Multi-size spheroid formation using microfluidic funnels.

We present a microfluidic platform for automatic multi-size spheroid formation within constant volume hanging droplets (HDs) from a single inlet loading of a constant cell concentration. The platform introduces three technological improvements over the existing spheroid formation platforms: 1) cell seeding control is achieved by enrichment of a cell solution rather than dilution; 2) cell seeding in each HD is fully independent and pre-programmable at the design stage; 3) the fabricated chip operates well using a hydrophobic PDMS surface, ensuring long-term storage possibility for device usage. Pre-programmed cell seeding densities at each HD are achieved using a "microfluidic funnel" layer, which has an array of cone-shaped wells with increasing apex angles acting as a metering unit. The integrated platform is designed to form, treat, stain, and image multi-size spheroids on-chip. Spheroids can be analyzed on-chip or easily transferred to conventional well plates for further processing. Empirically, enrichment factors up to 37× have been demonstrated, resulting in viable spheroids of diameters ranging from 230-420 µm and 280-530 µm for OV90 and TOV112D cell lines, respectively. We envision that microfluidic funnels and single inlet multi-size spheroid (SIMSS) chips will find broad application in 3D biological assays where size-dependent responses are expected, including chemoresponse assays, photodynamic therapy assays, and other assays involving drug transport characterization in drug discovery.

Autonomous microfluidic capillaric circuits replicated from 3D-printed molds.

We recently developed capillaric circuits (CCs) - advanced capillary microfluidic devices assembled from capillary fluidic elements in a modular manner similar to the design of electric circuits (Safavieh & Juncker, Lab Chip, 2013, 13, 4180-4189). CCs choreograph liquid delivery operations according to pre-programmed capillary pressure differences with minimal user intervention. CCs were thought to require high-precision micron-scale features manufactured by conventional photolithography, which is slow and expensive. Here we present CCs manufactured rapidly and inexpensively using 3D-printed molds. Molds for CCs were fabricated with a benchtop 3D-printer, poly(dimethylsiloxane) replicas were made, and fluidic functionality was verified with aqueous solutions. We established design rules for CCs by a combination of modelling and experimentation. The functionality and reliability of trigger valves - an essential fluidic element that stops one liquid until flow is triggered by a second liquid - was tested for different geometries and different solutions. Trigger valves with geometries up to 80-fold larger than cleanroom-fabricated ones were found to function reliably. We designed retention burst valves that encode sequential liquid delivery using capillary pressure differences encoded by systematically varied heights and widths. Using an electrical circuit analogue of the CC, we established design rules to ensure strictly sequential liquid delivery. CCs autonomously delivered eight liquids in a pre-determined sequence in <7 min. Taken together, our results demonstrate that 3D-printing lowers the bar for other researchers to access capillary microfluidic valves and CCs for autonomous liquid delivery with applications in diagnostics, research and education.

Pulsed resources at tundra breeding sites affect winter irruptions at temperate latitudes of a top predator, the snowy owl.

Irruptive migration is mostly observed in species specialized on pulsed resources and is thought to be a response to unpredictable changes in food supply. We assessed two alternative hypotheses to explain the periodic winter irruptions of snowy owls Bubo scandiacus every 3-5 years in temperate North America: (a) the lack-of-food hypothesis, which states that a crash in small mammal abundance on the Arctic breeding grounds forces owls to move out of the tundra massively to search for food in winter; (b) the breeding-success hypothesis, which states that high abundance of tundra small mammals during the summer allows for high production of young, thus increasing the pool of migrants moving south the following winter. We modeled winter irruptions of snowy owls in relation to summer food resources and geographic location. Winter abundance of owls was obtained from citizen-based surveys from 1994 to 2011 and summer abundance of small mammals was collected in summer at two distant sites in Canada: Bylot Island, NU (eastern High Arctic) and Daring Lake, NWT (central Low Arctic). Winter owl abundance was positively related to prey abundance during the previous summer at both sites and tended to decrease from western to eastern temperate North America. Irruptive migration of snowy owls was therefore best explained by the breeding success hypothesis and was apparently caused by large-scale summer variations in food. Our results, combined with previous findings, suggest that the main determinants of irruptive migration may be species specific even in a guild of apparently similar species.

Normal optic nerve head topography in the early stages of dementia of the Alzheimer type.

In view of the existing controversy as to whether or not the optic nerve head (ONH) is altered in Alzheimer disease, we used modern imaging technology to evaluate the ONH structure in individuals with dementia of the Alzheimer type (DAT). Real-time topographical images of the ONH were obtained with a Heidelberg retina tomograph from individuals in the early stages of DAT and age-matched controls. The various ONH parameters examined in this study did not differ significantly between DAT and age-matched subjects. These results suggest that the deficits in visual function that are known to occur in DAT are not related to ONH structural anomalies, at least in the earlier stages of the disease.

Tattooing and body piercing among adolescent detainees: relationship to alcohol and other drug use.

PURPOSE: The purpose of this preliminary study was to document self-reported tattooing and body piercing behavior among a sample of 860 adolescent detainees. Additionally, the study examined the relationship of alcohol and drug use to tattooing and body piercing--an often overlooked HIV risk behavior. METHODS: Adolescents (N = 860) participating in a substance use and HIV risk reduction intervention were surveyed upon entrance to a Youth Development Campus (YDC). RESULTS: Twenty-nine percent of the sample (N = 245) had at least one tattoo, and more than half (69%) had at least one body piercing. Fifteen percent had two or more tattoos, while 28% had three or more piercings. Although a small percentage of the youth reported knowingly sharing needles for tattoos or piercings (2% and 1.5%, respectively), 21% had tattoos that had been administered unprofessionally and 20% had unprofessionally administered piercings. Marijuana and alcohol were the highest reported substances used in this sample, 62% and 54%, respectively. Alcohol, marijuana, antidepressants, and sedatives were significant correlates of having tattoos. Alcohol was found to be a marginally significant (P = .052) correlate of body piercing. CONCLUSION: The popularity of tattooing and piercing and the risk involved with these activities make them an HIV risk behavior worthy of address. Risk reduction messages to youth should consistently address these behaviors and focus on them as they relate to substance use.

Neuroretinal function is normal in early dementia of the Alzheimer type.

We recently demonstrated that retinal ganglion cell function, optic nerve head parameters and the retinal nerve fiber layer thickness are not altered in early dementia of the Alzheimer type (DAT). Our current objective was to assess whether the function of cells located more distally in the retina is also unaffected by the disease. We evaluated 23 individuals with early to moderate DAT and 23 healthy age-matched subjects, all displaying clinically normal visual function. Scotopic and photopic flash electroretinograms (fERGs) and oscillatory potentials (OPs) were recorded. The amplitude and latency of the retinal potentials did not differ between DAT and control subjects. Our current results showing normal fERGs and OPs in early DAT indicate that the underlying neurons giving rise to these signals are not impaired by the disease process. These data support and extend our recent findings suggesting that visual deficits in DAT do not stem from neuroretinal dysfunction.

Effects of washout and dose-escalation periods on the efficacy, safety, and tolerability of galantamine in patients previously treated with donepezil: ongoing clinical trials.

With the increasing number of acetylcholinesterase inhibitors (AChEIs) being marketed for the treatment of Alzheimer's disease (AD), physicians will need protocols for discontinuing one AChEI and initiating another ("switching"). Three clinical trials have been designed to provide data that will assist in the determination of the optimal conditions for switching patients from donepezil (the most widely prescribed AChEI) to galantamine (the most recently approved AChEI). The main objective of these studies is to investigate the effects of different washout periods (0 to 7 days) and dose-escalation schedules (fixed, fast vs slow) on the efficacy, safety, and tolerability of galantamine in patients with AD who were previously taking donepezil. The duration of the trials ranges from 12 to 52 weeks, and the last trial is expected to end in May 2002. No conclusions can yet be drawn from these ongoing trials, but the results should be helpful in establishing guidelines for physicians to use when switching patients with AD from donepezil to galantamine.

An evaluation of the retinal nerve fiber layer thickness by scanning laser polarimetry in individuals with dementia of the Alzheimer type.

PURPOSE: To determine, using scanning laser polarimetry, whether or not the retinal nerve fiber layer (RNFL) is altered in dementia of the Alzheimer type (DAT). METHODS: Thirty individuals with mild to moderate DAT and 30 healthy age-matched controls participated in the study. Fundus images were acquired with a Nerve Fiber Analyzer. RNFL thickness measurements were obtained under an ellipse located 1.75 disc diameter from the optic nerve head (ONH) center. RESULTS: No differences in RNFL thickness were observed between DAT and healthy subjects. The regional distribution of RNFL thickness was similar between the two test groups, with the RNFL being thickest in the superior and inferior retinal segments relative to the nasal and temporal regions. CONCLUSIONS: Our data indicate that the RNFL is not altered in DAT, at least in the earlier stages of the disease.

Rivastigmine for Alzheimer's disease: Canadian interpretation of intermediate outcome measures and cost implications.

BACKGROUND: Clinical studies have shown that patients with Alzheimer's disease (AD) who are treated with rivastigmine have statistically significantly better scores on 5 scales used to assess AD than control patients receiving placebo. However, the clinical meaning and cost implications of these differences are not clear. OBJECTIVE: The purpose of this study was to assess the clinical meaning and cost implications of statistically significant results obtained in clinical trials of rivastigmine for the treatment of AD. Potential cost implications for the health care system, caregivers, and society are considered. METHODS: Data on clinical effects of rivastigmine were obtained from published North American and European clinical studies of patients with mild to moderately severe AD receiving rivastigmine 6 to 12 mg/d (n = 828) or placebo (n = 647). Differences in scores on the Alzheimer's Disease Assessment Scale-Cognitive Function, Clinician's Interview-Based Impression of Change with both clinical and caregiver information considered, Progressive Deterioration Scale, Mini-Mental State Examination (MMSE), and Global Deterioration Scale were assessed. A convenience panel of 9 Canadian specialists experienced in the treatment of AD provided their opinions on the clinical importance of the trial results. Chart review was performed to identify specific behaviors that improved, and cost implications of improvements were assessed. RESULTS: The panel determined that statistically significant differences in scores on all scales except the MMSE were likely associated with functional or cognitive differences that were clinically relevant for patients, reflecting stabilization that would have beneficial consequences for caregivers and health care resource use. Subsequent chart review showed that improvement on specific scale items confirmed the physician panel's opinion. Analysis of possible cost implications to society indicated that medication expenditures would be offset largely by delays in the need for paid home care and institutionalization, positive effects on caregiver health, and less time lost from work for the caregiver. CONCLUSIONS: From the perspective of a Canadian specialist panel, rivastigmine treatment for AD produces clinically relevant effects for patients that are beneficial to caregivers. These effects suggest decreased use of caregiver resources and delays in the need for institutionalization, both of which reduce societal costs.

[Psychometric properties of the French version of the Modified Mini-Mental State (3MS) in elderly patients evaluated in geriatric psychiatry]. / Les propriétés psychométriques de la version française du Modified Mini-Mental State (3MS) avec des patients âgés suivis en psychiatrie gériatrique.

OBJECTIVE: This research evaluates the psychometric properties of the French version of the Modified Mini-Mental State (3MS), an instrument for the screening of dementia, in a sample of patients seen in geriatric psychiatry. METHODS: Subjects (N = 94, 63 to 93 years of age) were outpatients of a service in geriatric psychiatry. In addition to the 3MS, a battery of tests evaluating the cognitive functioning and depressive symptomatology was administered. RESULTS: Test-retest reliability coefficient was 0.87 for a subsample of 35 subjects. An exploratory factor analysis revealed 4 factors accounting for 63.2% of the variance. Cut-off scores of 79 to 80 (with years of education > or = 8) and 71 to 72 (with years of education < or = 7) presented the best combination sensitivity/specificity, respectively 0.80 and 0.96. CONCLUSIONS: This study documents the psychometric properties of the French version of the 3MS for use in patients seen in geriatric psychiatry, in suggesting cut-off scores which take into account the level of education. This study underlines the influence of sociodemographic variables on test performance.

Translation of clinical and neuropsychological instruments into French: the CERAD experience.

The increasing number of international and epidemiological studies of Alzheimer's disease points to the need for linguistically equivalent translations of measures for identifying the presence, types, and severity of dementia in cross-cultural populations. In translating the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuropsychological instruments into French, several linguistic issues have emerged such as semantic, phonetic, and word-frequency equivalences. In verbal memory tests, these problems, though minor in appearance, can be major pitfalls in studies comparing cognitive function in populations differing in language. Description of the translation procedure and examples of problems encountered are presented, with measures taken to resolve them.

Deep left parietal lobe syndrome: conduction aphasia and other neurobehavioural disorders due to a small subcortical lesion.

A patient with sudden onset of conduction aphasia in the context of an ischaemic stroke is reported. Other neurological and neuropsychological findings included bilateral ideomotor apraxia, right hemisensory defect and paradoxical left ear extinction on a dichotic listening test. Lesion location, as inferred from magnetic resonance imaging, involved a restricted subcortical area in the left parietal lobe, near the lateral wall of the cerebral ventricle. The anatomical correlate for each of the clinical findings is discussed in the light of classical anatomo-clinical correlations. It is concluded that this tetrad constitutes a specific syndrome which may be easily recognised and ascribed to a single lesion in the deep white matter of the left parietal lobe.

Reexamining the concept of adolescence: differences between adolescent boys and girls in the context of their families.

As part of a larger study on family functioning, the authors administered a questionnaire on individual attitudes toward family values to 158 Japanese-American and Caucasian families. Differences between the generations on questions of authority and responsibility were predictable; few differences were found between ethnic groups. However, differences were striking between adolescent boys and girls, regardless of ethnicity: Girls valued family affiliation, closeness, and emotional expression significantly more highly than did boys. The authors emphasize the need for families to value girls' needs for closeness and emotional expression as highly as boys' needs for independence and self-differentiation. They suggest that the concept of separation-individuation as the major goal of adolescence be reexamined.

The lateralizing and localizing value of adversion in epileptic seizures.

We studied 24 patients who had adversion as the first clinical manifestation of seizures. Seizures were recorded with depth electrodes as part of the evaluation for possible surgery for epilepsy. Head rotation did not help to lateralize the epileptic focus clinically, because deviations occurred ipsilaterally to the EEG focus in some patients, and because some patients had head rotation in either direction despite a unifocal epileptogenic abnormality. Furthermore, no cortical localization was consistently linked to either direction or degree of adversion. Adversion has no consistent lateralizing or localizing value.