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Materials that are evaluated for bioengineering purposes are carefully tested to evaluate cellular interactions with respect to biocompatibility and in some cases cell differentiation. A key perspective that is often considered is the ability for decellularized synthetic or natural based matrices to facilitate cell migration or tissue ingrowth. Current methods of measuring cell migration range from simple scratch assays to Boyden chamber inserts and fluorescent imaging of seeded spheroids. Many of these methods require tissue processing for histological analysis and fixing and staining for imaging, which can be difficult and dependent on the stability of the hydrogel subject. Herein we present a simple platform that can be manufactured using 3D printing and easily applied to in vitro cell culture, allowing the researcher to image live cellular migration into a cellular materials. We found this to be an adaptable, cheap, and replicable technique to evaluate cellular interaction that has applications in the research and development of hydrogels for tissue engineering purposes.

This paper contends that sociotherapy, a sociologically informed approach to therapy, is a viable alternative to the diagnostic model recognized by the College of Registered Psychotherapists in Ontario (CRPO). The Psychotherapy Act (2007) along with the Regulated Health Professions Act (1991) gives the CRPO authorization to regulate the practice of psychotherapy and to control titles affiliated with the act of psychotherapy. I offer a discussion of sociotherapy and socioanalysis as clinical alternatives to the conservative and normalizing approaches endorsed by the College. I situate sociotherapy and socioanalysis in the discipline of sociology and in relation to Freudian psychoanalysis. I offer my own sociotherapeutic practice as an illustration of how the societal and the psychological, the social, and the psychic must be engaged in concert. I underscore the importance of dialogue, as opposed to diagnostics, interpretation as opposed to assessments and psychosocial contemplation as opposed to cognitive-behavioral treatment in clinical practice.

Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivoknockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies.

Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = SCC/SD), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors). This risk can be evaluated by considering the cocrystal SA and drug dose/solubility ratio (D0D= Cdose/SD), which in tandem represent the maximum theoretical supersaturation that a cocrystal may generate, the driving force for drug precipitation, and the potential for dose-/solubility-limited absorption. cocrystals with SA and D0Dvalues above critical supersaturation are prone to rapid precipitation, often negating their utility as a solubility enhancement tool. This work presents a mechanistic approach to controlling the dissolution–supersaturation–precipitation behavior of cocrystal systems, whereby relationships between SA, D0D, and the drug-solubilizing power of surfactants (SPD= SD,T/SD,aq) are used to fine-tune cocrystal-inherent supersaturation by rational additive selection. Experimental results with danazol–vanillin cocrystal demonstrate how SA, D0D, and SPDare key thermodynamic parameters to understanding the kinetic cocrystal behavior and how the risks of cocrystal development may be mitigated through the mechanistic formulation design.

This work reports the first cocrystal of the basic drug posaconazole (PSZ). PSZ is poorly water-soluble and has low and erratic bioavailability based on its large positive food effect and high solubility–pH dependence. The structure and enhanced properties of the discovered 2:3 cocrystal with 4-aminobenzoic acid (4ABA) are presented in this study. Single-crystal X-ray diffraction revealed that the two non-superimposable PSZ molecules interact with three 4ABA molecules through O–H···O, N–H···O, and N–H···N hydrogen bonds. Cocrystal and drug solubilities were measured in biorelevant media, and the cocrystal solubility advantage (SA = Scocrystal/Sdrug) was calculated to be 139 in FaSSIF and 48 in FeSSIF. Cocrystal dissolution generated supersaturation levels (σmax= Cmax/Sdrug) of 16 in FaSSIF and 8 in FeSSIF and resulted in relative area under the curve (RAUC = AUCcocrystal/AUCdrug) increases of 4 and 13 times, respectively, compared to drug. This study demonstrates the utility of cocrystals to improve the solubility and dissolution behavior of drugs with poor biopharmaceutical properties.

Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = Scocrystal/Sdrug). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams. The tunability of cocrystal SA is dependent on the selective drug-solubilizing power of surfactants (SPdrug= (ST/Saq)drug). This cocrystal property is used to generate SA–SP diagrams that facilitate surfactant selection and provide a framework for evaluating how SA influences drug concentration–time profiles associated with cocrystal dissolution, drug supersaturation, and precipitation (DSP). Experimental results with indomethacin-saccharin cocrystal and surfactants (sodium lauryl sulfate, Brij, and Myrj) demonstrate the log-linear relationship characteristic of SA–SP diagrams and the dependence of σmaxand dissolution area under the curve (AUC) on SA with characteristic maxima at a threshold supersaturation where drug nucleation occurs. This approach is expected to streamline cocrystal formulation as it facilitates additive selection by considering the interplay between thermodynamic (SA) and kinetic (DSP) processes.

This article brings the psychoanalysis of Bracha L. Ettinger to the question of mourning in the television series Transparent. As evident in the television series, and in everyday life, there is a troubling metonymy linking trans* lives with death. The appeal to death is often in stark contrast to the way trans* people experience their transitions as giving form to a new and invigorating commitment to life. Despite this, there can be something haunting and unspoken bothering familial relations post-transition. These cryptic experiences are well dramatized in Transparent. From a matrixial perspective, a transition always involves Others and rechoreographs intimate relations in conscious and nonconscious ways. Part of what happens post-transition is a non-cognized change in the matrixial web. Because so much of the matrixial is associated with metaphors of reproduction, life and death, it may be that the vocabulary of death (as metonymy of loss) is used to condense a vicissitude of unprocessed experiences in the matrixial. In other words, we lack ways to work through what has been changed in the relationality between intimate Others occasioned by a transition. The signifier “death” thus overwrites interpersonal familial relations. This article offers a way to understand and unpack the metonymic association using three key psychoanalytic concepts: the psychic crypt, the cryptic carriance, and the transcryptum. By bringing these concepts to the question of “mourning without loss” (van der Weele 2017) in Transparent, this article considers how transitions can enable a “working through” of unacknowledged familial trauma passed down between and within generations.

The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract. Blood samples were taken to determine ibuprofen plasma levels. In this work, an in-depth statistical and pharmacokinetic analysis was performed to explain which underlying GI variables are determining the systemic concentrations of ibuprofen between (inter-) and within (intra-) subjects. In addition, the obtained plasma profiles were deconvoluted to link the fraction absorbed with the fraction dissolved. Multiple linear regressions were performed to explain and quantitatively express the impact of underlying GI physiology on systemic exposure of the drug (in terms of plasma Cmax/AUC and plasma Tmax). The exploratory analysis of the correlation between plasma Cmax/AUC and the time to the first phase III contractions postdose (TMMC-III) explains ∼40% of the variability in plasma Cmaxfor all fasted state subjects. We have experimentally shown that the in vivo intestinal dissolution of ibuprofen is dependent upon physiological variables like, in this case, pH and postdose phase III contractions. For the first time, this work presents a thorough statistical analysis explaining how the GI behavior of an ionized drug can explain the systemic exposure of the drug based on the individual profiles of participating subjects. This creates a scientifically based and rational framework that emphasizes the importance of including pH and motility in a predictive in vivo dissolution methodology to forecast the in vivo performance of a drug product. Moreover, as no extensive first-pass metabolism is considered for ibuprofen, this study demonstrates how intraluminal drug behavior is reflecting the systemic exposure of a drug.

The purpose of this study was to enhance the solubility and dissolution of a poorly water-soluble drug, tadalafil (TDF), by cocrystal formation with malonic acid (MOA), to characterize the cocrystal structure and to quantify the cocrystal solution behavior. The crystal structure revealed a 1:1 stoichiometry, wherein the TDF molecules form a double layered structure through N–H···O═C interactions linked to a catemeric chain of MOA molecules via O–H···O hydrogen bonds. Cocrystal solubility advantage (SA defined as Scocrystal/Sdrug) or supersaturation index was determined from eutectic point measurements to be 102 to 129 in the pH range of 1 to 3. Cocrystal dissolution generated supersaturation levels (Cmax/Sdrug) of 30 in buffer and 120 in the presence of a nucleation inhibitor, HPMC. The amorphous form of TDF generated supersaturation three times lower than cocrystal in buffer, and not significantly different from cocrystal in the presence of HPMC. Thus, supersaturation index is a valuable metric for assessing the risk of cocrystal conversion during kinetic studies and for predicting conditions when the usage of a precipitation inhibitor may significantly increase cocrystal exposure levels.

Your article in the recent issue of CAPPER's on emergency preparedness ('Plan for the Worst, Hope for the Best,' July/August) was very interesting and informative, and it can be adapted [...]

Several letters to the editor are presented in response to articles in previous issues including "Hardware Stores Aim for the Future" in the March/April 2012 issue, "Plan for the Worst, Hope for the Best" in the July/August 2012 issue, and "What's That Smell?" in the May/June 2012 issue.

BACKGROUND Formal olfactory testing may be useful as a bedside tool to help differentiate between conditions such as atypical parkinsonism, dementia, and psychiatric conditions. However, the neural basis of olfactory dysfunction, the effect of concurrent cognitive deficits on olfactory testing results, and the exact prevalence of olfactory deficits in populations with corticobasal syndrome (CBS) and the frontal variant of frontotemporal dementia (FTD-FV) are to date unclear. OBJECTIVE To assess the prevalence and the neural basis of olfactory recognition deficits in patients with a clinical diagnosis of CBS or FTD-FV. DESIGN Retrospective study of clinical, neuropsychological, and imaging data. SETTING National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS Twenty-five patients with CBS, 22 with FTD-FV, and 12 age-matched control subjects. MAIN OUTCOME MEASURES Results of neuropsychological evaluation, formal olfactory recognition testing (University of Pennsylvania Smell Identification Test [UPSIT]), and voxel-based morphometry analysis of structural magnetic resonance images of the brain. RESULTS Mean UPSIT percentile scores were 31.6% for the CBS group and 9.5% for the FTD-FV group. The voxel-based morphometry correlations between local gray matter and UPSIT scores showed a significant volume effect in the right midfrontal gyrus for the FTD-FV patients and in the right insula, right midfrontal gyrus, and bilateral inferior frontal gyrus for the patients with CBS. A linear regression analysis of the UPSIT scores revealed as significant predictors the general memory score of the Wechsler Memory Scale and the Boston Naming Test total score for the patients with FTD-FV and the Mattis Dementia Rating Scale total score for the patients with CBS. CONCLUSIONS Our data showed a more severe olfactory impairment for CBS patients than previously reported. We also showed a significant relationship between formal olfactory recognition testing scores and specific cognitive domains. These findings could be useful to clinically differentiate FTD-FV and CBS from other dementing illnesses and movement disorders.Arch Neurol. 2009;66(1):92-96--

There is growing evidence that plasmacytoid dendritic cells (pDC) are involved in the innate recognition of various microbes. However, the precise consequences of pathogen recognition on pDC activation and function are incompletely understood. Using a novel transgenic mouse model that facilitates the isolation of highly pure pDC populations, we found that influenza virus PR/8, a TLR7 ligand, and CpG 1826 oligonucleotide, a TLR9 ligand, induced surprisingly divergent activation programs in these cells. pDC stimulated with PR/8 produced large amounts of type I IFNs, and CpG 1826‐stimulated pDC expressed higher levels of costimulatory molecules and proinflammatory cytokines and induced stronger proliferation of T cells. Transcriptome analysis uncovered the differential regulation in pDC of 178 and 1577 genes by PR/8 and CpG 1826, respectively. These differences may relate to the activation of discrete signaling pathways, as evidenced by distinct ERK1/2 and p38 MAPK phosphorylation kinetics. Finally, pDC isolated ex vivo during PR/8 infection or after i.v. CpG 1826 injection resembled their in vitro counterparts, corroborating that these cells can adopt specialized phenotypes in vivo. Thus, pDC display remarkable functional flexibility, which emphasizes their versatile functions in antimicrobial immunity and inflammatory processes.

[The Romans] created the cult of the Vestal Virgins, high-minded priestesses of the goddess Vesta, Guardian Angel of Mankind and Keeper of the Hearth. These priestesses were educated in special normal training schools, were forbidden to marry, were subjected to drastic moral codes, and were accorded social position of preeminence.Spinster teachers were hired so frequently in the late nineteenth and early twentieth centuries that they eventually became an important part of the cultural landscape.Single women seem forever to unnerve, anger and unwittingly scare large swaths of the population, both female and male.”

Lymphocytes home to peripheral lymph nodes (PLNs) via high endothelial venules (HEVs) in the subcortex and incrementally larger collecting venules in the medulla. HEVs express ligands for L-selectin, which mediates lymphocyte rolling. L-selectin counterreceptors in HEVs are recognized by mAb MECA-79, a surrogate marker for molecularly heterogeneous glycans termed peripheral node addressin. By contrast, we find that medullary venules express L-selectin ligands not recognized by MECA-79. Both L-selectin ligands must be fucosylated by α(1,3)-fucosyltransferase (FucT)-IV or FucT-VII as rolling is absent in FucT-IV+VII−/− mice. Intravital microscopy experiments revealed that MECA-79–reactive ligands depend primarily on FucT-VII, whereas MECA-79–independent medullary L-selectin ligands are regulated by FucT-IV. Expression levels of both enzymes paralleled these anatomical distinctions. The relative mRNA level of FucT-IV was higher in medullary venules than in HEVs, whereas FucT-VII was most prominent in HEVs and weak in medullary venules. Thus, two distinct L-selectin ligands are segmentally confined to contiguous microvascular domains in PLNs. Although MECA-79–reactive species predominate in HEVs, medullary venules express another ligand that is spatially, antigenically, and biosynthetically unique. Physiologic relevance for this novel activity in medullary microvessels is suggested by the finding that L-selectin–dependent T cell homing to PLNs was partly insensitive to MECA-79 inhibition.

Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

Intravital multiphoton imaging of the tumor milieu allows for the dissection of intricate and dynamic biological processes in situ. Herein, we present a step-by-step protocol for setting up an experimental cancer imaging model that has been optimized for solid tumors such as breast cancer and melanoma implanted in the flanks of mice. This protocol can be utilized for dissecting tumor-immune cell dynamics in vivoor other tumor-specific biological questions.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease in which unknown arthrogenic autoantigen is presented to CD4+T cells. The strong association of the disease with an epitope within the HLA‐DR chain shared between various alleles of HLA‐DR4 and DR1 emphasizes the importance of antigen presentation. This immune response predominantly occurs in the synovial tissue and fluid of the joints and autoreactive T cells are readily demonstrable in both the synovial compartment and blood. Circulating dendritic cells (DC) are phenotypically and functionally identical with normal peripheral blood (PB) DC. In the synovial tissue, fully differentiated perivascular DC are found in close association with T cells and with B cell follicles, sometimes containing follicular DC. These perivascular DC migrate across the activated endothelium from blood and receive differentiative signals within the joint from monocyte‐derived cytokines and CD40‐ligand+T cells. In the SF, DC manifest an intermediate phenotype, similar to that of monocyte‐derived DC in vitro.Like a delayed‐type hypersensitivity response, the rheumatoid synovium represents an effector site. DC at many effector sites have a characteristic pattern of infiltration and differentiation. It is important to note that the effector response is not self‐limiting in RA autoimmune inflammation. In this article, we argue that the presentation of self‐antigen by DC and by autoantibody‐producing B cells is critical for the perpetuation of the autoimmune response. Permanently arresting this ongoing immune response with either pharmaceutical agents or immunotherapy is a major challenge for immunology. J. Leukoc. Biol.66: 286–292; 1999.

Histamine H2 receptor antagonists have been reported to protect the gastric mucosa of animals and humans against aspirin-induced damage. It is unclear, however, whether this protective effect can be observed at doses less than those needed to markedly inhibit gastric acid secretion. We have developed a single-dose endoscopic assay system of aspirin-induced gastric mucosal injury in normal conscious dogs. In this model, severe gastric mucosal injury and a decrease in the pH of the gastric luminal contents were consistently demonstrated 2 h after the oral administration of 100 mg/kg of aspirin. Pretreatment with three histamine H2 receptor antagonists (cimetidine, ranitidine, BMY-25271), prevented both of these effects in a dose-related manner. All three H2 receptor antagonists reduced gastric mucosal injury only at doses that were greater than those required to prevent the aspirin-induced decrease in gastric luminal pH or to inhibit histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. Plasma levels of aspirin were not altered by histamine H2 receptor antagonism. These results indicate that acid inhibition is an important component of the mechanisms whereby histamine H2 receptor antagonists protect the gastric mucosa from aspirin-induced damage in the dog.

Dendritic cells (DC) can be generated by culture of adherent peripheral blood (PB) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). There is controversy as to whether these DC arise from proliferating precursors or simply from differentiation of monocytes. DC were generated from myeloid-enriched PB non-T cells or sorted monocytes. DC generated from either population functioned as potent antigen-presenting cells. Uptake of [3H]-thymidine was observed in DC cultured from myeloid-enriched non-T cells. Addition of lipopolysaccharide or tumor necrosis factor-? led to maturation of the DC, but did not inhibit proliferation. Ki67+ cells were observed in cytospins of these DC, and by double staining were CD3-CD19-CD11c-CD40-and myeloperoxidase+, suggesting that they were myeloid progenitor cells. Analysis of the starting population by flow cytometry demonstrated small numbers of CD34+CD33-CD14- progenitor cells, and numerous granulocyte-macrophage colony-forming units were generated in standard assays. Thus, production of DC in vitro from adherent PB cells also enriches for progenitor cells that are capable of proliferation after exposure to GM-CSF. Of clinical importance, the yield of DC derived in the presence of GM-CSF and IL-4 cannot be expanded beyond the number of starting monocytes. © 1998 by The American Society of Hematology.

Murine epidermis contains 2 distinct cell populations which contribute to the skin immune system, Langerhans cells (LC), and dendritic epidermal T cells (DETC). LCs are important in the induction of immunity against a wide range of antigens; however, the function of DETC is unclear. To investigate the roles of these epidermal cells (EC) in protective antitumor immunity, an in vivo model of an ultraviolet radiation-induced fibrosarcoma, UV-13-1, was used. Mice were immunized with tumor antigen-pulsed EC followed 10 days later by an injection into the ear of 10⁵ tumor cells, which did not lead to formation of a detectable tumor, but was intended to simulate the influence of a developing tumor on the ensuing immune response. The mice were then challenged with 2 × 10⁶ viable tumor cells in each flank, sufficient to result in growth of a measurable tumor. Protective immunity was induced by DETC, and shown to be long-lasting, with tumors inoculated 160 days after immunization being effectively rejected. The effector cells responsible for protective immunity were CD8⁺ T cells. Delayed-type hypersensitivity generated by tumor antigen-pulsed EC was dependent on Lcs, with no involvement of DETCs. This response, in contrast to that of DETC, required prior culture of EC with GM-CSF, but failed to inhibit tumor growth or incidence. Thus DETC and LC can both activate antitumor immune responses, although only the DETC-dependent response results in protective immunity in the presence of a developing tumor. © 1997 Wiley-Liss, Inc.

The effect of 6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one hydrochloride monohydrate (BL-3459) on platelet function and experimental thrombosis was evaluated in a series of in vitro, ex vivo and in vivo animal experiments. Potent inhibition of platelet aggregation for BL-3459 was demonstrated by both in vitro and ex vivo techniques. In vitro, EC50 levels were less than 1 mug/ml regardless of the aggregating substance used or the species of animal from which platelet-rich plasma was obtained. After oral administration to rats and dogs, BL-3459 was rapidly absorbed and had a long duration of action. Ex vivo ED50 values were in the range of 2 to 3 mg/kg p.o. In addition, BL-3459 (1-10 mg/kg) demonstrated significant oral activity in a variety of in vivo animal models. BL-3459 inhibited elevation in screen filtration pressure induced by hemorrhage in dogs, endotoxemic death in rats, intravascular thrombosis produced by electrical stimulation of the carotid artery of the dog and thrombosis induced by means of a biolaser in the microvasculature of the rabbit ear chamber. In contrast to acetylsalicylic acid, BL-3459 had little effect on bleeding time in guinea pigs. Oral or intraduodenal administration of BL-3459 to dogs lowered aortic blood pressure, stroke volume and peripheral vascular resistance, while elevating cardiac rate and cardiac contractile force. Thus, it had little effect on the estimated cardiac output. These cardiovascular effects were mediated, in large part, through direct-acting mechanisms. BL-3459 exhibited weak antiserotonin activity in isolated smooth muscle preparations. While the precise mechanism of action of BL-3459 has not yet been determined, indications are that the compound may prove useful in the prevention of intravascular thrombosis.

The chemical carcinogen 7, 12-dimethylbenz(a)anthracene (DMBA) depletes Langerhans cells from murine epidermis. Application of contact sensitizers to DMBA-treated skin induces specific immunological tolerance due to a DMBA-resistant epidermal antigen presenting cell (APC) migrating to local lymph nodes where it presents antigen in a way which activates suppressor cells. As alterations in local lymph node lymphocytes may enhance the ability of the DMBA-resistant APC to activate suppressor cells, these cells were examined in DMBA-treated mice. Lymph nodes in DMBA-treated mice had normal morphology but were larger and contained increased numbers of lymphocytes. Cell cycle analysis revealed that these lymphocytes did not arise from division within the lymph node, suggesting alterations in homing properties of lymphocytes. Contact sensitizer applied to DMBA-treated skin did not increase lymphocyte division, possibly due to suppressor cell inhibition of the development of effector lymphocytes. DMBA treatment had no effect on B cells or Ia expression, but decreased levels of the T lymphocyte cell surface molecule Thy-1, and increased L3T4 and Lyt-2 as quantitated by flow cytofluorimetry. These changes could influence the development of immune responses as these T cell molecules are receptors involved in lymphocyte interactions.

Replacement of N-formyl peptide receptor (FPR) domains with those from a homologous receptor, FPR2, resulted in chimeric receptors displaying low binding affinity to fMet-Leu-Phe (fMLF). To characterize fMLF binding domain, we adopted a “gain-of-function” approach by selective replacement of non-conserved residues in the FPR2 portion of the chimeric receptors with those from the FPR. This led to the identification of 3 clusters of residues required for high-affinity fMLF binding. Introduction of 2 positively charged amino acids, Arg84and Lys85, dramatically improved binding affinity of one chimeric receptor (Kdfrom 105 nM to 1.6 nM). Similarly, restoration of either Gly89/His90or Phe102/Thr103improved the binding affinity of another chimeric receptor from a Kdof 275 nM to a 2.3 Kdand 3.3 nM, respectively. Increased ligand binding affinity was accompanied by a gain in calcium mobilization capability, suggesting functional coupling to G proteins. These results demonstrate the presence of structural determinants in the first extracellular loop and its adjacent transmembrane domains that are essential for high affinity fMLF binding.

Etintidine is a competitive antagonist of histamine H2-receptors in the isolated spontaneously beating guinea-pig right atrium with a pA2 value of 6.6 relative to values of 6.2, 6.7 and 7.3 for cimetidine, ranitidine and tiotidine, respectively. Low affinities for histamine H1 (pA2 = 4.2), cholinergic (pA2 = 4.4) and beta adrenergic (pA2 = 3.8) receptors indicated that etintidine has a high degree of specificity for the H2-receptor. The other antagonists studied also exhibited low affinities for these receptors; however, relative to these compounds, etintidine demonstrated a somewhat greater affinity for cholinergic receptors. Etintidine also antagonized basal gastric acid secretion in the conscious gastric fistula rat and histamine, pentagastrin, carbachol, 2-deoxy-D-glucose and meal-stimulated gastric acid secretion in conscious gastric fistula and Heidenhain pouch dogs. After oral administration to conscious Heidenhain pouch dogs, ED50 values for the inhibition of near maximal gastric acid secretion stimulated by histamine were 7.1, 5.4, 0.74 and 0.69 mumol/kg for cimetidine, etintidine, ranitidine and tiotidine, respectively. Onset and duration of the gastric antisecretory activities of the four compounds were similar. The order of potency as histamine H2-receptor and gastric antisecretory antagonists was cimetidine less than etintidine less than ranitidine less than tiotidine. Based on the high degree of specificity for the H2-receptor and its potent gastric antisecretory activity, etintidine may prove to be a useful agent in the treatment of peptic ulcer disease.

This essay presents transgender people's utilization of public restrooms in various countries including the U.S. and Canada. It looks at the activism of gender rights activists who assert that public facilities must be trans-inclusive and that the GLBT people must be protected from gender discrimination. It mentions the growing debates regarding trans-inclusive human rights legislation. The author also suggests the construction of toilet that may cultivate new relationship between people.

The imidazo(1,2‐a)pyridines (VIII), (X), and (XIII), prepared via coupling of the 2‐aminoethyl sulfides (VI) with the ethers (VII) or (IX) as shown in the reaction scheme, are tested as potential antisecretory and cytoprotective antiulcer agents.