.2, 75.0) vs 72.5 (63.6, 80.3) IU; p = 0.01] and resulted in lower mean plasma insulin concentration [186 (171, 260) vs 252 (198, 336) pmol/l; p = 0.002]. Lower plasma insulin was also documented overnight [160 (136, 192) vs 191 (133, 252) pmol/l; p = 0.01, pooled nights]. Ra_total was similar [26.3 (21.9, 28.0) vs 25.4 (21.0, 29.2) µmol/kg/min; p = 0.19] during the two interventions as was Rd [25.8 (21.0, 26.9) vs 25.2 (21.2, 28.8) µmol/kg/min; p = 0.46]. CONCLUSIONS: A 25% reduction in prandial boluses during closed-loop therapy maintains similar glucose control in adolescents with T1D whilst lowering overall plasma insulin levels. It remains unclear whether closed-loop therapy with a 25% reduction in prandial boluses would prevent postprandial hypoglycaemia.

Cell-based articular cartilage repair: the link between development and regeneration.

Clinical efforts to repair damaged articular cartilage (AC) currently face major obstacles due to limited intrinsic repair capacity of the tissue and unsuccessful biological interventions. This highlights a need for better therapeutic strategies. This review summarizes the recent advances in the field of cell-based AC repair. In both animals and humans, AC defects that penetrate into the subchondral bone marrow are mainly filled with fibrocartilaginous tissue through the differentiation of bone marrow mesenchymal stem cells (MSCs), followed by degeneration of repaired cartilage and osteoarthritis (OA). Cell therapy and tissue engineering techniques using culture-expanded chondrocytes, bone marrow MSCs, or pluripotent stem cells with chondroinductive growth factors may generate cartilaginous tissue in AC defects but do not form hyaline cartilage-based articular surface because repair cells often lose chondrogenic activity or result in chondrocyte hypertrophy. The new evidence that AC and synovium develop from the same pool of precursors with similar gene profiles and that synovium-derived chondrocytes have stable chondrogenic activity has promoted use of synovium as a new cell source for AC repair. The recent finding that NFAT1 and NFAT2 transcription factors (TFs) inhibit chondrocyte hypertrophy and maintain metabolic balance in AC is a significant advance in the field of AC repair. The use of synovial MSCs and discovery of upstream transcriptional regulators that help maintain the AC phenotype have opened new avenues to improve the outcome of AC regeneration.

Association of selenium and copper with lipids in umbilical cord blood.

Altered levels of selenium and copper have been linked with altered cardiovascular disease risk factors including changes in blood triglyceride and cholesterol levels. However, it is unclear whether this can be observed prenatally. This cross-sectional study includes 274 singleton births from 2004 to 2005 in Baltimore, Maryland. We measured umbilical cord serum selenium and copper using inductively coupled plasma mass spectrometry. We evaluated exposure levels vis-à-vis umbilical cord serum triglyceride and total cholesterol concentrations in multivariable regression models adjusted for gestational age, birth weight, maternal age, race, parity, smoking, prepregnancy body mass index, n-3 fatty acids and methyl mercury. The percent difference in triglycerides comparing those in the highest v. lowest quartile of selenium was 22.3% (95% confidence interval (CI): 7.1, 39.7). For copper this was 43.8% (95% CI: 25.9, 64.3). In multivariable models including both copper and selenium as covariates, copper, but not selenium, maintained a statistically significant association with increased triglycerides (percent difference: 40.7%, 95% CI: 22.1, 62.1). There was limited evidence of a relationship of increasing selenium with increasing total cholesterol. Our findings provide evidence that higher serum copper levels are associated with higher serum triglycerides in newborns, but should be confirmed in larger studies.

Safety of closed-loop therapy during reduction or omission of meal boluses in adolescents with type 1 diabetes: a randomized clinical trial.

We evaluated the safety and efficacy of closed-loop therapy with meal announcement during reduction and omission of meal insulin boluses in adolescents with type 1 diabetes (T1D). Twelve adolescents with T1D [six male; mean (s.d.) age 15.9 (1.8) years; mean (s.d.) glycated haemoglobin (HbA1c) 77 (27) mmol/mol] were studied in a randomized crossover study comparing closed-loop therapy with meal announcement with conventional pump therapy over two 24-h stays at a clinical research facility. Identical meals were given on both occasions. The evening meal insulin bolus was calculated to cover half of the carbohydrate content of the meal and no bolus was delivered for lunch. Plasma glucose levels were in the target range of 3.9-10 mmol/l for a median [interquartile range (IQR)] of 74 (55,86)% of the time during closed-loop therapy with meal announcement and for 62 (49,75)% of the time during conventional therapy (p = 0.26). Median (IQR) time spent with plasma glucose levels > 10 mmol/l [23 (13,39) vs. 27 (10,50)%; p = 0.88] or < 3.9 mmol/l [1(0,4) vs. 5 (1,10)%; p = 0.24] and mean [standard deviation (SD)] glucose levels [8.0 (7.6,9.3) vs. 7.7 (6.6,10.1) mmol/l, p = 0.79] were also similar. In conclusion, these results assist home testing of closed-loop delivery with meal announcement in adolescents with poorly controlled T1D who miscalculate or miss meal insulin boluses.

Glucose turnover after replacement of usual therapy by insulin in insulin-naive type 2 diabetes subjects.

CONTEXT: Discontinuation of anti-hyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for inpatients with type 2 diabetes (T2D). The effects on glucose turnover when these agents are acutely withdrawn are poorly understood and may be of importance when insulin therapy is initiated. OBJECTIVE: Our objective was to investigate alterations in glucose turnover after acute withdrawal of noninsulin therapy. DESIGN AND SETTING: This was a randomized crossover study at a clinical research facility. PARTICIPANTS: Participants included 12 insulin-naive subjects with T2D. METHODS: Subjects attended two 24-hour visits. Standard therapy was discontinued and replaced by closed-loop insulin delivery during the intervention visit. Usual anti-hyperglycemic therapy was continued during the control visit. Systemic glucose appearance (Ra) and glucose disposal (Rd) were measured using a tracer dilution technique with iv [6,6-(2)H2]glucose. RESULTS: Plasma glucose profiles during both visits were comparable (P = .48). Glucose Ra increased during the day (21.4 [19.5, 23.5] vs 18.6 [17.0, 21.6) µmol/kg/min, P = .019) and decreased overnight (9.7 [8.5, 11.4] vs 11.6 [10.3, 12.9] µmol/kg/min, P = .004) when the usual therapy was discontinued and replaced with insulin. Increased daytime glucose Rd (21.2 [19.4, 23.9] vs 18.8 [18.3, 21.7] µmol/kg/min, P = .002) and decreased overnight Rd (10.4 [9.1, 12.0] vs 11.8 [10.7, 13.7] µmol/kg/min, P = .005) were observed when the usual therapy was discontinued, whereas daytime peripheral insulin sensitivity was reduced (47.8 [24.8, 66.1] vs 62.5 [34.8, 75.8] nmol/kg/min per pmol/L, P = .034). CONCLUSION: In T2D, acute discontinuation of anti-hyperglycemic therapy and replacement with insulin increases postprandial Ra and reduces peripheral insulin sensitivity. Insulin dose initiation may need to compensate for these alterations.

Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model.

Genetic and idiopathic forms of Parkinson's disease (PD) are characterized by loss of dopamine (DA) neurons and typically the formation of protein inclusions containing the alpha-synuclein (α-syn) protein. Environmental contributors to PD remain largely unresolved but toxins, such as paraquat or rotenone, represent well-studied enhancers of susceptibility. Previously, we reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. We hypothesized that this metabolite from a common soil bacterium could enhance neurodegeneration in combination with PD susceptibility gene mutations or toxicants. Here, we report that exposure to the metabolite in C. elegans DA neurons expressing human α-syn or LRRK2 G2019S exacerbates neurodegeneration. Using the PD toxin models 6-hydroxydopamine and rotenone, we demonstrate that exposure to more than one environmental risk factor has an additive effect in eliciting DA neurodegeneration. Evidence suggests that PD-related toxicants cause mitochondrial dysfunction, thus we examined the impact of the metabolite on mitochondrial activity and oxidative stress. An ex vivo assay of C. elegans extracts revealed that this metabolite causes excessive production of reactive oxygen species. Likewise, enhanced expression of a superoxide dismutase reporter was observed in vivo. The anti-oxidant probucol fully rescued metabolite-induced DA neurodegeneration, as well. Interestingly, the stress-responsive FOXO transcription factor DAF-16 was activated following exposure to the metabolite. Through further mechanistic analysis, we discerned the mitochondrial defects associated with metabolite exposure included adenosine triphosphate impairment and upregulation of the mitochondrial unfolded protein response. Metabolite-induced toxicity in DA neurons was rescued by complex I activators. RNA interference (RNAi) knockdown of mitochondrial complex I subunits resulted in rescue of metabolite-induced toxicity in DA neurons. Taken together, our characterization of cellular responses to the S. venezuelae metabolite indicates that this putative environmental trigger of neurotoxicity may cause cell death, in part, through mitochondrial dysfunction and oxidative stress.

Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease.

14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.

Exposure assessment of a mercury spill in a Nevada school -- 2004.

BACKGROUND: Although mercury is toxic, few studies have measured exposure in children who handled elemental mercury briefly. In 2004, a student spilled approximately 60 milliliters of mercury at a Nevada school. Within 12 hours, all students were removed from the source of exposure. We conducted an exposure assessment at the school. METHODS: We administered questionnaires and obtained urine samples from students. Using two-sample t-tests, we compared urine mercury levels from students who self-reported exposure to mercury levels of other students. RESULTS: Two-hundred students participated, including 55/62 (89%) who were decontaminated. The students' geometric mean urine mercury level was 0.36 microg/L (95% confidence interval 0.32-0.40 microg/L). The student who brought the mercury to school was the only one to have an elevated urine mercury level (11.4 microg/L). CONCLUSION: Despite environmental contamination, mercury exposure may have been minimized because of rapid identification of the elemental mercury spill and decontamination.

Computerized color-vision test based upon postreceptoral channel sensitivities.

An automated, computerized color-vision test was designed to diagnose congenital red-green color-vision defects. The observer viewed a yellow appearing CRT screen. The principle was to measure increment thresholds for three different chromaticities, the background yellow, a red, and a green chromaticity. Spatial and temporal parameters were chosen to favor parvocellular pathway mediation of thresholds. Thresholds for the three test stimuli were estimated by four-alternative forced-choice (4AFC), randomly interleaved staircases. Four 1.5-deg, 4.2 cd/m2 square pedestals were arranged as a 2 x 2 matrix around the center of the display with 15-minute separations. A trial incremented all four squares by 1.0 cd/m2 for 133 ms. One randomly chosen square included an extra increment of a test chromaticity. The observer identified the different appearing square using the cursor. Administration time was approximately 5 minutes. Normal trichromats showed clear Sloan notch as defined by log (deltaY/deltaR), whereas red-green color defectives generally showed little or no Sloan notch, indicating that their thresholds were mediated by their luminance system, not by the chromatic system. Data from 107 normal trichromats showed a mean Sloan notch of 0.654 (SD = 0.123). Among 16 color-vision defectives tested (2 protanopes, 1 protanomal, 6 deuteranopes, & 7 deuteranomals), the Sloan notch was between -0.062 and 0.353 for deutans and was < -0.10 for protans. A sufficient number of color-defective observers have not yet been tested to determine whether the test can reliably discriminate between protans and deutans. Nevertheless, the current data show that the test can work as a quick diagnostic procedure (functional trichromatism or dichromatism) of red-green color-vision defect.

Surface attachment of nanoparticles using oligonucleotides.

Colloidal polymer particles are widely used in a variety of applications ranging from chromatography to surface modified bioreactors in protein arrays. In the present study, surface attachment of polystyrene particles to a polystyrene substrate has been performed using oligonucleotide hybridization. Thiolated complementary oligomers of cytosine and guanine have been covalently coupled to a pyridyl disulphide (PDS) modified polyethyleneglycol tether, forming part of a triblock copolymer which is adsorbed to the polystyrene surfaces via hydrophobic polypropylene oxide center blocks. The ability to withstand shear forces was studied using a laminar flow cell and the uptake of oligomers on the particles was quantified using two complementary techniques: UV-spectroscopy and sedimentation field flow fractionation. The possibility to tether particles in a flow cell suitable for practical use in e.g. a FIA-system is demonstrated.

High-resolution organellar genome analysis of Triticum and Aegilops sheds new light on cytoplasm evolution in wheat.

We have utilised polymorphic chloroplast microsatellites to analyse cytoplasmic relationships between accessions in the genera Triticum and Aegilops. Sequencing of PCR products revealed point mutations and insertions/deletions in addition to the standard repeat length expansion/contraction which most likely represent ancient synapomorphies. Phylogenetic analyses revealed three distinct groups of accessions. One of these contained all the non- Aegilops speltoides S-type cytoplasm species, another comprised almost exclusively A, C, D, M, N, T and U cytoplasm-type accessions and the third contained the polyploid Triticum species and all the Ae. speltoides accessions, further confirming that Ae. speltoides or a closely related but now extinct species was the original B-genome donor of cultivated polyploid wheat. Successive decreases in levels of genetic diversity due to domestication were also observed. Finally, we highlight the importance of elucidating longer-term evolutionary processes operating at microsatellite repeat loci.

Measuring synthesis rates of muscle creatine kinase and myosin with stable isotopes and mass spectrometry.

We investigated a novel strategy for measuring the synthesis rate of proteins in skeletal and cardiac muscle. Mass isotopomer distribution analysis allows measurement of the isotopic enrichment of the true biosynthetic precursor for proteins (tRNA-amino acids), but cannot easily be applied to slow turnover muscle proteins due to insufficient isotope incorporation into multiply labeled species. Using a rapid turnover protein from the same tissue, however, might reveal tRNA-amino acid enrichment. We tested this strategy in rats on muscle creatine kinase (CK). A trypsinization peptide (3647u) containing 5 leucine repeats was identified by computer-simulated digestion of CK and then isolated from trypsin hydrolysates. Mass isotopomer abundances were determined by electrospray ionization-magnetic sector-mass spectrometry after in vivo administration of [(2)H(3)]leucine. Myosin heavy chain was also isolated and hydrolyzed to free amino acids. Muscle tRNA-amino acids were well labeled, by direct measurement. Enrichments of M(+1) and M(+2) mass isotopomers in the CK-peptide were measurable but low (consistent with a CK half-life of 3-10 days). Incorporation into skeletal muscle myosin indicated a half-life of 54 days. In conclusion, the general strategy of measuring protein kinetics by quantifying mass isotopomer abundances of mid-sized peptides from protein hydrolysates is effective, but CK does not turn over rapidly in muscle, contrary to previous reports. Identification of a rapid turnover muscle protein would be useful for this purpose.

Fibrinogen adsorption by PS latex particles coated with various amounts of a PEO/PPO/PEO triblock copolymer.

Polystyrene (PS) latex particles of different sizes were adsorption coated with the polymeric surfactant Pluronic F108 (PEO129-PPO56-PEO129). The commercial surfactant was found to have a bimodal molecular weight distribution. However, the maximum surface concentrations resulting from adsorption of either the purified high molecular weight component or the composite were identical. An increase in the copolymer surface concentration on 252-nm particles was found to decrease their fibrinogen uptake exponentially. At maximum copolymer surface concentration, the fibrinogen uptake was two orders of magnitude lower than that of bare particles (down from 3.3 mg/m2 to 0.03 mg/m2). This surface protection was equally effective whether the adsorption involved the bimodal polymer surfactant or the purified high molecular weight fraction. The PEO tail mobility was investigated with electron paramagnetic resonance (EPR), and found to increase with an increase in polymer surface concentration. The comparatively slow motion of the PEO chains at low surface concentration indicated that not only the PPO block, but also the PEO blocks interacted hydrophobically with the PS surface. When the copolymer surface concentration was increased, the PEO tails were gradually being released, acquiring higher mobility as the surface became covered by the more strongly binding PPO blocks. Results obtained with F108 coated particles of different sizes showed that particle size had a significant effect on the fibrinogen uptake, with larger particles showing larger fibrinogen uptakes.

Psychological distress of cancer and clinical trial participation: a review of the literature.

The House of Commons Select Committee on Science and Technology 2000 state that currently less than 5% of adult patients with solid tumours are entered into clinical trials. They recommend that increasing the number of adult cancer patients entering clinical trials must become a high priority. Health-care providers need to prepare themselves for this proposed increase in trial participants by assessing the current status of care and implementing changes within the current infrastructure to provide optimal holistic care. Cancer can change a patient's life either for better or for worse. At one extreme, having cancer leads to enhanced appreciation of life and closer bonds with others. However, at the other extreme, cancer combined with its treatment is viewed as an event that evokes distress and emotional anguish taxing the individual's ability to cope. In the last 25 years, owing to the advent of clinical trials, progress has been made in cancer treatment. Clinical trials may be hailed as the saviour to many therapeutic dilemmas. Treatments are now available which can offer patients hope of cure. Nevertheless, many participants may fear, for the purpose of research, that they may be assigned to less than optimal therapy or that their care will be carried out in a sterile scientific atmosphere devoid of humane and personal consideration. These and other reasons may cause unacceptable personal distress that overrides the potential therapeutic gain. Cancer diagnosis coupled with the ramifications of clinical trial involvement can have significant psychological implications. They may trigger the onset of a mood disorder or exacerbate a present symptom. This article will identify mood disorders in the cancer population, focus on the participants' needs in the clinical trial arena and investigate the influence trial participation has on psychological status.