An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer

Cystic fibrosis (CF) is an inherited disease of epithelial cell ion transport that is associated with pathology in multiple organ systems, including lung, pancreas, and liver. As treatment of the pulmonary manifestations of CF has improved, management of CF liver disease has become increasingly important in adult patients. This report describes an approach for treating CF liver disease by somatic gene transfer. In situ hybridization and immunocytochemistry analysis of rat liver sections indicated that the endogenous CFTR (cystic fibrosis transmembrane conductance regulator) gene is primarily expressed in the intrahepatic biliary epithelial cells. To specifically target recombinant genes to the biliary epithelium in vivo, recombinant adenoviruses expressing lacZ or human CFTR were infused retrograde into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days. These studies suggest that it may be feasible to prevent CF liver disease by genetically reconstituting CFTR expression in the biliary tract, using an approach that is clinically feasible.     

Propagation of granulocytic Ehrlichia spp. from human and equine sources in HL-60 cells induced to differentiate into functional granulocytes

Ehrlichia spp. from human and equine sources in the northeastern Unites States were detected by PCR, isolated, and propagated in the HL-60 promyelocytic leukemia cell line. Growth of Ehrlichia from both equine and human sources was enhanced by addition of retinoic acid, which causes granulocytic differentiation of the HL-60 cells. DNA sequencing of a portion of the 16S rDNA gene supported the hypothesis that the same pathogen was responsible for both equine and human granulocytic ehrlichiosis.     

Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia

Infants with congenital diaphragmatic hernia (DH) and profound pulmonary hypoplasia are currently unsalvageable. The authors previously demonstrated that tracheal ligation (TL) accelerates fetal lung growth and reverses the pulmonary hypoplasia of fetal nephrectomy. The purpose of this study was to determine if the pulmonary hypoplasia of experimental DH could be similarly reversed and, if so, whether the resulting lungs would show better function than those of their DH counterparts. Eighteen fetal lambs were divided into three experimental groups of six animals each. In group 1, DH was created at 90 days' gestation. In group 2, DH was created at 90 days' gestation and TL performed during the same operation. Group 3 consisted of sham-operated controls. These animals were delivered near full-term, and their lungs analyzed by standard morphometric techniques. Ten additional fetal lambs were divided into two experimental groups of five animals each. In group 4, DH was created at 90 days' gestation. In group 5, DH was created at 90 days' gestation and TL performed 20 days later, at 110 days' gestation. These animals were pressure-ventilated via tracheostomy over a 2-hour period in which PaO2, PaCO2, and compliance were measured. Intratracheal pressure (ITP) was measured at the time of delivery in all groups. Upon retrieval, DH animals had abdominal viscera in the chest and small lungs; in contrast, DH/TL animals had the herniated viscera reduced from the chest by enlarged lungs. DH/TL lungs showed markedly increased growth, with significant increases in lung volume:body weight ratio (LV:BW; P = .0001), alveolar surface area (ALV.SA; P = .0001), and alveolar number (ALV#) (P = .0001) when compared with those of the DH or control group. This growth was associated with a normal maturation pattern based on histological appearance, normal airspace fraction, and normal alveolar numerical density. ITP in the DH/TL group was increased when compared with that of DH and control animals (P = .0001). Total lung DNA and protein were both elevated in the DH/TL animals (P = .0001). However, the DNA:protein ratio remained normal, suggesting lung growth had occurred through cell proliferation, not by hypertrophy. When ventilated over a range of settings, DH/TL lungs were more compliant (P = .0001) and achieved higher PaO2s (P < .003) and lower PaCO2s (P = .0001) than their DH counterparts. From these data, the authors conclude: (1) Experimental fetal DH produces hypoplastic lungs that are not capable of adequate gas exchange with conventional ventilation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Nanocell logic gates for molecular computing

Molecular electronics seeks to build electrical devices to implement computation - logic and memory - using individual or small collections of molecules. These devices have the potential to reduce device size and fabrication costs, by several orders of magnitude, relative to conventional CMOS. However, the construction of a practical molecular computer will require the molecular switches and their related interconnect technologies to behave as large-scale diverse logic, with input/output wires scaled to molecular dimensions. It is unclear whether it is necessary or even. possible to control the precise regular placement and interconnection of these diminutive molecular systems. This paper describes genetic algorithm-based simulations of molecular device structures in a nanocell where placement and connectivity of the internal molecular switches are not specifically directed and the internal topology is generally disordered. With some simplifying assumptions, these results show that it is possible to use easily fabricated nanocells as logic devices by setting the internal molecular switch states after the topological molecular assembly is complete. Simulated logic devices include an inverter, a NAND gate, an XOR gate and a 1-bit adder. Issues of defect and fault tolerance are addressed.     

Dynamic thermographic imaging for estimation of regional perfusion in the tuberculin reaction in healthy adults

A sensitive method for measurement of the volume of blood flow through the skin, based on the kinetics of reheating after localised cooling, is described in this paper. This method has been used to study the tuberculin reaction as a model of cutaneous delayed-type hypersensitivity (DHS) in man. Over the positive reaction there is accelerated reheating similar in kinetics and extent to that seen after maximal hyperaemia induced by intradermal injection of histamine or prostaglandin E2. The earlier phase of reheating (10-100 s) is more dependent on blood flow, whereas the later phase (100-300 s) is apparently more dependent on non-perfusion heat exchange mechanisms, including conduction. The reheat kinetic method is largely dependent on blood flow in the deep dermal vessels (diameter > 50 microns), whereas the alternative approach of measurement of the velocity of flow of erythrocytes in the microcirculation by laser Doppler (LD) flowmetry gives results biased towards the most superficial dermal circulation. Previous studies with LD flowmetry have shown that the blood velocity is greatest at the centre of weak and strong reactions, while in the most intense reactions it is raised at the centre but maximal at the periphery (central relative slowing, CRS) raising the possibility of central ischaemia. The reheat kinetics approach has now indicated that the deep dermal circulation is not impaired in CRS reactions. It is concluded that there must be partial obstruction of the parts of the microcirculation communicating between the deep and superficial dermal plexuses, presumably from the accumulation of exudate oedema in the most intense tuberculin reactions.     

Finance and the technology-trade nexus

This paper sketches the contours of the evolving international/monetary system and examines the various roles of the intemediation mechanisms. Then it examines the extent to which the financial system is independent from the “real economy” and the various ways in which it impacts it. The paper discusses some views in good currency on the dynamics of the technology-trade-finance nexus and shows how the financial system influences organization, location and technology choices in meso-innovation systems. The final section of the paper looks at the policy implications that might be derived from the analysis and suggests some directions for the future research.     

Information processing deficits associated with developmental coordination disorder: a meta-analysis of research findings

A meta-analysis was conducted to identify information processing factors that characterise children with Developmental Coordination Disorder (DCD). A total of 50 studies yielded 374 effect sizes based on 983 DCD and 987 control children. A mild generalised performance deficit was indicated, since motor-impaired children were inferior on almost all measures of information processing. There were, however, several areas where their deficiencies were more pronounced. The greatest deficiency was in visual-spatial processing. This was evident regardless of whether or not the tasks involved a motor component. Most other deficiencies were in the small-to-moderate range and included kinaesthetic and cross-modal processing. The findings support the notion that perceptual problems, particularly in the visual modality, are associated with difficulties in motor coordination.     

Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observation in blood

The development of a hypoglycemic alarm system using a subcutaneous glucose sensor implies that a decrease in blood glucose is rapidly followed by a decrease in the signal generated by the sensor. In a first set of experiments the linearity and the kinetics of the response of sensors implanted in the subcutaneous tissue of normal rats were investigated during a progressive increase in plasma glucose concentration: the sensitivities determined between 5 and 10 mM and between 10 and 15 mM were not significantly different, and a 5-10 min delay in the sensor's response was observed. In a second set of experiments, performed in diabetic rats, the kinetics of the decrease in subcutaneous glucose concentration following insulin administration was monitored during a decrease in plasma glucose level, from 15 to 3 mmol/L. During the 20 first min following insulin administration, the sensor monitored glucose concentration in subcutaneous tissue with no lag time. Subsequently, the decrease in the estimation of subcutaneous glucose concentration preceded that of plasma glucose. This phenomenon was not observed when the same sensors were investigated in vitro during a similar decrease in glucose concentration and may be due to a mechanism occurring in vivo, such as the effect of insulin on glucose transfer from the interstitial space to the cells surrounding the sensor. It reinforces the interest of the use of implantable glucose sensors as a part of a hypoglycemic alarm.     

A Programmable Pulse Sequence Generator for an NMR Relaxometer

A pulse sequence generator for NMR relaxometer is described. The operation mode is loaded into the internal memory of the device by a program from a personal computer via a PCI bus. The project is realized on two MAX7000S and Cyclone (Altera) chips using the Qartus II 4.0 software. The basic parameters of the device are as follows: the minimal pulse length is 50 ns, the time resolution is 10 ns, the maximum number of pulses is 1024, and the number of controlled output channels is 8. This device, operating in the automatic mode as part of the hardware-software NMR system, makes possible recording, processing, and storing experimental results in electronic form.