Nonlinear microfluidics: device physics, functions, and applications.

The microfluidic flow is typically laminar due to the dominant viscous effects. At Reynolds numbers far below 1 (Re ≪ 1), the fluid inertia can be neglected. For the steady flow of incompressible Newtonian fluids, it approaches linear Stokes flow. At intermediate Re, there exists a weak-inertia flow regime where secondary flows such as Dean vortices are accessible for microfluidic manipulations. Apart from the fluid inertia, other nonlinear factors such as the non-Newtonian fluid properties, concurrent flow of dissimilar fluids, compliant fluidic structures and stimuli-responsive materials can also cause intriguing flow behaviours. Through proper designs, they can be applied for a variety of microfluidic components including mixers, valves, oscillators, stabilizers and auto-regulators etc., greatly enriching the microfluidic flow control and manipulation strategies. Due to its unique working characteristics and advantages, nonlinear microfluidics has increasingly attracted extensive attention. This review presents a systematic survey on this subject. The designs of typical nonlinear microfluidic devices, their working mechanisms, key applications, and the perspective of their future developments will be discussed. The nonlinear microfluidic techniques are believed to play an essential role in the next generation of highly-integrated, automated, and intelligent microfluidics.

Fetal growth at different gestational periods and risk of impaired childhood growth, low childhood weight and obesity: a prospective birth cohort study.

OBJECTIVE: To examine the longitudinal associations of fetal growth with adverse child growth outcomes and to assess whether maternal metabolic factors modify the associations. DESIGN: Prospective cohort study. SETTING: Born in Guangzhou Cohort Study, China. POPULATION: A total of 4818 mother-child pairs. METHODS: Fetal growth was assessed according to estimated fetal weight (EFW) from 22 weeks of gestation until birth and the measurement of the birthweight. Fetal growth Z-scores were computed from random effects in the multilevel linear spline models to represent fetal size in early pregnancy (22 weeks of gestation) and growth in mid-pregnancy (22-27 weeks of gestation), early third trimester (28-36 weeks of gestation) and late third trimester (≥37 weeks of gestation). MAIN OUTCOME MEASURES: Z-scores for childhood stunting, low weight, overweight or obesity, length/height for age (LAZ/HAZ), weight for age (WAZ) and body mass index for age (BMIZ) at the age of 3 years. Adjusted associations were examined using multiple Poisson or linear regression models. RESULTS: Increased Z-scores of fetal size in early pregnancy and growth in mid-pregnancy and early third trimester were associated with a higher risk of childhood overweight or obesity (risk ratios 1.25-1.45). Fetal growth in each period was negatively associated with stunting and low weight, with the strongest associations observed for fetal size in early pregnancy and growth in mid-pregnancy. The results for continuous outcomes (LAZ/HAZ, WAZ and BMIZ) were similar. The associations of fetal growth with overweight or obesity in childhood were stronger among mothers who were underweight and who were overweight or obese than among mothers of normal weight. CONCLUSIONS: Accelerated fetal growth before 37 weeks of gestation is associated with children who are overweight or obese, whereas the critical period for stunting and low weight occurs before 28 weeks of gestation. TWEETABLE ABSTRACT: Fetal growth during different periods is differentially associated with childhood stunting, underweight and overweight or obesity.

Distribution of common pathogens in patients with pyogenic liver abscess in China: a meta-analysis.

Pyogenic liver abscess (PLA) is a potentially life-threatening disease in many parts of the world, especially in Asia. The aim of this study was to quantify the proportion of common pathogens in patients with PLA in China, using a meta-analysis method based on systematic review of published studies. Several electronic databases were searched to identify the studies reporting the pathogens of PLA. We performed a meta-analysis to calculate the pooled proportion of pathogens and subgroup analysis among the included studies using R 3.1.1 software. In total, 183 studies were included in our final analysis, Klebsiella spp (54 %), Escherichia spp (29 %), Enterobacter spp (9 %), Proteus spp (6 %) and Pseudomonas spp (5 %) comprised the major gram-negative bacteria. Gram-positive bacteria mainly included Staphylococcus spp (13 %), Streptococcus spp (8 %) and Enterococcus spp (7 %). The distribution of pathogens in PLA patients were different in different economic regions in China. The proportion of Klebsiella spp had an upward tendency in recent years compared to other pathogens. In addition, the proportion of common pathogens in PLA patients with diabetes mellitus (DM) were carried out indicating that the dominant pathogens were Klebsiella spp (66 %), Escherichia spp (21 %) and Enterobacter spp (11 %). This meta-analysis showed that the main pathogens of PLA were Klebsiella spp, Escherichia spp, Staphylococcus spp, and Enterobacter spp in China. To ensure a precise estimate of the epidemiology of the pathogens, further large-scale or even a population-based study is needed.

Three-dimensional digital visible heart model and myocardial pathological characteristics of fetal single ventricle connected with aortic coarctation.

This study aimed to provide data for imaging diagnosis and clinical surgical plans by reconstructing a three-dimensional (3-D) digital visible heart model of single ventricle (SV) connection with aortic coarctation (CoA) and characterizing the myocardial and vascular wall pathological characteristics. Fifteen miscarried fetus cadavers with SV and CoA were selected. Fourteen cardiac specimens were systematically reviewed for segmental anatomy and conventional histological examinations. One fetus cadaver was used to obtain the structural dataset of the fetal body and to reconstruct a 3-D digital visible heart model. Specimen pathological dissection indicated hypertrophic myocardium SV, significant aortic wall thickening, and localized coarctation area elevation. Ten cases of SV with left ventricular morphology displayed a large muscle ridge and solitus normally aligned great arteries. Five cases of SV with right ventricular morphology had coarse, parallel trabeculations and received a common atrioventricular valve. The reconstructed 3-D heart and the main internal structures were realistic, which were beneficial for clinical and image teaching of fetal heart development. The change of characteristics of the myocardium and great vascular wall was obvious and may be the critical cause leading to progressive dysfunction in the postnatal heart.

Aeroelasticity-based fluid agitation for lab-on-chips.

In this study, we report a robust agitation method for small-volume liquids. It utilizes an elastic diaphragm as the bottom of a liquid chamber, upon which an initial tension is also applied to enhance the aeroelasticity effects at small/micro scales. As a result, spontaneous vibration of the diaphragm can be induced by an external air flow, which further provides fluid agitations. The device structure is simple and can be easily fabricated at low cost. More importantly, the vibration amplitude is controllable and varies widely from several tens to several hundred micrometers depending on the applied air pressure. The resulting agitation is effective and applicable at high viscosities of up to 900 cSt. The influences of air pressure and liquid viscosity on the vibration frequency are discussed. Potential applications of this technique for solid particle agitation, focusing and fluid mixing are also demonstrated.

Converting steady laminar flow to oscillatory flow through a hydroelasticity approach at microscales.

We report a hydroelasticity-based microfluidic oscillator that converts otherwise steady laminar flow to oscillatory flow. It incorporates an elastic diaphragm to enhance nonlinearity of the flow. Negative differential flow resistance is observed. High-frequency oscillatory flow is produced passively through interactions among hydrodynamic, elastic and inertial forces, without resorting to external actuators and control equipment. Driven by fluid flow and pressure, this device can operate in either steady laminar flow or oscillatory flow states, or work as a valve. Its applications for flow control and operation, and mixing enhancement are demonstrated.

A microfluidic mixer with self-excited 'turbulent' fluid motion for wide viscosity ratio applications.

In micromixer studies, compared with the design, modeling and characterization, the influence of the fluid properties on mixing has been less discussed. This topic is of practical significance as the properties of diverse biological and chemical liquids to be mixed have large variations. Here, we report a microfluidic mixer for mixing fluids with widely different viscosities. It contains an interconnected multi-channel network through which the bulk fluid volumes are divided into smaller ones and chaotically reorganized. Then, the multiple fluid streams are driven into an expansion chamber which triggers viscous flow instabilities. Experiments with the co-flow of glycerol and aqueous solutions show an automatic transition of the flow from a steady state to a 'turbulent' state, significantly enhancing the mixing. This observation is rather interesting considering that it occurs in a passive flow and the average Reynolds number involved is small. Further testing indicates that this mixer works well at viscosity ratio (chi) up to the order of 10(4).

Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis.

Interferon (IFN) has been used in the treatment of chronic hepatitis B for decades. Beneficial effects including hepatitis B e antigen/HBV DNA seroclearance have been documented. However, the effect of treatment on the prevention of cirrhosis and hepatocellular carcinoma (HCC) development remains controversial. We conducted a meta-analysis of available literature to evaluate whether IFN reduces the incidence of liver cirrhosis and HCC in patients with chronic hepatitis B. Twelve clinical controlled trials, including 2082 patients and comparing IFN with no treatment, were selected. Data on the incidence of liver cirrhosis and HCC in IFN treated and untreated patients were extracted from each study. The evaluation of preventive effectiveness was performed with an intention-to-treat method. The relative risk (RR) and 95% confidence interval (CI) of the main outcomes as a measure of efficacy were used. Meta-analysis was performed using fixed-effect or random-effect methods, depending on absence or presence of significant heterogeneity. Analyses were performed with STATA version 9.0 and Review Manager Version 4.2. Five studies including the data on development of liver cirrhosis, and eleven studies including the data on development of HCC were analyzed. There was no evidence for publication bias on the funnel plot or by Egger's test, and the heterogeneity test indicated that the variation of trial-specific RR was not statistically significant. A different incidence of liver cirrhosis and HCC was observed between treated and untreated patients. The RR of liver cirrhosis and HCC was 0.65 (95% CI: 0.47, 0.91) and 0.59 (95% CI: 0.43, 0.81), respectively. In conclusion, the results of this meta-analysis indicate that IFN prevents or delays the development of liver cirrhosis and HCC in patients with chronic hepatitis B.

Chaotic micromixers using two-layer crossing channels to exhibit fast mixing at low Reynolds numbers.

We report two chaotic micromixers that exhibit fast mixing at low Reynolds numbers in this paper. Passive mixers usually use the channel geometry to stir the fluids, and many previously reported designs rely on inertial effects which are only available at moderate Re. In this paper, we propose two chaotic micromixers using two-layer crossing channels. Both numerical and experimental studies show that the mixers are very efficient for fluid manipulation at low Reynolds numbers, such as stretching and splitting, folding and recombination, through which chaotic advection can be generated and the mixing is significantly promoted. More importantly, the generation of chaotic advection does not rely on the fluid inertial forces, so the mixers work well at very low Re. The mixers are benchmarked against a three-dimensional serpentine mixer. Results show that the latter is inefficient at Re = 0.2, while the new design exhibits rapid mixing at Re = 0.2 and at Re of O(10(-2)). The new mixer design will benefit various microfluidic systems.

Prenatal dexamethasone rescues heart hypoplasia in fetal rats with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Patients and rats with congenital diaphragmatic hernia (CDH) have lung and heart hypoplasia. Prenatal steroids improve lung hypoplasia in CDH rats. The current study tests the hypothesis that prenatal dexamethasone could rescue heart hypoplasia in rats with CDH. METHODS: Timed pregnant rats received intragastrically either 100 mg nitrofen or oil on day 9.5, and other animals had the same treatment with, in addition, either 0.25 mg/kg dexamethasone intraperitoneally or no treatment on days 19 and 20. Fetuses were recovered on day 21, and heart weight to body weight ratios, heart DNA, protein, and glycogen were measured in fresh specimens. Left-to-right ventricular diameter and aortic-to-pulmonary diameter ratios were measured after formalin fixation. RESULTS: Wet heart weight to body weight, left-to-right ventricular diameter, and aortic-to-pulmonary root diameter ratios, which were lower in fetuses exposed only to nitrofen than in their oil controls, were similar in those exposed to nitrofen plus dexamethasone than in their corresponding oil plus dexamethasone controls. Total heart DNA, which was decreased in fetuses exposed to nitrofen with CDH in comparison with their controls, was increased in those receiving nitrofen and dexamethasone in comparison with theirs. Protein to DNA ratio was decreased in all rats with CDH irrespective of their exposure or not to dexamethasone. Glycogen to DNA ratio was higher in all dexamethasone-treated fetuses than in those without this treatment. No gross histologic differences were seen among groups. CONCLUSIONS: Heart hypoplasia in rats with CDH is in part rescued by prenatal dexamethasone treatment as expressed by increased number of smaller myocytes with higher glycogen content. Prenatal steroids could modify heart involvement in human fetuses with CDH as well.

The contribution of the adriamycin-induced rat model of the VATER association to our understanding of congenital abnormalities and their embryogenesis.

The adriamycin-induced rat model of the VATER association has provided a means of studying the morphogenesis of a variety of major congenital structural abnormalities similar to those seen in humans with the VATER association. Most interest has been centered on the foregut, where the model has clarified some aspects of the development of esophageal atresia (EA), tracheal agenesis, and other communicating bronchopulmonary foregut malformations. It has demonstrated aberrations in the nerve supply to the esophagus in EA and allowed the study of tracheomalacia. A relationship between an abnormal notochord, foregut abnormalities, and vertebral defects has been shown, and the model has reignited interest in the role of the notochord as a regional organizer of axial development. The normal temporospatial characteristics of apoptosis during fore- and hindgut development is disturbed in this model, resulting in abnormal morphology. The indications are that this model will continue to clarify the processes that lead to many of the structural congenital abnormalities that are seen in infants born with the VATER association.

Down-regulation of thyroid transcription factor-1 gene expression in fetal lung hypoplasia is restored by glucocorticoids.

The thyroid transcription factor (TTF)-1 has an essential role in lung morphogenesis and development. It is involved in the transcription of surfactant proteins (SP), which are critical in respiratory function. Neonates with congenital diaphragmatic hernia die of respiratory failure caused by pulmonary hypoplasia with associated biochemical immaturity. To gain new insights into the causes of this disorder and the effect of prenatal hormonal treatment on reducing mortality in these infants, we evaluated the expression of TTF-1 as marker of lung morphogenesis and SP-B as marker of lung maturity. Using a rat model of lung immaturity, we show that TTF-1 and SP-B messenger RNA (mRNA) levels are drastically reduced in congenital lung hypoplasia. Interestingly, prenatal dexamethasone (Dex) treatment increased both TTF-1 and SP-B mRNAs over control levels when administered to rats with lung hypoplasia, but it had no effect on TTF-1 or a moderate effect on SP-B mRNA when administered to control rats. TRH alone also increases TTF-1 and SP-B mRNA levels but to a lesser extent than Dex. When administered together with Dex, TRH counteracts the induction observed with the glucocorticoid. The decrease in TTF-1 mRNA levels in lung hypoplasia is paralleled by a down-regulation of TTF-1 protein levels, as well as by a decrease in the TTF-1/DNA complex when the TTF-1-binding site of the SP-B promoter was used as a probe. Both parameters were reestablished after glucocorticoid treatment. Moreover, the regulation of TTF-1 gene expression described in this report is accompanied by the same regulation in its promoter activity, as demonstrated in transfection experiments performed in H-441 human lung-derived adenocarcinoma cells. In conclusion, our data demonstrate, for the first time, that lung hypoplasia and the associated respiratory dysfunction caused by SP-B deficiency are caused, in part, by down-regulation of TTF-1 gene expression. The observations that prenatal glucocorticoid treatment induces the expression of TTF-1 supports routine in utero glucocorticoid treatment of patients expected to have lung hypoplasia.

Malformaciones esqueléticas en la atresia de esófago: estudio clínico y esperimental / Squeletal malformations in esophageal atresia: clinical and experimental study

Las asociaciones malformativas nos dan la clave para comprender la embriogénesis de sus componentes.El objetivo de nuestro trabajo es comparar las malformaciones esqueléticas(ME)de un modelo teratogénico de atresia de esófago(AE) en fetos de ratas con ME de la AE clínica y esbozar un posible mecanismo patogénico común.Para ello revisamos las historias y radiografías de 443 niños con AE tratados entre los años 1965 y 1996.Se indujo la aparición de AE en las camadas de 16 ratas mediante la inyección de adriamicina en los días 8 y 9 de la gestación.A los embriones recuperados se les tiño el esqueleto de azul alcián y rojo alizarina para evidenciar la presencia de anomalías.De los 443 pacientes estudiados,239(53,9 por ciento)tenían una o más malformaciones esqueléticas asociadas,siendo las más frecuentes:hipersegmentación vertebral(n=102)hipoplasia sacra(n=42)vértebras malformadas principalmente torácicas(n=47) e hipoplasia radial y del pulgar(n=57).De 52 embriones de rata con atresia de esófago todos ellos tenían alguna anomalía esquelética,siendo frecuentes las vértebras torácicas malformadas(n=52) y la hipoplasia sacra(n=27).La asociación de malformaciones esofágicas,vertebrales y de los miembros en el mismo individuo,sugiere que estas anomalías se deben a un mecanismo patogénico común tanto en la rata,como en el humano,capaces de alterar tanto la segmentación como la organización del mesodermo paraxial durante la organogénesis.La naturaleza de las malformaciones encontradas sugiere que los genes Hox podrían estar involucrados en la etiología de la AE

Malformaciones esqueléticas en la atresia de esófago: estudio clínico y esperimental / Squeletal malformations in esophageal atresia: clinical and experimental study

Las asociaciones malformativas nos dan la clave para comprender la embriogénesis de sus componentes.El objetivo de nuestro trabajo es comparar las malformaciones esqueléticas(ME)de un modelo teratogénico de atresia de esófago(AE) en fetos de ratas con ME de la AE clínica y esbozar un posible mecanismo patogénico común.Para ello revisamos las historias y radiografías de 443 niños con AE tratados entre los años 1965 y 1996.Se indujo la aparición de AE en las camadas de 16 ratas mediante la inyección de adriamicina en los días 8 y 9 de la gestación.A los embriones recuperados se les tiño el esqueleto de azul alcián y rojo alizarina para evidenciar la presencia de anomalías.De los 443 pacientes estudiados,239(53,9 por ciento)tenían una o más malformaciones esqueléticas asociadas,siendo las más frecuentes:hipersegmentación vertebral(n=102)hipoplasia sacra(n=42)vértebras malformadas principalmente torácicas(n=47) e hipoplasia radial y del pulgar(n=57).De 52 embriones de rata con atresia de esófago todos ellos tenían alguna anomalía esquelética,siendo frecuentes las vértebras torácicas malformadas(n=52) y la hipoplasia sacra(n=27).La asociación de malformaciones esofágicas,vertebrales y de los miembros en el mismo individuo,sugiere que estas anomalías se deben a un mecanismo patogénico común tanto en la rata,como en el humano,capaces de alterar tanto la segmentación como la organización del mesodermo paraxial durante la organogénesis.La naturaleza de las malformaciones encontradas sugiere que los genes Hox podrían estar involucrados en la etiología de la AE

[The effect of enriched branched chain amino acid solution with hypocaloric TPN on acute phase protein, plasma amino acid profile metabolism in postoperative children].

From 1988 to 1990, 27 postoperative children with aganglionic megacolon were studied prospectively. They were randomly divided into three groups according to the postoperative fluid supply: group A, dextrose, group B, balanced amino acid solution (24% branch chain amino acid); and group C, solution enriched with branched chain amino acid (45% BCAA). The serum acute phase protein and plasma amino acid profile were observed. Nitrogen balance was monitored daily in all groups during the perioperative period. The data showed that prealbumin, transferrin rose more rapidly in group C than in group A and group B. The solution of 45% BCAA was found to be superior to balanced 24% BCAA in normalizing the disorder of plasma amino acid spectrum on the 3rd day and 7th day after operation. Urea nitrogen excretion was reduced in group C more rapidly than in group A and group B on the 4th day after operation. Using solution enriched branched chain amino acid with hypocaloric TPN in postoperative children can achieve an effective nitrogen sparing effect.