Pulmonary edema in cocaine smokers

Cocaine smoking can cause a number of medical complications. Pneumomediastinum and pneumothorax due to barotrauma have been the most common radiographic abnormalities reported in the medical literature. The hospital records of five patients with pulmonary edema who smoked cocaine just before admission were reviewed. Except for cocaine abuse no other possible cause for the pulmonary edema was found. Although chest radiographic abnormalities in these patients are uncommon, these cases are reported to inform the radiologist of this possible complication of cocaine smoking. The presence of pulmonary edema in a young, otherwise healthy patient without predisposing risk factors should alert the radiologist to the possible diagnosis of cocaine abuse.     

Histidine-rich glycoprotein is present in human platelets and is released following thrombin stimulation

Histidine-rich glycoprotein, and alpha 2-glycoprotein in human plasma, has been shown to interact with heparin, with the high-affinity lysine- binding site of plasminogen, with divalent cations, and is associated with the rosette formation between erythrocytes and lymphocytes. A specific enzyme-linked immunosorbent assay for histidine-rich glycoprotein has been developed and used to demonstrate that histidine- rich glycoprotein is present in human platelets. Histidine-rich glycoprotein was detected and quantified in detergent extracts of washed human platelets, with a mean level of 371 ng/10(9) platelets. Plasma histidine-rich glycoprotein, either in the platelet suspending medium or on the surface of the platelets, accounted for less than 3.4% of the detectable platelet histidine-rich glycoprotein. Histidine-rich glycoprotein was also demonstrated in human bone marrow megakaryocytes by immunofluorescence. The extent of histidine-rich glycoprotein release from platelets was dependent on the thrombin dose and correlated directly with the extent of serotonin release. The platelet and plasma histidine-rich glycoprotein were similar by immunochemical analysis. Anti-histidine-rich glycoprotein IgG did not inhibit platelet aggregation. Histidine-rich glycoprotein released by platelets following thrombin stimulation may play a significant role in modulating inflammatory events in the microenvironment of the platelet plug.     

MR imaging of the scrotum: pathologic conditions

The utility of high-resolution magnetic resonance (MR) imaging in studying a variety of intratesticular and extratesticular pathologic conditions was assessed. The high magnetic signal intensity of the testis provided an excellent background for visualization of intratesticular abnormalities. Except for old blood, all intratesticular processes were less intense than testis, especially on T2-weighted images. The visualization of the tunica albuginea is a distinct advantage, allowing its assessment in cases of trauma or testicular tumors. Epididymal and spermatic cord abnormalities were easily recognized. All pathologic conditions were best seen on T2-weighted images acquired in the coronal plane. Balanced images allowed for tissue characterization.     

Induction of a cross-reactive idiotype dextran-positive antibody response in two IgH-Cb mouse strains treated with anti-J558 cross-reactive idiotype antibodies

The effect of IdX-specific rabbit and allogeneic antiidiotype antibodies (Ab2) was investigated in vivo in Igh-Cb mouse strains with respect to the induction of a cross-reactive idiotype (IdX)-positive anti-alpha (1-3) Dextran (Dex) response. These C.B20 and C57Bl/6 mice have an allotype-linked incapacity to respond with IdX-positive anti-alpha (1-3) Dex antibodies upon conventional immunization with Dex B1355. 7 d after the rabbit Ab2 injections, IdX-positive Ig (Ab3) and IdX-positive anti-alpha (1-3) Dex antibodies (Ab1') were detected in the sera of each tested mouse. The affinity-purified Ab1' were idiotypically indistinguishable from reference BALB/c IdX-positive myeloma proteins and BALB/c anti-alpha (1-3) Dex antibodies (Ab1) in a competitive inhibition radioimmunoassay, while Ab3 Ig appeared idiotypically deficient and did not bind to Dex. The response to the alpha (1-6) linkage of Dex was not affected in these mice. A large fraction of the Ab1' and Ab3 responses of both mouse strains were of the IgG1 class. The Ab1' antibodies differed from BALB/c Ab1 by lower relative binding to five of eight tested Dex, and by expressing the Igh4b allotype determinants on the IgG1 antibodies. This study identifies the products of a VHDex gene that appears to be under regulatory control in the Ighb mice. Its association with the b haplotype suggests that this gene may differ structurally from the BALB/c VHDex gene.     

Tissue culture studies in Hodgkin’s disease morphologic, cytogenic, cell surface, and enzymatic properties of cultures derived from splenic tumors

Monolayer and suspension cell cultures prepared from Hodgkin's disease tumors in the spleen were examined microscopically and by cytogenetics, tested for lymphocyte and monocyte cell surface properties, and assayed for enzymes by histochemical and spectrophotometric techniques. Hodgkin's disease monolayer cultures were composed of rapidly proliferating round and polygonal cells that were capable of propagation in vitro for an indefinite period of time. Abnormal aneuploid chromosomes were found in short-term Hodgkin's disease monolayers that had been passaged 16-20 times, and in established cell lines carried in culture longer than 3 yr and passaged more than 200 times. Cells fromHodgkin's disease monolayers contained lysozyme (muramidase), fluoride-resistant alpha naphthol acetate esterase, acid and alkaline phosphatase, and chymotrypsin-like activity. The monolayers did not exhibit specific cell surface markers or phagocytosis. Suspension cultures derived from Hodgkin's disease monolayers were composed of cells with aneuploid karyotypes and similar enzymes. The Hodgkin's disease suspension culture cells had surface receptors for complement and IgGFc, lacked surface or cytoplasmic immunoglobulin, and did not form Erosettes, react with an antithymocyte serum, nor exhibit phagocytosis. Normal monolayer culture cells, derived from adult spleen and human fetal spleen and thymus, were composed of spindle cells with a diploid number of chromosomes that could be carried for only a finite period of time in vitro. Normal cultured cells contained similar esterases and phosphatases, but were devoid of lysozyme and chymotrypsin-like activity. The morphologic, cytogenetic, cell surface, and enzymatic findings indicate that our Hodgkin's disease monolayer and suspension cultures are composed of cells with many properties suggesting an origin from monocytes (macrophages) rather than lymphocytes or fibroblasts. The presence of aneuploid karyotypes is consistent with a neoplastic origin and derivation from a malignant cell of Hodgkin's disease.     

Estimating health expenditure shares from household surveys

Objective

To quantify the effects of household expenditure survey characteristics on the estimated share of a household’s expenditure devoted to health.

Methods

A search was conducted for all country surveys reporting data on health expenditure and total household expenditure. Data on total expenditure and health expenditure were extracted from the surveys to generate the health expenditure share (i.e. fraction of the household expenditure devoted to health). To do this the authors relied on survey microdata or survey reports to calculate the health expenditure share for the particular instrument involved. Health expenditure share was modelled as a function of the survey’s recall period, the number of health expenditure items, the number of total expenditure items, the data collection method and the placement of the health module within the survey. Data exists across space and time, so fixed effects for territory and year were included as well. The model was estimated by means of ordinary least squares regression with clustered standard errors.

Findings

A one-unit increase in the number of health expenditure questions was accompanied by a 1% increase in the estimated health expenditure share. A one-unit increase in the number of non-health expenditure questions resulted in a 0.2% decrease in the estimated share. Increasing the recall period by one month was accompanied by a 6% decrease in the health expenditure share.

Conclusion

The characteristics of a survey instrument examined in the study affect the estimate of the health expenditure share. Those characteristics need to be accounted for when comparing results across surveys within a territory and, ultimately, across territories.     

Molecular requirements for inhibition of the chemokine receptor CCR8 – probe-dependent allosteric interactions

BACKGROUND AND PURPOSE

Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.

EXPERIMENTAL APPROACH

The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gα_i signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148.

KEY RESULTS

All compounds were highly potent inverse agonists with EC₅₀ values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC₅₀ values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [¹²⁵I]-CCL1 (K_i 3.4–842 nM), whereas the affinities measured against [¹²⁵I]-MC148 were less widely spread (K_i 0.37–27 nM), and matched the inverse agonist potencies.

CONCLUSION AND IMPLICATIONS

Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties.     

NF-κB-dependent IL-8 induction by prostaglandin E2 receptors EP1 and EP4

Background and Purpose

Recent studies suggested a role for PGE₂ in the expression of the chemokine IL-8. PGE₂ signals via four different GPCRs, EP₁-EP₄. The role of EP₁ and EP₄ receptors for IL-8 induction was studied in HEK293 cells, overexpressing EP₁ (HEK-EP₁), EP₄ (HEK-EP₄) or both receptors (HEK-EP₁ + EP₄).

Experimental Approach

IL-8 mRNA and protein induction and IL-8 promoter and NF-κB activation were assessed in EP expressing HEK cells.

Key Results

In HEK-EP₁ and HEK-EP₁ + EP₄ but not HEK or HEK-EP₄ cells, PGE₂ activated the IL-8 promoter and induced IL-8 mRNA and protein synthesis. Stimulation of HEK-EP₁ + EP₄ cells with an EP₁-specific agonist activated IL-8 promoter and induced IL-8 mRNA and protein, whereas a specific EP₄ agonist neither activated the IL-8 promoter nor induced IL-8 mRNA and protein synthesis. Simultaneous stimulation of HEK- EP₁ + EP₄ cells with both agonists activated IL-8 promoter and induced IL-8 mRNA to the same extent as PGE₂. In HEK-EP₁ + EP₄ cells, PGE₂-mediated IL-8 promoter activation and IL-8 mRNA induction were blunted by inhibition of IκB kinase. PGE₂ activated NF-κB in HEK-EP₁, HEK-EP₄ and HEK-EP₁ + EP₄ cells. In HEK-EP₁ + EP₄ cells, simultaneous activation of both receptors was needed for maximal PGE₂-induced NF-κB activation. PGE₂-stimulated NF-κB activation by EP₁ was blocked by inhibitors of PLC, calcium-signalling and Src-kinase, whereas that induced by EP₄ was only blunted by Src-kinase inhibition.

Conclusions and Implications

These findings suggest that PGE₂-mediated NF-κB activation by simultaneous stimulation of EP₁ and EP₄ receptors induces maximal IL-8 promoter activation and IL-8 mRNA and protein induction.