Maximum Penalized Likelihood Kernel Regression for Fast Adaptation

This paper proposes a nonlinear generalization of the popular maximum-likelihood linear regression (MLLR) adaptation algorithm using kernel methods. The proposed method, called maximum penalized likelihood kernel regression adaptation (MPLKR), applies kernel regression with appropriate regularization to determine the affine model transform in a kernel-induced high-dimensional feature space. Although this is not the first attempt of applying kernel methods to conventional linear adaptation algorithms, unlike most of other kernelized adaptation methods such as kernel eigenvoice or kernel eigen-MLLR, MPLKR has the advantage that it is a convex optimization and its solution is always guaranteed to be globally optimal. In fact, the adapted Gaussian means can be obtained analytically by simply solving a system of linear equations. From the Bayesian perspective, MPLKR can also be considered as the kernel version of maximum a posteriori linear regression (MAPLR) adaptation. Supervised and unsupervised speaker adaptation using MPLKR were evaluated on the Resource Management and Wall Street Journal 5K tasks, respectively, achieving a word error rate reduction of 23.6% and 15.5% respectively over the speaker-independently model.     

Real-time patch-cram detection of intracellular cGMP reveals long-term suppression of responses to NO and muscarinic agonists

Cyclic GMP (cGMP) is a crucial intracellular messenger in neuronal, muscle, and endocrine cells. The intracellular concentration of cGMP is regulated by various neurotransmitters, including acetylcholine (ACh) and nitric oxide (NO). While much is known about the biochemical steps leading to cGMP synthesis, little is known about cGMP kinetics in intact cells. Here, we use "patch-cramming," in which an excised, inside-out membrane patch containing cyclic nucleotide-gated ion channels is used as a biosensor, to obtain the first real-time measurements of cGMP in intact cells. Patch-cramming experiments on neuroblastoma cells show that both muscarinic agonists and NO rapidly elevate cGMP. NO elicits cGMP responses repeatedly without decrement, whereas responses to muscarinic agonists exhibit a profound and prolonged desensitization. Remarkably, muscarinic agonists also cause long-term (>30 min) suppression (LTS) of cGMP responses elicited by NO. Biochemical measurements reveal that rat sympathetic neurons also exhibit LTS of cGMP, suggesting that LTS is a widespread mechanism that may contribute to synaptic plasticity.     

Binding and lysing of blood clots using MRX-408

RATIONALE AND OBJECTIVES: A thrombus-specific ultrasound contrast agent, MRX-408, has been developed recently. This agent consists of phospholipid-coated microbubbles with a ligand capable of targeting the GPIIb/IIIa receptor, thereby allowing the microbubbles to bind with thrombi rich in activated platelets. In vitro and in vivo animal experiments have been conducted to examine imaging enhancement and sonothrombolysis using this agent compared with a nontargeted agent. METHODS: For clot binding, blood-smeared slides were incubated with microbubbles and examined under a light microscope. Change in backscatter signals from the blood clots after binding was examined by both an ultrasound scanner and two single-element transducers arranged in a transmitter-receiver pair. For clot lysis, either 1-MHz or 20-KHz ultrasound was used to enhance the lysing effects of MRX-408 with or without urokinase. RESULTS: Evidence of binding was demonstrated under a microscope. In vitro experiments showed that the "acoustic signature", or properties, of blood clots changed after binding. Clots became more echogenic and nonlinear. In vivo fundamental ultrasound imaging confirmed that as a result of binding, blood clots were more visible, the area of detection was improved, and shadowing behind clots was more noticeable. Under 1-MHz ultrasound and 30 minutes of treatment, lysis efficiency reached 34% with MRX-408, whereas there was no visible clot lysis with saline. CONCLUSION: The results of these preliminary studies show that as a contrast agent, MRX-408 enhanced clots under ultrasound imaging and facilitated sonothrombolysis with or without thrombolytic drugs.     

A novel polymer microneedle fabrication process for active fluidic delivery

In this article, we explore a new fabrication process for a flexible, all polymer, active fluidic delivery system, incorporating a fusion of laser micromachining and microfabrication techniques as well as rapid prototyping technology. Here, we show selective fluidic delivery from isolated microchannels through an electrochemically driven pumping reaction, demonstrate the dispensing of dose volumes up to 5.5 μl, and evaluate the device’s performance in terms of its delivery speed and ejection efficiency. Finally, we move this work toward an implantable microfluidic drug delivery device by investigating the device’s biocompatibility through a statistical approach that overviews the viability of bovine aortic endothelial cells on polyimide and silicon substrates.     

In-vitro study of medial strain distribution in the femur during impaction grafting

Impaction bone grafting (IBG) is widely used for revision hip surgery to compensate for bone stock loss. It is performed by impacting morsellized allograft into the femoral canal and acetabulum prior to cementing new total hip components. Per- and post-operative femoral fractures and post-operative implant subsidence are major complications in IBG. The aim of this study was to investigate the strain distribution on the medial side of the femur during impaction grafting and the subsequent stability of the stem under uniaxial cyclic loading. The Exeter IBG technique was used in conjunction with Howmedica X-change instrumentation. Sawbones composite femora were used. An impactometer, which provides a known impaction energy and momentum, was used to standardize the impaction process. Three drop heights, 130, 260, and 390 mm, were used for proximal impaction. In-vitro medial hoop strains and the number of impacts were recorded. A drop height of 260 mm was found to provide sufficient energy for impaction without introducing excessive strains to achieve implant stability. Furthermore, a feasibility study was performed on the use of a proximal impaction cap (PIC) to restrain extrusion of the graft during impaction. Although no significant difference in impaction strains or stem stability in uniaxial cylic loading was found by using a PIC, it is postulated that the design of a proximal impactor could be improved to assist with proximal stem alignment and graft containment.     

Development of a web-based system for engineering change management

Engineering changes (ECs) are changes and/or modifications in forms, fits, functions, materials, dimensions, etc., of products and constituent components. ECs usually induce a series of downstream changes. Multiple disciplines and responsibilities are therefore involved in managing ECs. Previous investigations conducted by the authors and other researchers have shown that paper-based and standalone computerised EC management (ECM) systems have limited support for such intensive teamwork and close communication. This paper proposes to establish a web-based framework that supports ECM procedures and activities. A web-based ECM system is able to provide better information sharing, simultaneous data access and processing and more prompt communication and feedback. The amount of paperwork and the throughput time of managing ECs are significantly reduced while the effectiveness and the efficiency are substantially improved. This paper focuses on discussing the issues of design, development, and implementation of this prototype web-based ECM system.     

Collection and transfusion of blood and blood components in the United States, 1989

A poor response to L-DOPA in addition to parkinsonian, cerebellar, and autonomic signs is commonly regarded as indicative of clinical multiple system atrophy (MSA). We compared the motor response to a single oral administration of 250 mg L-DOPA/25 mg carbidopa in eight MSA patients and eight Parkinson's disease (PD) patients with the "on-off" phenomenon, evaluating L-DOPA peripheral pharmacokinetics. Motor response was consistently good in all PD patients, but only four MSA patients had a (moderate) response. Pharmacokinetic parameters did not differ between the groups. The varying extent of putaminal damage could be responsible for the differing motor response to L-DOPA in MSA patients.     

Age incidence of meningococcal infection England and Wales, 1984-1991

Gene transfer with vectors derived from murine retroviruses is restricted to cells which are proliferating and synthesizing DNA at the time of infection. This suggests that retroviral-mediated gene transfer might permit targeting of gene integration into malignant cells in organs composed mainly of quiescent nonproliferating cells, such as in the brain. Accordingly, selective introduction of genes encoding for susceptibility to otherwise nontoxic drugs ("suicide" genes) into proliferating brain tumors may be used to treat this cancer. We investigated the efficacy and dynamics of in vivo transduction of growing brain tumors with the herpes simplex-thymidine kinase gene followed by administration of the antiviral drug ganciclovir. Ganciclovir is phosphorylated by thymidine kinase to toxic triphosphates that interfere with DNA synthesis, resulting in the preferential death of the transduced tumor cells. Rats inoculated with 4 x 10(4) 9L gliosarcoma cells into the frontal lobe were treated 7 days later with an intratumoral stereotaxic injection of murine fibroblasts (NIH 3T3 cells) that were producing a retroviral vector containing the herpes simplex-thymidine kinase gene. Controls received vector producer and nonproducer NIH 3T3 cell lines containing the Escherichia coli lacZ (beta-galactosidase) gene as well as nonproducer NIH 3T3 cells containing the thymidine kinase gene. The animals were rested for 7 days to allow time for in situ transduction of the proliferating tumor cells with the herpes-thymidine kinase retroviral vector. The animals were then treated with ganciclovir, 15 mg/kg i.p. twice a day for 14 days. Gliomas receiving an injection of 3-5 x 10(6) thymidine kinase producer cells regressed completely in 23 of 30 rats given ganciclovir therapy, while 25 of 26 control rats developed large tumors. Intratumoral injection of a lower concentration of thymidine kinase vector producer cells (1.8 x 10(6)) resulted in a lower frequency of tumor regression (5 of 13 rats). To estimate the efficiency of in vivo gene transfer, 9L brain tumors were given injections of 5 x 10(6) beta-galactosidase vector producer cells. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranaside staining revealed maximal staining of beta-galactosidase within the tumor 7-14 days after injection of the vector producer cells. In vivo transduction rates in harvested tumors ranged from 10 to 70%. There was no evidence of transduction of the surrounding normal neural tissue. Occasional blood vessel endothelial cells within or adjacent to the tumor were observed to be 5-bromo-4- chloro-3-indolyl-beta-D-galactopyranaside positive.(ABSTRACT TRUNCATED AT 400 WORDS)     

Activation of the mouse heart adenosine 5',5"'-P1-P4-tetraphosphate receptor

We have previously demonstrated that mouse brain membrane fractions have a specific, saturable receptor for diadenylated nucleotides. Binding is specific for two adenosines, and the length of the phosphate bridge is critical, with four phosphates being optimal [Hilderman et al. (1991) J. Biol. Chem. 266, 6915-6918]. In this report, we demonstrate that adenosine 5',5"'-P1,P4-tetraphosphate (Ap4A) binding to its receptor is dependent upon an activation step that requires divalent cations and a serine protease. Monoclonal antibodies (Mabs) are identified that inhibit Ap4A binding to its membrane receptor. These antibodies recognize a 212-kDa membrane protein. However, SDS-PAGE analysis of Ap4A cross-linked to membrane fractions reveals that Ap4A is not attached to the 212-kDa peptide but to a 30-kDa polypeptide. Appearance of the 30-kDa polypeptide is dependent on the activation step, and one of the inhibitory antibodies blocks its appearance. We suggest that the protease-dependent processing step involves cleavage of the 212-kDa component with the appearance of an active 30-kDa receptor.     

Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children

We have followed the growth of stature, sitting height, skinfolds, muscle widths measured radiologically, and skeletal maturity in growth hormone-deficient patients in whom hGH was given and withheld in alternating three-month periods throughout puberty (referred to as "off-hGH" and "on-hGH" periods). Six boys and four girls had true isolated GH deficiency and developed puberty spontaneously. Two boys had gonadotrophin deficiency plus GH deficiency, and five boys had multiple deficiencies; in these boys the signs of puberty were induced by hormone treatment. Boys with true isolated deficiency grew about two-thirds as much in height in the off-hGH periods as in the on-hGH periods; their total gain in height during the adolescent spurt would have been about 20 cm, instead of 30 cm, if hGH had been discontinued at the beginning of puberty. The effect of hGH was entirely on growth in leg-length, however, which virtually ceased during the off-hGH periods. Growth in sitting height altered little when hGH was withdrawn. Growth in limb muscles, however, was GH dependent throughout puberty; during the majority of periods when hGH was withheld, muscle was actually lost; this occurred in the boys who were receiving large doses of testosterone as well as in those producing their own normal amounts. Subcutaneous fat diminished when hGH was given and increased when it was withdrawn; this occurred independently of administration of testosterone. There was little evidence that growth of pubic and axillary hair progressed faster during on-hGH periods, except perhaps in patients with multiple deficiencies. There was some evidence, however, that bone age progressed less rapidly during on-hGH periods than during off-hGH periods in the patients with isolated deficiency. The results in the girls agreed with those in boys so far as stature was concerned, but the relationship with sitting height and leg length appeared to be different; the reasons for this are discussed. We conclude that all children with GH deficiency should continue on treatment with hGH throughout puberty, ideally until growth ceases.