IgE-Mediated Hypersensitivity Reactions to Cannabis in Laboratory Personnel

Background: There have been sporadic reports of hypersensitivity reactions to plants of the Cannabinaceae family (hemp and hops), but it has remained unclear whether these reactions are immunologic or nonimmunologic in nature. Objective: We examined the IgE-binding and histamine-releasing properties of hashish and marijuana extracts by CAP-FEIA and a basophil histamine release test. Methods: Two workers at a forensic laboratory suffered from nasal congestion, rbinitis, sneezing and asthmatic symptoms upon occupational contact with hashish or marijuana, which they had handled frequently for 25 and 16 years, respectively. Neither patient had a history of atopic disease. Serum was analyzed for specific IgE antibodies to hashish or marijuana extract by research prototype ImmunoCAP, and histamine release from basophils upon exposure to hashish or marijuana extracts was assessed. Results were matched to those of 4 nonatopic and 10 atopic control subjects with no known history of recreational or occupational exposure to marijuana or hashish. Results: Patient 1 had specific IgE to both hashish and marijuana (CAP class 2), and patient 2 to marijuana only (CAP class 2). Controls proved negative for specific IgE except for 2 atopic individuals with CAP class 1 to marijuana and 1 other atopic individual with CAP class 1 to hashish. Stimulation of basophils with hashish or marijuana extracts elicited histamine release from basophils of both patients and 4 atopic control subjects. Conclusions: Our results suggest an IgE-related pathomechanism for hypersensitivity reactions to marijuana or hashish. Copyright (C) 2011 S. Karger AG, Base

Some aspects of electrical conduction in granular systems of various dimensions

We report on measurements of the electrical conductivity in both a 2D triangular lattice of metallic beads and in a chain of beads. The voltage/current characteristics are qualitatively similar in both experiments. At low applied current, the voltage is found to increase logarithmically in a good agreement with a model of widely distributed resistances in series. At high enough current, the voltage saturates due to the local welding of microcontacts between beads. The frequency dependence of the saturation voltage gives an estimate of the size of these welded microcontacts. The DC value of the saturation voltage (~ 0.4 V per contact) gives an indirect measure of the number of welded contact carrying the current within the 2D lattice. Also, a new measurement technique provides a map of the current paths within the 2D lattice of beads. For an isotropic compression of the 2D granular medium, the current paths are localized in few discrete linear paths. This quasi-onedimensional nature of the electrical conductivity thus explains the similarity between the characteristics in the 1D and 2D systems.Comment: To be published in The European Physical Journal

Profiling Protein Sâ Sulfination with Maleimideâ Linked Probes

Cysteine residues are susceptible to oxidation to form Sâ sulfinyl (Râ SO2H) and Sâ sulfonyl (Râ SO3H) postâ translational modifications. Here we present a simple bioconjugation strategy to label Sâ sulfinated proteins by using reporterâ linked maleimides. After alkylation of free thiols with iodoacetamide, Sâ sulfinated cysteines react with maleimide to form a sulfone Michael adduct that remains stable under acidic conditions. Using this sequential alkylation strategy, we demonstrate differential Sâ sulfination across mouse tissue homogenates, as well as enhanced Sâ sulfination following pharmacological induction of endoplasmic reticulum stress, lipopolysaccharide stimulation, and inhibitors of the electron transport chain. Overall, this study reveals a broadened profile of maleimide reactivity across cysteine modifications, and outlines a simple method for profiling the physiological role of cysteine Sâ sulfination in disease.Maleimide, but not iodoacetamide, reacts with aryl and alkyl sulfinic acid standards and Sâ sulfinated proteins to give a sulfonylâ succinimide adduct that is stable under acidic conditions. This sequential alkylation strategy can be used for selective sulfinic acid labeling in biological samples. This study reveals a broadened profile of maleimide reactivity across cysteine modifications in proteins.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138861/1/cbic201700137_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138861/2/cbic201700137.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138861/3/cbic201700137-sup-0001-misc_information.pd

Sister Mary Joseph's Nodule at a University Teaching Hospital in Northwestern Tanzania: A Retrospective Review of 34 cases.

Sister Mary Joseph's nodule is a metastatic tumor deposit in the umbilicus and often represents advanced intra-abdominal malignancy with dismal prognosis. There is a paucity of published data on this subject in our setting. This study was conducted to describe the clinicopathological presentation and treatment outcome of this condition in our environment and highlight challenges associated with the care of these patients, and to proffer solutions for improved outcome. This was a retrospective study of histologically confirmed cases of Sister Mary Joseph's nodule seen at Bugando Medical Centre between March 2003 and February 2013. Data collected were analyzed using descriptive statistics. A total of 34 patients were enrolled in the study. Males outnumbered females by a ratio of 1.4:1. The vast majority of patients (70.6%) presented with large umbilical nodule > 2 cm in size. The stomach (41.1%) was the most common location of the primary tumor. Adenocarcinoma (88.2%) was the most frequent histopathological type. Most of the primary tumors (52.9%) were poorly differentiated. As the disease was advanced and metastatic in all patients, only palliative therapy was offered. Out of 34 patients, 11 patients died in the hospital giving a mortality rate of 32.4%. Patients were followed up for 24 months. At the end of the follow-up period, 14(60.9%) patients were lost to follow-up and the remaining 9 (39.1%) patients died. Patients survived for a median period of 28 weeks (range, 2 to 64 weeks). The nodule recurred in 6 (26.1%) patients after complete excision. Sister Mary Joseph's nodule of the umbilicus is not rare in our environment and often represents manifestation of a variety of advanced intra-abdominal malignancies. The majority of the patients present at a late stage and many with distant metastases. The patient's survival is very short leading to a poor outcome. Early detection of primary cancer at an early stage may improve the prognosis

Polymeric Nanoparticle PET/MR Imaging Allows Macrophage Detection in Atherosclerotic Plaques

Author Manuscript 2013 March 02.Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention. Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ([superscript 89]Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P<0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of [superscript 89]Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE[superscript −/−]) mice (standard uptake value, ApoE[superscript −/−] mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased [superscript 89]Zr-DNP plaque signal (P<0.05) and inflammatory gene expression (P<0.05). Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.National Heart, Lung, and Blood InstituteNational Institutes of Health (U.S.). Dept. of Health and Human Services (HHSN268201000044C)National Institutes of Health (U.S.). Dept. of Health and Human Services (R01-HL096576)National Institutes of Health (U.S.). Dept. of Health and Human Services (R01-HL095629)National Institutes of Health (U.S.). Dept. of Health and Human Services (T32-HL094301

A discrete geometric approach for simulating the dynamics of thin viscous threads

We present a numerical model for the dynamics of thin viscous threads based on a discrete, Lagrangian formulation of the smooth equations. The model makes use of a condensed set of coordinates, called the centerline/spin representation: the kinematical constraints linking the centerline's tangent to the orientation of the material frame is used to eliminate two out of three degrees of freedom associated with rotations. Based on a description of twist inspired from discrete differential geometry and from variational principles, we build a full-fledged discrete viscous thread model, which includes in particular a discrete representation of the internal viscous stress. Consistency of the discrete model with the classical, smooth equations is established formally in the limit of a vanishing discretization length. The discrete models lends itself naturally to numerical implementation. Our numerical method is validated against reference solutions for steady coiling. The method makes it possible to simulate the unsteady behavior of thin viscous jets in a robust and efficient way, including the combined effects of inertia, stretching, bending, twisting, large rotations and surface tension

PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients

Patterns and flow in frictional fluid dynamics

Pattern-forming processes in simple fluids and suspensions have been studied extensively, and the basic displacement structures, similar to viscous fingers and fractals in capillary dominated flows, have been identified. However, the fundamental displacement morphologies in frictional fluids and granular mixtures have not been mapped out. Here we consider Coulomb friction and compressibility in the fluid dynamics, and discover surprising responses including highly intermittent flow and a transition to quasi-continuodynamics. Moreover, by varying the injection rate over several orders of magnitude, we characterize new dynamic modes ranging from stick-slip bubbles at low rate to destabilized viscous fingers at high rate. We classify the fluid dynamics into frictional and viscous regimes, and present a unified description of emerging morphologies in granular mixtures in the form of extended phase diagrams

Myocardial Infarction Accelerates Atherosclerosis

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, apoE$^{−/−}$ mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression

Macrophages retain hematopoietic stem cells in the spleen via VCAM-1

Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)[superscript +] macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE[superscript −/−] mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques