Deviating from IDSA treatment guidelines for non-purulent skin infections increases the risk of treatment failure in emergency department patients.

The Infectious Disease Society of America (IDSA) publishes guidelines regularly for the management of skin and soft tissue infections; however, the extent to which practice patterns follow these guidelines and if this can affect treatment failure rates is unknown. We observed the treatment failure rates from a multicentre retrospective ambulatory cohort of adult emergency department patients treated for a non-purulent skin infection. We used multivariable logistic regression to examine the role of IDSA classification and whether adherence to IDSA guidelines reduced treatment failure. A total of 759 ambulatory patients were included in the cohort with 17.4% failing treatment. Among all patients, 56.0% had received treatments matched to the IDSA guidelines with 29.1% over-treated, and 14.9% under-treated based on the guidelines. After adjustment for age, gender, infection location and medical comorbidities, patients with a moderate infection type had three times increased risk of treatment failure (adjusted risk ratio (aRR) 2.98; 95% confidence interval (CI) 1.15-7.74) and two times increased risk with a severe infection type (aRR 2.27; 95% CI 1.25-4.13) compared with mild infection types. Patients who were under-treated based on IDSA guidelines were over two times more likely to fail treatment (aRR 2.65; 95% CI 1.16-6.05) while over-treatment was not associated with treatment failure. Patients ⩾70 years of age had a 56% increased risk of treatment failure (aRR 1.56; 95% CI 1.04-2.33) compared with those <70 years. Following the IDSA guidelines for non-purulent SSTIs may reduce the treatment failure rates; however, older adults still carry an increased risk of treatment failure.

Electrokinetic pixels with biprimary inks for color displays and color-temperature-tunable smart windows.

We report on the advanced implementation of the biprimary color system in applications where subtractive color is performed inside a single pixel to alter the magnitude and color of reflection (electronic paper displays) or the optical transmission and color temperature (smart windows). A novel device structure can switch between four states: clear, black, either of two complementary colors from RGB and CMY sets, and also mixed states between one of these four states. The device structure utilizes an electrokinetic pixel structure, which combines the spectral performance of in-plane electrophoretic devices with the improved switching speeds of vertical electrophoresis. The electrophoretic dispersions are dual-particle dual-colored and are controlled using two traditional planar electrokinetic electrodes on the front and back substrates, along with a third electrode conveniently located at the perimeter of each unit cell. Demonstrated performance includes contrast ratios reaching ~10∶1, reflectance of ~62%, and transparency of ~75%. For electronic paper displays, these results provide a pathway to double the reflective performance compared to the traditional RGBW color-filter approach. For smart windows, the technology provides not only control of shade (transmission) but also provides complete control over color temperature. Furthermore, this three-electrode device can be roll-to-roll fabricated without need for any alignment steps, requiring only a single micro-replication step followed by self-aligned contact printing of the third electrode.

Dental hygienists' perception of preparation and use for ultrasonic instrumentation.

OBJECTIVES: Ultrasonic scaling technology has evolved dramatically providing greater clinical utility subgingivally including instrumentation of light deposits and biofilm disruption. It is unknown whether dental hygiene curriculum has kept pace with the progression and reflects current applications. The first part of this two-part study aimed to determine new dental hygiene graduates' use and perceptions of preparedness in ultrasonic instrumentation. Part 2 investigates ultrasonic curriculum from the programme director perspective and will be reported on in a subsequent paper. METHOD: Part 1 of the study surveys recently graduated Canadian dental hygienists about their use and perceptions of preparedness with ultrasonic instruments through an electronic questionnaire developed for this study. RESULTS: Participants reported using ultrasonics about half of their instrumentation time predominantly with magnetostrictive technology. Use focussed on heavier deposits with straight, slim inserts. Subjects were generally satisfied with ultrasonic education and felt reasonably well prepared in using ultrasonics. Higher levels of perceived preparedness were most associated with graduates from the 3-year diploma programme, whereas graduates from 18-month programmes were associated with greater levels of confidence in using ultrasonics. Confidence with ultrasonics did not have an effect on subsequent use - mostly all participants increased use once in practice. An earlier introduction and more practice time in school were both associated with increased feelings of preparation and confidence. CONCLUSIONS: New dental hygiene graduates perceive greater preparedness, confidence and use of ultrasonic instrumentation within a more traditional paradigm. In addition, the results indicate a potential incorrect and/or inappropriate application of current technology.

Evx1 is a postmitotic determinant of v0 interneuron identity in the spinal cord.

Interneurons in the ventral spinal cord are essential for coordinated locomotion in vertebrates. During embryogenesis, the V0 and V1 classes of ventral interneurons are defined by expression of the homeodomain transcription factors Evx1/2 and En1, respectively. In this study, we show that Evx1 V0 interneurons are locally projecting intersegmental commissural neurons. In Evx1 mutant embryos, the majority of V0 interneurons fail to extend commissural axons. Instead, they adopt an En1-like ipsilateral axonal projection and ectopically express En1, indicating that V0 interneurons are transfated to a V1 identity. Conversely, misexpression of Evx1 represses En1, suggesting that Evx1 may suppress the V1 interneuron differentiation program. Our findings demonstrate that Evx1 is a postmitotic determinant of V0 interneuron identity and reveal a critical postmitotic phase for neuronal determination in the developing spinal cord.

Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1.

Spinal interneurons help to coordinate motor behavior. During spinal cord development, distinct classes of interneurons are generated from progenitor cells located at different positions within the ventral neural tube. V0 and V1 interneurons derive from adjacent progenitor domains that are distinguished by expression of the homeodomain proteins Dbx1 and Dbx2. The spatially restricted expression of Dbx1 has a critical role in establishing the distinction in V0 and V1 neuronal fate. In Dbx1 mutant mice, neural progenitors fail to generate V0 neurons and instead give rise to interneurons that express many characteristics of V1 neurons-their transcription factor profile, neurotransmitter phenotype, migratory pattern, and aspects of their axonal trajectory. Thus, a single progenitor homeodomain transcription factor coordinates many of the differentiated properties of one class of interneurons generated in the ventral spinal cord.

Regulation of vertebrate neural cell fate by transcription factors.

Evidence that region- and cell-type-specific transcription factors regulate morphogenesis and differentiation of the vertebrate nervous system comes from numerous studies, including descriptions of discrete patterns of expression during neural development and analysis of mutant phenotypes. Recently published works provide insights into the roles of vertebrate transcription factors in regulating the generation of neural precursors, regionalization of the nervous system, and subsequent differentiation of specific cell types within these regions. For instance, misexpression studies in Xenopus embryos show that the newly isolated basic helix-loop-helix protein NeuroD is able to promote neurogenesis, whereas analysis of mouse embryos mutant for the homeobox gene En-1 demonstrates that this transcription factor is required for proper development of the midbrain-hindbrain region. A recent study in chick shows that the combinatorial expression of Islet-1, Lim-1, and two other LIM homeobox genes, Islet-2 and Lim-3, defines subclasses of motor neurons in the spinal cord, supporting a model where combinatorial repertoires of transcription factors may act to generate diverse cell types.

Fate of midbrain dopaminergic neurons controlled by the engrailed genes.

Deficiencies in neurotransmitter-specific cell groups in the midbrain result in prominent neural disorders, including Parkinson's disease, which is caused by the loss of dopaminergic neurons of the substantia nigra. We have investigated in mice the role of the engrailed homeodomain transcription factors, En-1 and En-2, in controlling the developmental fate of midbrain dopaminergic neurons. En-1 is highly expressed by essentially all dopaminergic neurons in the substantia nigra and ventral tegmentum, whereas En-2 is highly expressed by a subset of them. These neurons are generated and differentiate their dopaminergic phenotype in En-1/En-2 double null mutants, but disappear soon thereafter. Use of an En-1/tau-LacZ knock-in mouse as an autonomous marker for these neurons indicates that they are lost, rather than that they change their neurotransmitter phenotype. A single allele of En-1 on an En-2 null background is sufficient to produce a wild type-like substantia nigra and ventral tegmentum, whereas in contrast a single allele of En-2 on an En-1 null background results in the survival of only a small proportion of these dopaminergic neurons, a finding that relates to the differential expression of En-1 and En-2. Additional findings indicate that En-1 and En-2 regulate expression of alpha-synuclein, a gene that is genetically linked to Parkinson's disease. These findings show that the engrailed genes are expressed by midbrain dopaminergic neurons from their generation to adulthood but are not required for their specification. However, the engrailed genes control the survival of midbrain dopaminergic neurons in a gene dose-dependent manner. Our findings also suggest a link between engrailed and Parkinson's disease.

Cyclic-AMP-induced c-fos expression and its relevance to differentiation of a transformed mast cell line.

The effects of cyclic AMP on expression of the oncogenes c-myc, c-myb and c-fos in murine P815 mastocytoma cells were examined in relation to growth and differentiation. Induction of differentiation in mastocytoma cells by cyclic AMP was accompanied by a rapid increase in c-fos expression. Cyclic AMP induced stable expression of c-fos mRNA by increasing c-fos transcription 4-5-fold and slightly increasing the stability of c-fos mRNA. However, a high level of c-fos expression was not essential for differentiation of two temperature sensitive-mutant P815 cell lines, as c-fos mRNA did not increase in differentiating temperature-sensitive P815 cells. These results do not support an essential role for c-fos expression in the differentiation of mast cells. Although c-myc expression was lower after growth arrest by cyclic AMP, this decrease did not correlate with growth inhibition by cyclic AMP, since c-myc expression decreased only after cells had started to arrest in G1 phase.

The ubiquitous transactivator Zfp-38 is upregulated during spermatogenesis with differential transcription.

We describe the complete nucleotide sequence of a full length cDNA clone encoding a new mouse zinc finger protein gene, Zfp-38 and localize it on chromosome 5 by the interspecific backcross analysis. The N-terminal domain of the Zfp-38 protein (64 kDa) contains 358 amino acids and the C-terminal domain of 197 residues encodes 7 zinc fingers. We also present evidence that Zfp-38 is a strong transcriptional activator. The transactivation domain was localized in the non finger region and a fusion protein containing 112 amino acid residues from this region of the Zfp-38 and the DNA binding domain of the yeast Gal 4 protein, very efficiently transactivated the expression of a reporter CAT plasmid, harboring the Gal4 target site. By in situ hybridization and northern blotting technique, the Zfp-38 transcript can be detected at a highly elevated level during spermatogenesis. Its expression accompanies the progression from pachytene spermatocytes to round spermatids. The undifferentiated spermatogonia or the haploid elongated spermatid and the spermatozoa do not show any detectable level of the transcript. Interestingly, other tissues express low levels of a slightly shorter transcript with a different 5' end as determined by RNase protection. The presence of both a transcriptional activating domain and 7 DNA binding zinc fingers, coupled with the cell type(s) specific expression pattern, suggests that Zfp-38 has the potential to regulate transcription during spermatogenesis.

Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.

We tested the hypothesis that the nuclear proto-oncogene c-fos is involved in long-term potentiation (LTP) of the perforant path-dentate gyrus synapse in awake freely moving rats. High-frequency stimulation that produced LTP induced c-fos mRNA and protein in the dentate granule cells but not in CA1, CA3, or the entorhinal cortex. However, the degree of LTP induction did not correlate with the degree of c-fos induction. Agents that interfered with the production of LTP (e.g. NMDA antagonists) also prevented c-fos induction. Low-frequency stimulation did not lead to either LTP or c-fos induction. However, c-fos induction did not necessarily follow LTP production because some high-frequency stimulation protocols that produced good LTP did not lead to c-fos induction. Thus, c-fos induction is clearly not related to LTP production in unanaesthetized rats, but it remains to be determined if it plays some role in LTP maintenance.

Pax genes and neural tube defects in the mouse.

The Pax genes encode a family of transcription factors that are expressed in restricted regions of the developing embryo. Several Pax genes are expressed in the developing nervous system where they are believed to regulate the morphogenesis of neural structures. Loss-of-function mutations in the Pax-3 gene have been identified in a number of alleles of the mouse mutant splotch. In homozygous splotch embryos closure of the neural tube is defective with embryos exhibiting spina bifida and/or exencephaly. Other structures in which Pax-3 is expressed are also affected, most notably those tissues derived from the neural crest and somites.

Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons.

During early development, multiple classes of interneurons are generated in the spinal cord including association interneurons that synapse with motor neurons and regulate their activity. Very little is known about the molecular mechanisms that generate these interneuron cell types, nor is it known how axons from association interneurons are guided toward somatic motor neurons. By targeting the axonal reporter gene &tgr;-lacZ to the En1 locus, we show the cell-type-specific transcription factor Engrailed-1 (EN1) defines a population of association neurons that project locally to somatic motor neurons. These EN1 interneurons are born early and their axons pioneer an ipsilateral longitudinal projection in the ventral spinal cord. The EN1 interneurons extend axons in a stereotypic manner, first ventrally, then rostrally for one to two segments where their axons terminate close to motor neurons. We show that the growth of EN1 axons along a ventrolateral pathway toward motor neurons is dependent on netrin-1 signaling. In addition, we demonstrate that En1 regulates pathfinding and fasciculation during the second phase of EN1 axon growth in the ventrolateral funiculus (VLF); however, En1 is not required for the early specification of ventral interneuron cell types in the embryonic spinal cord.

Identification of NKL, a novel Gli-Kruppel zinc-finger protein that promotes neuronal differentiation.

The proneural basic helix-loop-helix proteins play a crucial role in promoting the differentiation of postmitotic neurons from neural precursors. However, recent evidence from flies and frogs indicates that additional factors act together with the proneural bHLH proteins to promote neurogenesis. We have identified a novel zinc finger protein, neuronal Kruppel-like protein (NKL), that positively regulates neurogenesis in vertebrates. NKL is expressed in Xenopus primary neurons and in differentiating neuronal precursors in the intermediate zone of the mouse and chick neural tube. In frog embryos, NKL is induced by overexpression of Neurogenin (Ngn), arguing that NKL is downstream of the proneural determination genes. Our results show that NKL and a NKL/VP16 fusion protein promote differentiation of neuronal precursors in the embryonic chick spinal cord. Following in ovo misexpression of NKL, neuroepithelial cells exit the cell cycle and differentiate into neurons. Similarly, NKL/VP16 induces extra primary neurons in frogs and upregulates expression of the neural differentiation factors, Xath3 and MyT1, as well as the neuronal markers, N-tubulin and elrC. Our findings establish NKL as a novel positive regulator of neuronal differentiation and provide further evidence that non-bHLH transcription factors function in the neuronal differentiation pathway activated by the vertebrate neuronal determination genes.

Cyclic AMP, nuclear protein kinase and the PY815 cell cycle.

A substantial increase in cyclic AMP-dependent protein kinase activity occurred in nuclei of PY815 mastocytoma cells during G1 phase growth arrest by DB cyclic AMP and the increased nuclear protein kinase was accompanied by changes in nuclear protein phosphorylation. However, there was no obligatory association between the rise in nuclear cyclic AMP-dependent protein kinase in G1 phase and growth arrest because nuclear cyclic AMP-dependent protein kinase also increased during G1 phase in cycling PY815 cells synchronized with amethopterin. These observations suggest that maintenance of high cyclic AMP levels during G1 phase may cause growth arrest by activating a cyclic AMP-dependent protein kinase that normally increases in PY815 cell nuclei during G1 phase.

Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.

The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.