Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

A Phase-Locked Loop Epilepsy Network Emulator.

Most seizure forecasting employs statistical learning techniques that lack a representation of the network interactions that give rise to seizures. We present an epilepsy network emulator (ENE) that uses a network of interconnected phase-locked loops (PLLs) to model synchronous, circuit-level oscillations between electrocorticography (ECoG) electrodes. Using ECoG data from a canine-epilepsy model (Davis et al. 2011) and a physiological entropy measure (approximate entropy or ApEn, Pincus 1995), we demonstrate the entropy of the emulator phases increases dramatically during ictal periods across all ECoG recording sites and across all animals in the sample. Further, this increase precedes the observable voltage spikes that characterize seizure activity in the ECoG data. These results suggest that the ENE is sensitive to phase-domain information in the neural circuits measured by ECoG and that an increase in the entropy of this measure coincides with increasing likelihood of seizure activity. Understanding this unpredictable phase-domain electrical activity present in ECoG recordings may provide a target for seizure detection and feedback control.

Control of targeting ligand display by pH-responsive polymers on gold nanoparticles mediates selective entry into cancer cells.

Selective targeting of cells for intracellular delivery of therapeutics represents a major challenge for pharmaceutical intervention in disease. Here we show pH-triggered receptor-mediated endocytosis of nanoparticles via surface ligand exposure. Gold nanoparticles were decorated with two polymers: a 2 kDa PEG with a terminal folate targeting ligand, and a di-block copolymer including a pH-responsive and a hydrophilic block. At the normal serum pH of 7.4, the pH-responsive block (apparent pKa of 7.1) displayed a hydrophilic extended conformation, shielding the PEG-folate ligands, which inhibited cellular uptake of the nanoparticles. Under pH conditions resembling those of the extracellular matrix around solid tumours (pH 6.5), protonation of the pH-responsive polymer triggered a coil-to-globule polymer chain contraction, exposing folate residues on the PEG chains. In line with this, endocytosis of folate-decorated polymer-coated gold nanoparticles in cancer cells overexpressing folate receptor was significantly increased at pH 6.5, compared with pH 7.4. Thus, the tumour acidic environment and high folate receptor expression were effectively exploited to activate cell binding and endocytosis of these nanoparticles. These data provide proof-of-concept for strategies enabling extracellular pH stimuli to selectively enhance cellular uptake of drug delivery vectors and their associated therapeutic cargo.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

Modeling the effects of proteins on pH in plasma.

Stewart's model of plasma acid-base balance (Can. J. Physiol. Pharmacol. 61: 1444-1461, 1983) has three weaknesses in the treatment of weak acids: 1) the combination of all weak acids into one entity, 2) inappropriate chemistry for the protein combination with H+, and 3) undocumented values for the dissociation parameters. The present study models serum albumin acid-base properties by fixed negative charges and the association of H+ with the imidazole side chain of histidine. This model has three parameters: 1) the net negative fixed charge (21 eq/mol), 2) the number of histidine residues (16/mol), and 3) the association constant for the imidazole side chain (1.77 x 10(-7) eq/l), all determined from published values. The model was compared with that of Figge, Mydosh, and Fencl (J. Lab. Clin. Med. 120: 713-719, 1992) and with the pH data of Figge, Rossing, and Fencl (J. Lab. Clin. Med. 117: 453-467, 1991). The predictions of pH were excellent, comparable to those found by Figge, Mydosh, and Fencl. The model has the advantages that its structure and parameter values are supported by the literature and that the acid-base effects of factors modifying protein can be investigated.

Weekly variability in total body water using 2H2O dilution in college-age males.

The variability in measuring total body water (TBW) using deuterium oxide (2H2O) dilution has not been extensively tested. The purpose of this study was to determine the variability of weekly measurements of TBW utilizing the 2H2O dilution technique in 10 males and to determine the amount of biological versus technical variability using a generalizability ANOVA (GENOVA). Ten male subjects aged 21-32 yr were tested on four separate occasions for body weight (BW), underwater weight (UwWt), and TBW. BW remained quite stable across the four sessions with a 0.7% coefficient of variation (CV). Both UwWt and TBW had a CV of 4% across the four sessions. No differences were found between TBW estimates from plasma, saliva, or urine. GENOVA analysis determined that 25-50% of the total variability in measuring TBW was attributed to the sample analysis/separation procedures. Four percent of the TBW in these subjects was 1.8 l. This technique would therefore not be expected to detect changes less than 0.9 l (50% of 1.8 l). The estimates of %FAT from TBW were lower but not significantly different from UwWt. Blood, urine, and saliva were able to produce similarly repeatable measures of TBW.

Validity of the computer science and applications (CSA) activity monitor in children.

PURPOSE: The purpose of this study was to evaluate the validity of the CSA activity monitor as a measure of children's physical activity using energy expenditure (EE) as a criterion measure. METHODS: Thirty subjects aged 10 to 14 performed three 5-min treadmill bouts at 3, 4, and 6 mph, respectively. While on the treadmill, subjects wore CSA (WAM 7164) activity monitors on the right and left hips. VO2 was monitored continuously by an automated system. EE was determined by multiplying the average VO2 by the caloric equivalent of the mean respiratory exchange ratio. RESULTS: Repeated measures ANOVA indicated that both CSA monitors were sensitive to changes in treadmill speed. Mean activity counts from each CSA unit were not significantly different and the intraclass reliability coefficient for the two CSA units across all speeds was 0.87. Activity counts from both CSA units were strongly correlated with EE (r = 0.86 and 0.87, P < 0.001). An EE prediction equation was developed from 20 randomly selected subjects and cross-validated on the remaining 10. The equation predicted mean EE within 0.01 kcal.min-1. The correlation between actual and predicted values was 0.93 (P < 0.01) and the SEE was 0.93 kcal.min-1. CONCLUSION: These data indicate that the CSA monitor is a valid and reliable tool for quantifying treadmill walking and running in children.

Adolescents' perceptions of a health survey using multimedia computer-assisted self-administered interview.

OBJECTIVE: To ascertain young people's perceptions of an adolescent health survey when administered by multimedia computer assisted self-administered Interview (M-CASI) through analysis of (1) questionnaire item responses and (2) focus group interviews. SETTING: Auckland, New Zealand, 1999. STUDY TYPE: Pilot testing of a 488-item branching questionnaire delivered using a youth-oriented and user-friendly M-CASI interface in a variety of settings using both desktop and laptop computers. Post pilot focus groups of participants identifying their perceptions and experiences of the survey. SAMPLE: 110 school students aged 12 to 18 years. RESULTS: The mean number of questions answered by participants was 316 with the median time to completion being 48 minutes. On average 65% of the total number of questions were seen and of these 1.5% were deliberately not answered. A high level of acceptability and enjoyment of M-CASI was found in the analysis of focus group responses and agreed with the item responses relating to M-CASI within the questionnaire itself. Participants identified privacy and confidentiality as being particularly important for the honesty of their responses. The passive matrix screens of the computers were popular as they could only be viewed from in front. CONCLUSIONS: M-CASI is an acceptable instrument for the administration of a youth health survey. Laptop computers with passive matrix screens are able to enhance perceptions of privacy and confidentiality, which may improve honesty of responses. IMPLICATIONS: M-CASI is now feasible and offers advantages in health surveying.

The economic value of children: a case study from rural India.

PIP: This study compares the theses of Mamdami, that India's poor have large families as an investment, and Vlassoff, that only a weak connection exists between a child's economic utility and household fertility. Data used in the study were based on a sample of 18 children in Bihar state, India, on 1) expenditures on children, 2) opportunity costs of raising children, 3) child earnings, 4) child earnings given to parents, 5) alternative investments, 6) discount rates appropriate for parents to use, 7) parents' perceptions of the economic value of children, and 8) family size. Costs estimated included food, clothing, schooling, health, other, and opportunity costs in bearing and raising children. Benefits include estimated values for work within and outside the family. 2 balances indicate that 7 or 8 children, aged 6 to 15, provide more labor than they cost to keep. Data suggest that children become valuable to parents at about age 9 or 10. From this age on, benefits increasingly outweigh costs; by the age of 16 or 17, children have repaid their initial costs to parents. Comparing the value of children against local bank interest rates shows that in all cases but one, children provided a better economic investment than savings accounts. The authors suggest that children are an even greater economic investment in poorer households. Doling out condoms and pills is no substitute for child wealth. In Bihar, improving people's economic well-being may be a prerequisite to fertility decline.^ieng

Permeability of cat skeletal muscle capillaries to small solutes.

Permeability-surface area products (PS) for 51Cr-EDTA, [3H]mannitol, [14C]urea, and 22Na were measured in isolated, perfused, lower hindlimb muscles of anesthetized cats. The tracers were added stepwise to the arterial inflow, and Evans blue-labeled albumin was the reference indicator. At flow rates > 70 ml.min-1.100 g-1, the PS values (+/- SE) were 5.0 +/- 0.5, 7.6 +/- 1.2, 17.8 +/- 1.4, and 21.0 +/- 1.4 (n = 7, 4, 5, and 3 animals, respectively). The ratio of simultaneous PS measurements of mannitol and urea was 0.42 +/- 0.02 (n = 9), significantly less than the free diffusion coefficient ratio (0.49), indicating the presence of restricted diffusion. PS measurements were also made during osmotic flow (4.2 +/- 0.6 ml.min-1.100 g-1) induced by 20% NaCl. The data clearly showed that osmotic transients did not alter small solute permeability. Pore models were used to show that the PS data and previously reported reflection coefficient data were consistent with a single description of the capillary wall. This model contained a water-only pathway containing 60% of the hydraulic capacity and an extracellular route modeled by pores of 4 nm radius having 21,000 cm of area per unit membrane thickness (A/delta x).

Sieving of electrolytes at capillary wall of cat skeletal muscle by osmotic water flow.

To test the hypothesis that a significant proportion of transcapillary water flow occurs through solute-restricting channels, we investigated the effects of transcapillary water movement on plasma electrolytes in isolated perfused cat skeletal muscle. The lower hindlimbs of anesthetized cats were perfused with a plasma-albumin solution and were weighed to determine transcapillary water movement. Osmolality was increased 60-70 mosmol/kgH2O with sucrose, creating water fluxes of 8-10 ml.min-1.100 g-1, and the changes in the venous concentrations of sodium, potassium, and chloride were determined. The ion concentrations were all reduced by 6-7% with no significant difference between them. The amount of reduction was quantitatively explained by the flow of ion-free water from the interstitial space into plasma and the diffusion of electrolyte in the same direction. These findings support the hypothesis that important water-only transcapillary channels exist in mammalian skeletal muscle. The observations may also explain some of the electrolyte changes seen in intense exercise.

Effects of blood-free and protein-free perfusion on CFC in the isolated cat hindlimb.

To investigate the effects of blood and protein on capillary filtration coefficient (CFC), isolated cat hindlimbs were perfused at constant flow from a reservoir containing one of three perfusates: 1) an electrolyte solution also used for dialyzing bovine serum albumin (BSA) and hence labeled dialysate, 2) dialyzed 6.5-7.0 g/100 ml BSA, labeled albumin, and 3) albumin plus cat blood, labeled control. CFC during control perfusion averaged 0.0137 +/- 0.003 (SD, n = 26) and increased slowly with time. CFCs with dialysate and albumin were 3.1 +/- 0.56 (n = 11) and 1.7 +/- 0.52 (n = 15) times control, respectively. However, the ratio in a particular experiment depended on control CFC, the ratio being low when the control CFC was low and high when control CFC was high. The data can be explained if water flow occurs through two types of transcapillary pathways, one having a hydraulic capacity constant from animal to animal and insensitive to blood and protein, the second varying in hydraulic capacity and requiring blood and protein for its normal values.

Colloid osmotic pressure changes in isolated isogravimetric cat hindlimb.

The development of osmotic pressure, following the addition of bovine serum albumin (BSA) to the perfusate, was measured in an isogravimetric cat hindlimb fully dilated with papaverine. The changes in colloid osmotic pressure were followed by recording the changes in venous pressure (PVI) necessary to maintain constant weight. Capillary filtration coefficient (CFC) and vascular compliances were calculated from weight changes following steps in venous pressure. Venous BSA levels reached arterial within 1 min, and PVI reached a new steady state 13.1 +/- 0.9 (SE) min (n = 9 in 6 limbs) after adding BSA. This apparent delay in the development of the osmotic pressure agrees with earlier reports. However, when the BSA was added under constant venous pressure conditions, the fluid reabsorption reached its maximum rate within 1.5 min. The data suggest that the BSA is osmotically fully effective after the capillary washin. The slowness of the rise of PVI in the isogravimetric state is probably caused by the time necessary to absorb sufficient fluid from the interstitium to raise the capillary pressure to a level that balances the increased oncotic pressure. A mathematical model supports this explanation.

Analysis of the paired-tracer method of determining cell uptake.

The paired-tracer method has been used extensively for determining cell uptake of numerous substances, although the method of calculating uptake has no published theoretical support. We have investigated the effect of capillary permeability of the tracers on v, the uptake rate calculated directly from the ratio of tracer venous concentrations. For a simple mathematical model of plasma-tissue movement of lactate and an analytic expression for v, it has been shown that values of v calculated in the first moments after tracer injection depend almost entirely on the differences in tracer permeability-surface area product (PS). The model indicates v would never give the correct value of cell uptake. It is also shown that PS differences alone can explain the published values for lactate uptake obtained from v in skeletal muscle of the rat and dog.

Effect of plasma and red blood cells on water permeability in cat hindlimb.

Capillary filtration coefficient (CFC) was measured to investigate the effect of blood in the perfusate of an isolated, maximally vasodilated cat hindlimb. CFC was measured during perfusion with several different perfusates: a blood-albumin mixture, albumin alone, a plasma-albumin mixture, and a plasma-albumin mixture containing varying volumes of red blood cells. In some experiments the plasma was ultrafiltered to remove low-molecular-weight components. It was found that perfusion with albumin alone usually raised CFC above the level found with the blood-albumin mixture, plasma could reduce the CFC when CFC was elevated above that value obtained with the blood-albumin mixture, ultrafiltered plasma failed to reduce CFC when CFC was elevated, and the red cell content of the perfusate had no influence on CFC over the hematocrit range of 0-20% when the plasma solute concentrations were kept constant. It was concluded that the reduction of CFC by blood was caused by a small molecule (less than 10,000 mol wt) present in plasma.

Transport parameter estimation from lymph measurements and the Patlak equation.

Two methods of estimating protein transport parameters for plasma-to-lymph transport data are presented. Both use IBM-compatible computers to obtain least-squares parameters for the solvent drag reflection coefficient and the permeability-surface area product using the Patlak equation. A matrix search approach is described, and the speed and convenience of this are compared with a commercially available gradient method. The results from both of these methods were different from those of a method reported by Reed, Townsley, and Taylor [Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H1037-H1041, 1989]. It is shown that the Reed et al. method contains a systematic error. It is also shown that diffusion always plays an important role for transmembrane transport at the exit end of a membrane channel under all conditions of lymph flow rate and that the statement that diffusion becomes zero at high lymph flow rate depends on a mathematical definition of diffusion.

Health care delivery: perspectives of young people with chronic illness and their parents.

OBJECTIVE: To identify and compare perceptions of health care service delivery held by young people with chronic illness and their parents. METHODS: A convenience sample of young people with chronic illness and their parents were invited to complete a confidential self-report survey. The adolescents were aged 13-18 years inclusive and attended a specialist medical clinic. RESULTS: Participants comprised 53 young people (response rate 88%, 53/60) and 45 parents (response rate 75%, 45/60). Both young people and their parents rate honesty, confidentiality, having good medical knowledge and good listening skills as the most important qualities for a health care provider. Compared to the parent group, fewer young people report the presence of these desired qualities in their current health care provider. A quarter of young people (25%, 13/53) report they do not always trust health professionals to keep their information confidential, and 19% (10/53) of young people report having withheld information from a health professional due to a lack of trust. Some parents and young people would like to discuss a wider range of health topics, including mental health issues, than they currently do with their health provider. Young people and their parents report limited planning with their current health provider for transition to adult health services. CONCLUSIONS: Young people with chronic illnesses have significant levels of dissatisfaction with the health care they receive; this has the potential to impact on their use of health care services and their health outcomes. There is a need for increased provider awareness of the important qualities of health care service delivery to young people.

Dextran and capillary filtration coefficient in cat hindlimb.

To investigate the possible mechanisms through which dextran modifies capillary filtration coefficient (CFC), the effects of perfusion with a protein-free dextran solution were compared with those of perfusion with a Ringerlike solution. With the use of the isolated cat hindlimb, CFC was measured during perfusion at constant flow with three solutions, a control blood-albumin mixture, a Ringerlike solution called dialysate, and 3.7 g/dl dextran dissolved in dialysate. The solutions were warmed to 37-38 degrees C, bubbled with 95% O2-5% CO2, and contained 0.015 g/dl or more papaverine. CFC was calculated from the rate of limb weight gain following a step increase in venous pressure. Dextran perfusion increased CFC to 2.0 +/- 0.2 (SD, n = 8) times control, which was significantly less (P less than 0.001) than 3.1 +/- 0.6 (n = 8) times control previously reported for dialysate perfusion. The difference between the measured viscosity of dextran (1.35 cP) and dialysate (0.72) could account for this reduction. However, when a dialysate perfusion followed a dextran perfusion, CFC only increased to 2.3 +/- 0.4 (n = 8) times control. This value is also significantly less (P less than 0.01) than 3.1. This observation suggests 1) that dextran is retained within the transcapillary channel and 2) that dextran reduces CFC mainly by partially blocking the transcapillary channel rather than by increasing viscosity.

Suggested criteria for vision classification on the AAMD adaptive behavior scale.

The AAMD Adaptive Behavior Scale for Children and Adults is an instrument designed to assess the degree to which an individual has adapted to his environment. While one item of the scale refers to vision, no criteria have been established to indicate degree of vision impairment on such a scale. Such criteria are suggested including a supplement which describes other visual functions. A method of assessing visual acuity in non-verbal or uncooperative patients is given.