A de novo satellited short arm of the Y chromosome possibly resulting from an unstable translocation

A satellited long arm of the Y chromosome (Yqs) is considered a normal variation, whereas the presence of a satellite on the short arm of the Y (Yps) has never been described in the literature. A Yps chromosome could be clinically significant if the translocation resulting in Yps has relocated the testis-determining gene, SRY, to another chromosome. A carrier of such a translocation would therefore be at increased risk for having XX male and XY female offspring. Here we describe the first reported case of de novo Yps present in a phenotypically normal male. This Yps chromosome was positive for C-banding and nucleolus organizer region (NOR) staining and showed a hybridization signal for the beta-satellite sequence. Fluorescence in situ hybridization (FISH) analysis indicated that SRY was retained on the Yps and the translocation breakpoint on Yps was distal to the pseudoautosomal region. At prenatal diagnosis, a normal appearing Y chromosome was found in his son, and thus the satellite on Yps was lost during meiotic Xp-Yp pairing. This Yps chromosome was likely the product of an "unstable" translocation.     

Effects of cellular pharmacology on drug distribution in tissues

The efficacy of targeted therapeutics such as immunotoxins is directly related to both the extent of distribution achievable and the degree of drug internalization by individual cells in the tissue of interest. The factors that influence the tissue distribution of such drugs include drug transport; receptor/drug binding; and cellular pharmacology, the processing and routing of the drug within cells. To examine the importance of cellular pharmacology, previously treated only superficially, we have developed a mathematical model for drug transport in tissues that includes drug and receptor internalization, recycling, and degradation, as well as drug diffusion in the extracellular space and binding to cell surface receptors. We have applied this "cellular pharmacology model" to a model drug/cell system, specifically, transferrin and the well-defined transferrin cycle in CHO cells. We compare simulation results to models with extracellular diffusion only or diffusion with binding to cell surface receptors and present a parameter sensitivity analysis. The comparison of models illustrates that inclusion of intracellular trafficking significantly increases the total transferrin concentration throughout much of the tissue while decreasing the penetration depth. Increasing receptor affinity or tissue receptor density reduces permeation of extracellular drug while increasing the peak value of the intracellular drug concentration, resulting in "internal trapping" of transferrin near the source; this could account for heterogeneity of drug distributions observed in experimental systems. Other results indicate that the degree of drug internalization is not predicted by the total drug profile. Hence, when intracellular drug is required for a therapeutic effect, the optimal treatment may not result from conditions that produce the maximal total drug distribution. Examination of models that include cellular pharmacology may help guide rational drug design and provide useful information for whole body pharmacokinetic studies.     

Managing supply systems with partial information on shipment locations

This paper studies a supply system for a retailer who orders a single product from one manufacturer. Orders filled by the manufacturer pass through multiple transportation stages before reaching the retailer. Each stage represents either a physical location or a step in the delivery process. The lead time for a new order depends on the location of shipments against prior orders in transit. Shipments are not allowed to cross over in time. Thus, the movement of each shipment depends on the movements of shipments ahead of it and the resulting congestion. The retailer is able to track shipments as they move through the transportation channel. The retailer adopts an ordering policy that minimises the sum of his one-period holding and shortage costs, using available status information of shipments already in transit. The case where practical constraints prevent the retailer from obtaining a complete status of shipments at all stages in the transportation channel is considered. The methodology developed evaluates the value of partial shipment tracking information, and uses it to determine the optimal placement of a limited number of tracking devices. The methodology can also be used to evaluate the cost–benefit of placing additional tracking devices in the supply system.     

Evolution or revolution: where next for impact assessment?

Impact assessment (IA) has become one of the most prevalent environmental policy instruments today. Its introduction under the National Environmental Policy Act (US) in 1969 was revolutionary. Perhaps it is not surprising, then, that such a widely used tool has received its share of criticism, including that it fails to meet some of its fundamental goals. Over the last fifty years, IA has broadened in scope and application and embraced new techniques. It has followed evolved, but has not changed fundamentally.

We believe that IA must continue to change to meet the societal and environmental challenges of the 21^st century. But will it be enough for IA to progress through incremental change (evolution), or is a complete overhaul of impact assessment (revolution) needed? We provide some ideas as to what ‘evolution’ and ‘revolution’ may look like, but rather then offering a definitive way forward now, we invite stakeholders to present their thoughts and suggestions at the IAIA19 Annual Conference in Brisbane, which carries the same theme as the title of this article.     

Bradykinin increases the proportion of neonatal rat dorsal root ganglion neurons that respond to capsaicin and protons

A number of studies have examined bradykinin-induced sensitization of primary afferent neurons to mechanical or thermal stimuli. However, bradykinin-induced sensitization to other chemical stimuli has not been systematically addressed. We used primary cultures of dorsal root ganglion neurons from neonatal rats to determine whether bradykinin alters the responsiveness of individual neurons to capsaicin and protons. An increase in the concentration of free intracellular Ca2+ was used as a measure of a response to capsaicin or low pH. Pretreatment with bradykinin (30 nM) increased the proportion of "intermediate-size" (240-320 microm2) dorsal root ganglion neurons that responded to capsaicin (100 nM) or low pH (6.1). However, among "small-size" (160-239 microm2) neurons, bradykinin increased the proportion of neurons that responded to low pH (6.1) but not to capsaicin (10 or 100 nM). Because treatment with arachidonic acid (10 microM) did not mimic the effect of bradykinin and inhibition of cyclo-oxygenase and lipoxygenase with 5,8,11,14-eicosatetraynoic acid (10 microM) did not inhibit the effect of bradykinin on the response to capsaicin, it is not likely that the bradykinin-induced enhancement of neuronal responsiveness is mediated by arachidonic acid or its metabolites in this model. These results support the hypothesis that bradykinin sensitizes primary afferent neurons to other chemicals such as protons that are present in inflamed tissue, particularly by recruiting additional sensory neurons to respond to a given chemical stimulus. An increase in the number of responsive nociceptors that innervate inflamed tissue would contribute to hyperalgesia via spatial summation on spinal neurons in the pathway for pain. Furthermore, since bradykinin enhanced the responsiveness of small-size neurons that responded to protons but not to capsaicin, these data suggest that bradykinin-induced sensitization to protons and capsaicin occur by different mechanisms.     

Injection techniques to anesthetize the difficult tooth

Failure to achieve anesthesia can be a significant problem in the day-to-day practice of dentistry. The usual strategy following an anesthetic failure is to reinject. Therefore, a good understanding of conventional anesthetic techniques is important. But the practitioner also needs to have a broad armamentarium of injection strategies available for the "difficult-to-anesthetize cases". These strategies include the use of 5 percent lidocaine, intrapulpal injection, periodontal ligament injection and intraosseous injection. This paper will be a brief discussion of those techniques with an emphasis on the intraosseous injection.     

Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the "default" T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2-3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-gamma by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing- associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor alpha or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.     

Image registration based on boundary mapping

A new two-stage approach for nonlinear brain image registration is proposed. In the first stage, an active contour algorithm is used to establish a homothetic one-to-one map between a set of region boundaries in two images to be registered. This mapping is used in the second step: a two-dimensional transformation which is based on an elastic body deformation. This method is tested by registering magnetic resonance images to atlas images.