Suspended Liquid Subtractive Lithography: One-step generation of 3D channel geometries in viscous curable polymer matrices.

The miniaturization of synthesis, analysis and screening experiments is an important step towards more environmentally friendly chemistry, statistically significant biology and fast and cost-effective medicinal assays. The facile generation of arbitrary 3D channel structures in polymers is pivotal to these techniques. Here we present a method for printing microchannels directly into viscous curable polymer matrices by injecting a surfactant into the uncured material via a steel capillary attached to a 3D printer. We demonstrate this technique using polydimethylsiloxane (PDMS) one of the most widely used polymers for the fabrication of, e. g. microfluidic chips. We show that this technique which we term Suspended Liquid Subtractive Lithography (SLSL) is well suited for printing actuators, T-junctions and complex three dimensional structures. The formation of truly arbitrary channels in 3D could revolutionize the fabrication of miniaturized chips and will find broad application in biology, chemistry and medicine.

Accuracy of a dose-area product compared to an absorbed dose to water at a point in a 2 cm diameter field.

PURPOSE: Graphite calorimeters with a core diameter larger than the beam can be used to establish dosimetric references in small fields. The dose-area product (DAP) measured can theoretically be linked to an absorbed dose at a point by the determination of a profile correction. This study aims at comparing the DAP-based protocol to the usual absorbed dose at a point protocol in a 2 cm diameter field for which both references exist. METHODS: Two calorimeters were used, respectively, with a sensitive volume of 0.6 cm (for the absorbed dose at a point measurement) and 3 cm diameter (for the DAP measurement). Profile correction was calculated from a 2D dose mapping using three detectors: a PinPoint chamber, a synthetic diamond, and EBT3 films. A specific protocol to read EBT3 films was implemented and the dose-rate and energy dependences were studied to assure a precise measurement, especially in the penumbra and out-of-field regions. RESULTS: EBT3 films were found independent on dose rates over the range studied but showed a strong under-response (18%) at low energies. Depending on the dosimeter used for calculating the profile correction, a deviation of 0.8% (PinPoint chamber), 0.9% (diamond), or 1.9% (EBT3 films) was observed between the calibration coefficient derived from DAP measurements and the one directly established in terms of absorbed dose to water at a point. CONCLUSIONS: The DAP method can currently be linked to the classical dosimetric reference system based in an absorbed dose at a point only with a confidence interval of 95% (k = 2). None of the detectors studied can be used to determine an absorbed dose to water at a point from a DAP measurement with an uncertainty smaller than 1.2%.

Using a dose-area product for absolute measurements in small fields: a feasibility study.

To extend the dosimetric reference system to field sizes smaller than 2 cm × 2 cm, the LNE-LNHB laboratory is studying an approach based on a new dosimetric quantity named the dose-area product instead of the commonly used absorbed dose at a point. A graphite calorimeter and a plane parallel ion chamber with a sensitive surface of 3 cm diameter were designed and built for measurements in fields of 2, 1 and 0.75 cm diameter. The detector surface being larger than the beam section, most of the issues linked with absolute dose measurements at a point could be avoided. Calibration factors of the plane parallel ionization chamber were established in terms of dose-area product in water for small fields with an uncertainty smaller than 0.9%.

Comparison between absorbed dose to water standards established by water calorimetry at the LNE-LNHB and by application of international air-kerma based protocols for kilovoltage medium energy x-rays.

Nowadays, the absorbed dose to water for kilovoltage x-ray beams is determined from standards in terms of air-kerma by application of international dosimetry protocols. New standards in terms of absorbed dose to water has just been established for these beams at the LNE-LNHB, using water calorimetry, at a depth of 2 cm in water in accordance with protocols. The aim of this study is to compare these new standards in terms of absorbed dose to water, to the dose values calculated from the application of four international protocols based on air-kerma standards (IAEA TRS-277, AAPM TG-61, IPEMB and NCS-10). The acceleration potentials of the six beams studied are between 80 and 300 kV with half-value layers between 3.01 mm of aluminum and 3.40 mm of copper. A difference between the two methods smaller than 2.1% was reported. The standard uncertainty of water calorimetry being below 0.8%, and the one associated with the values from protocols being around 2.5%, the results are in good agreement. The calibration coefficients of some ionization chambers in terms of absorbed dose to water, established by application of calorimetry and air-kerma based dosimetry protocols, were also compared. The best agreement with the calibration coefficients established by water calorimetry was found for those established with the AAPM TG-61 protocol.

The LNE-LNHB water calorimeter for primary measurement of absorbed dose at low depth in water: application to medium-energy x-rays.

Water calorimeters are used to establish absorbed dose standards in several national metrology laboratories involved in ionizing radiation dosimetry. These calorimeters have been first used in high-energy photons of (60)Co or accelerator beams, where the depth of measurement in water is large (5 or 10 cm). The LNE-LNHB laboratory has developed a specific calorimeter which makes measurements at low depth in water (down to 0.5 cm) easier, in order to fulfil the reference conditions required by the international dosimetry protocols for medium-energy x-rays. This new calorimeter was first used to measure the absorbed dose rate in water at a depth of 2 cm for six medium-energy x-ray reference beams with a tube potential from 80 to 300 kV. The relative combined standard uncertainty obtained on the absorbed dose rate to water is lower than 0.8%. An overview of the design of the calorimeter is given, followed by a detailed description of the calculation of the correction factors and the calorimetric measurements.

From regional healthcare information organizations to a national healthcare information infrastructure.

Recently there has been increased focus on the need to modernize the healthcare information infrastructure in the United States. The U.S. healthcare industry is by far the largest in the world in both absolute dollars and in percentage of GDP (more than $1.5 trillion, or 15 percent of GDP). It is also fragmented and complex. These difficulties, coupled with an antiquated infrastructure for the collection of and access to medical data, lead to enormous inefficiencies and sources of error. Consumer, regulatory, and governmental pressure drive a growing consensus that the time has come to modernize the U.S. healthcare information infrastructure (HII). While such transformation may be disruptive in the short term, it will, in the future, significantly improve the quality, expediency, efficiency, and successful delivery of healthcare while decreasing costs to patients and payers and improving the overall experiences of consumers and providers. The launch of a national health infrastructure initiative in the United States in May 2004--with the goal of providing an electronic health record for every American within the next decade--will eventually transform the healthcare industry in general, just as information technology (IT) has transformed other industries in the past. The key to this successful outcome will be based on the way we apply IT to healthcare data and the services delivered through IT. This must be accomplished in a way that protects individuals and allows competition but gives caregivers reliable and efficient access to the data required to treat patients and to improve the practice of medical science. This paper describes key IT solutions and technologies that address the challenges of creating a nation-wide healthcare IT infrastructure. Furthermore we discuss the emergence of new electronic healthcare services and the current efforts of IBM Research, Software Group, and Healthcare Life Sciences to realize this new vision for healthcare.

Complex graphemes as functional spelling units: evidence from acquired dysgraphia.

The visual word recognition literature suggests that complex graphemes (or digraphs) such as CK function as units. This proposal has also been put forward in recent spelling models (Houghton and Zorzi, 2003) and the study we report on here provides initial empirical support for the claim. We performed detailed analyses of the spelling performance of two brain-damaged individuals with graphemic buffer deficits. Results revealed that (a) FM and BWN made fewer errors on consonant digraphs (e.g., CK) than on matched controls clusters (e.g., CR) and (b) BWN produced more transposition errors on vowel digraphs than on control clusters. These result support the view that digraphs are represented as units in which the relative order of constituent letters is encoded.

Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset.

Carbamylphosphate synthetase 1 (E.C. 6.3.4.16) deficiency is a rare autosomal recessive disorder of the urea cycle that can result in severe neonatal hyperammonemia. Since the genomic structure of the CPS1 gene was not yet elucidated, mutation detection was performed by analysis of transcripts in the past. Here, we present the entire DNA sequence of the human CPS1 gene including all exon-intron boundaries. Moreover, mutation analysis was performed in six patients leading to the detection of 9 novel mutations including the missense mutations c.2528T>C and c.2623A>G, the nonsense mutations c.712C>T and c.2115ins35bp, the splice site mutations c.1263+5G>C, c.3558+1G>C and c.4101+2T>C, and a small deletion c.3036_3038delGGT. The mutations c.2528T>C and c.2623A>G were identified on a double mutated allele. New data on the genomic structure of the CPS1 gene provided in this study are useful to characterize the heterogenous molecular basis of the disease in patients deficient for carbamylphosphate 1 deficiency.

[Value of fetal cerebral magnetic resonance imaging for the prenatal diagnosis and prognosis of corpus callosum agenesis]. / Intérêt de l'IRM cérébrale foetale pour le diagnostic et le pronostic prénatal des agénésies du corps calleux.

OBJECTIVE: To evaluate MR contribution to prenatal diagnosis and prognosis of corpus callosum agenesis suspected by ultrasound and to ascertain how and when this examination should be included part in prenatal management of such malformation. PATIENTS AND METHODS: During a six-year period from January 1st 1994 and December 31st 2000, fifteen patients (and fifteen fetuses) were referred to our fetal medicine unit with suspicion of corpus callosum agenesis on prenatal ultrasound. Cerebral MRI was performed in all cases to confirm prenatal diagnosis. In our study, prenatal MRI examinations were retrospectively studied and compared with neuropathological examinations (n=8) or postnatal imaging (n=6). RESULTS: Corpus callosum agenesis were either complete (n=13) or partial (n=1). All were visible on prenatal MRI but only six on prenatal ultrasound. In one case, ultrasound suspicion of corpus callosum agenesis was ruled-out (false positive on prenatal ultrasound) by fetal cerebral MRI. In five cases corpus callosum agenesis was an isolated finding whereas in 12 cases associated malformations were encountered (cerebral n=7 or extra-cerebral n=5). MR depicted 7 of the 12 associated neurologic abnormalities. CONCLUSION: Prenatal MRI is a valuable complementary technique for either diagnosis of corpus callosum agenesis and depiction of associated neurologic abnormalities. Superiority of MR on prenatal sonography and its help in post-mortem examination of the brain (help in the choice of the pathologic technique and localisation of the samples) makes it essential even when pregnancy termination is considered.

The Stat1 binding motif of the interferon-gamma receptor is sufficient to mediate Stat5 activation and its repression by SOCS3.

Signal transduction via the interferon-gamma (IFN-gamma) receptor requires the tyrosine phosphorylation of signal transducers and activators of transcription (Stats). Whereas tyrosine phosphorylation of Stat1 occurs in all cells, activation of Stat5 by IFN-gamma is cell type-restricted. Here we investigated the mechanism of Stat5 activation by the IFN-gamma receptor. In transfection assays both Stat5 isoforms, Stat5a and Stat5b, were phosphorylated on tyrosine in response to IFN-gamma. Stat5 activation required the presence of tyrosine 420 (Tyr-420) in the murine IFNGR1 receptor chain, which also serves as the Stat1 binding site. Moreover, a peptide including Tyr-440, the Stat1 binding site of the human IFNGR1 chain, conferred the ability upon a synthetic receptor to activate Stat5. Suppressor of cytokine signaling 3 (SOCS3) inhibited the activation of Stat5 by the IFN-gamma receptor, and the Tyr-440-containing peptide stretch was sufficient for repression. SOCS3 expression had little effect on the activity of Jak kinases not associated with cytokine receptors. In IFN-gamma-treated, Stat1-deficient fibroblasts Stat5 was inefficient in inducing transcription of a Stat-dependent reporter gene, suggesting it does not per se make a major contribution to the expression of IFN-gamma-responsive genes.

Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts.

UNLABELLED: Deficiencies of carbamoylphosphate synthetase or of ornithine transcarbamylase, two urea cycle enzymes located within mitochondria, often present as severe neonatal hyperammonaemic crises and have a poor prognosis. While genetic analysis of the X-chromosomal transmitted ornithine transcarbamylase deficiency (OTC) is performed by exon-wise mutation screening of genomic DNA in most cases, identification of mutations in the autosomal inherited carbamoylphosphate synthetase (CPS 1) deficiency requires analysis of transcripts due to the unknown genomic structure. We tested the hypothesis that CPS 1 and OTC are expressed at low levels in fibroblasts and indeed were able to amplify full-length cDNA from that source. Using a reverse transcriptase polymerase chain reaction based procedure we completely characterised the genetic background in five patients and identified three novel mutations and a novel polymorphism of the CPS 1 gene (deletion/insertion 2170delGCTCinsCCA, nonsense mutation 2359C > T, missense mutation 3161T > G and Thr1406Asn, respectively), as well as the missense mutations 482A > G and 994T > A of the OTC gene. CONCLUSION: Cultured fibroblasts are an easily accessible source for genetic analysis of inborn errors of urea cycle enzymes which are functionally expressed only in liver and gut.

Database resources of the National Center for Biotechnology Information.

In addition to maintaining the GenBank nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources that operate on the data in GenBank and a variety of other biological data made available through NCBI's Web site. NCBI data retrieval resources include Entrez, PubMed, LocusLink and the Taxonomy Browser. Data analysis resources include BLAST, Electronic PCR, OrfFinder, RefSeq, UniGene, HomoloGene, Database of Single Nucleotide Polymorphisms (dbSNP), Human Genome Sequencing, Human MapViewer, GeneMap'99, Human-Mouse Homology Map, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, Cancer Genome Anatomy Project (CGAP), SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheri-tance in Man (OMIM), the Molecular Modeling Database (MMDB) and the Conserved Domain Database (CDD). Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih. gov.

Discreteness and interactivity in spoken word production.

Five theories of spoken word production that differ along the discreteness-interactivity dimension are evaluated. Specifically examined is the role that cascading activation, feedback, seriality, and interaction domains play in accounting for a set of fundamental observations derived from patterns of speech errors produced by normal and brain-damaged individuals. After reviewing the evidence from normal speech errors, case studies of 3 brain-damaged individuals with acquired naming deficits are presented. The patterns these individuals exhibit provide important constraints on theories of spoken naming. With the help of computer simulations of the 5 theories, the authors evaluate the extent to which the error patterns predicted by each theory conform with the empirical facts. The results support a theory of spoken word production that, although interactive, places important restrictions on the extent and locus of interactivity.

Attention-referenced visual representations: evidence from impaired visual localization.

Spatial representations in the visual system were probed in 4 experiments involving A. H., a woman with a developmental deficit in localizing visual stimuli. Previous research (M. McCloskey et al., 1995) has shown that A. H.'s localization errors take the form of reflections across a central vertical or horizontal axis (e.g., a stimulus 30 degrees to her left localized to a position 30 degrees to her right). The present experiments demonstrate that A. H.'s errors vary systematically as a function of where her attention is focused, independent of how her eyes, head, or body are oriented, or what potential reference points are present in the visual field. These results suggest that the normal visual system constructs attention-referenced spatial representations, in which the focus of attention defines the origin of a spatial coordinate system. A more general implication is that some of the brain's spatial representations take the form of coordinate systems.

The analysis of drawing from memory performance in brain-damaged patients.

The drawing from memory task is frequently used in cognitive neuropsychology to investigate visual processing impairments. However, in surprising contrast to most other neuropsychological tests, the analyses of results on this task are most often based solely on qualitative judgements about the normality of a patient's performance. In most case reports, these judgements are not made with reference to normative data and are not made by individuals who are impartial with respect to the study (that is, using a blind rating procedure). There are several grounds for arguing that such analyses are inadequate. First, seemingly abnormal drawings made by a patient may well be within the range of performance shown by control subjects. Second, judgments that are not based on a blind rating procedure are likely to be influenced by knowledge about the patient's performance on other tasks. We describe an alternative assessment procedure that addresses both of these concerns.

Database resources of the National Center for Biotechnology Information.

In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval and resources that operate on the data in GenBank and a variety of other biological data made available through NCBI's Web site. NCBI data retrieval resources include Entrez, PubMed, LocusLink and the Taxonomy Browser. Data analysis resources include BLAST, Electronic PCR, OrfFinder, RefSeq, UniGene, Database of Single Nucleotide Polymorphisms (dbSNP), Human Genome Sequencing pages, GeneMap'99, Davis Human-Mouse Homology Map, Cancer Chromosome Aberration Project (CCAP) pages, Entrez Genomes, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, Cancer Genome Anatomy Project (CGAP) pages, SAGEmap, Online Mendelian Inheritance in Man (OMIM) and the Molecular Modeling Database (MMDB). Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih. gov

GenBank.

The GenBank((R))sequence database incorporates publicly available DNA sequences of >55 000 different organisms, primarily through direct submission of sequence data from individual laboratories and large-scale sequencing projects. Most submissions are made using the BankIt (Web) or Sequin programs and accession numbers are assigned by GenBank staff upon receipt. Data exchange with the EMBL Data Library and the DNA Data Bank of Japan helps ensure comprehensive worldwide coverage. GenBank data is accessible through NCBI's integrated retrieval system, Entrez, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome, mapping and protein structure information, plus the biomedical literature via PubMed. Sequence similarity searching is provided by the BLAST family of programs. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. NCBI also offers a wide range of WWW retrieval and analysis services based on GenBank data. The GenBank database and related resources are freely accessible via the NCBI home page at http://www.ncbi.nlm.nih.gov

When a rose is a rose in speech but a tulip in writing.

We report the pattern of performance on language tasks by a neurologically impaired patient, RCM, who makes semantic errors in writing to dictation and in written naming, but makes very few errors at all (and no semantic errors) in spoken naming, oral reading, or spontaneous speech. RCM also shows a significant effect of concreteness on spelling accuracy and other features of so-called "deep dysgraphia." However, it is shown that, unlike previously reported patients described as deep dysgraphic, RCM has intact semantic processing but impairment in accessing lexical-orthographic representations, at least for the items tested. These results demonstrate that the collection of features labelled as "deep dysgraphia" can arise from damage to different cognitive processes. Detailed analyses of RCM's performance across lexical tasks, at two different time periods of recovery, provide evidence that lexical orthographic representations can be either directly activated by lexical semantic representations, or activated by the interaction of lexical semantic and sublexical information from phonology-to-orthography conversion mechanisms.

GenBank.

The GenBank (Registered Trademark symbol) sequence database incorporates DNA sequences from all available public sources, primarily through the direct submission of sequence data from individual laboratories and from large-scale sequencing projects. Most submitters use the BankIt (Web) or Sequin programs to format and send sequence data. Data exchange with the EMBL Data Library and the DNA Data Bank of Japan helps ensure comprehensive worldwide coverage. GenBank data is accessible through NCBI's integrated retrieval system, Entrez, which integrates data from the major DNA and protein sequence databases along with taxonomy, genome and protein structure information. MEDLINE (Registered Trademark symbol) s from published articles describing the sequences are included as an additional source of biological annotation through the PubMed search system. Sequence similarity searching is offered through the BLAST series of database search programs. In addition to FTP, Email, and server/client versions of Entrez and BLAST, NCBI offers a wide range of World Wide Web retrieval and analysis services based on GenBank data. The GenBank database and related resources are freely accessible via the URL: http://www.ncbi.nlm.nih.gov