Opioid Peptide Deltorphin II Simulates the Cardioprotective Effect of Ischemic Preconditioning: Role of δ<Subscript>2</Subscript>-Opioid Receptors,Protein Kinase C,and K<Subscript>ATP</Subscript> Channels

The cardioprotective properties of a δ₂-opioid receptor agonist deltorphin II were studied in rats with coronary occlusion and reperfusion. Opioid receptor ligands and inhibitors (glybenclamide, chelerythrine, and 5-hydroxydecanoate) were injected intravenously before ischemia and reperfusion. A δ₂-opioid receptor agonist deltorphin II signifi cantly decreased the infarction zone/risk zone index. This effect was abolished by naltrexone, naloxone methiodide, and δ₂-opioid receptor antagonist naltriben, but not by a δ₁-opioid receptor antagonist BNTX. The infarct-limiting effect of deltorphin II was not observed after inhibition of protein kinase C or blockade of mitochondrial K_ATP channels.     

Involvement of NKR‐P2/NKG2D in DC‐mediated killing of tumor targets: indicative of a common,innate, target‐recognition paradigm?

DC are the most efficient antigen-presenting cells that regulate the immune response. Here, we demonstrate the expression of NK cell receptor protein-2 (NKR-P2) on rat and mouse DC, and we show that NKR-P2 gets reorganized upon antigen contact. DC activated with anti-NKR-P2 mAb exhibit enhanced apoptotic killing of tumor targets, whereas blocking the interaction between NKR-P2 and its ligand with rNKR-P2 abrogated apoptotic killing, suggesting NKR-P2 to function as an activating molecule on DC. In vivo injection of anti-NKR-P2 mAb augmented DC activity and delayed tumor progression. NKR-P2 signaling involved Ca(2+ )influx, culminating in the expression of the apoptosis-inducing molecule, TNF-alpha. Taken together, these observations suggest that NKR-P2 (the rat orthologue of human NKG2D) acts as a target-recognition molecule on DC.     

Burden of disease in Nari?o,Colombia, 2010

Objective:

This study sought to measure burden of disease and identifies health priorities from the Disability Adjusted Life Years (DALYs) indicator.

Methods:

This is the first study on burden of disease for a department in Colombia by using a standardized methodology. By using the

DALYs indicator, burden of disease was identified in the department of Nariño according to the guidelines established by the World Health Organization.

Results:

The DALYs in the Department of Nariño highlight the emergence of communicable, maternal, perinatal, and nutritional diseases during the first years of life; of accidents and lesions among youth, and non-communicable diseases in older individuals. Also, accidents and lesions are highlighted in men and non-communicable diseases in women.

Conclusions:

This study is part of the knowledge management process in the Departmental Health Plan for Nariño - Colombia 2012-2015 and contributes to the system of indicators of the 2012 ten-year public health plan. This research evidences that communicable diseases generate the biggest part of the burden of disease in the Department of Nariño, that DALYs due to non-communicable diseases are on the rise, and that accidents and lesions, especially due to violence are an important cause of DALYs in this region, which is higher than that of the country.     

Prevalence,resistance patterns,and characterization of integrons of <Emphasis Type="Italic">Shigella flexneri</Emphasis> isolated from Jiangsu Province in China, 2001–2011

Objective: To provide the epidemiology, resistance pattern, and characterization of integrons in Shigella flexneri isolated between 2001 and 2011 in Jiangsu Province. Method: A total of 624 strains of S. flexneri were collected from both outpatients and inpatients in hospitals in Jiangsu Province from January 2001 to December 2011. The Kirby–Bauer disk diffusion method was used to perform the antimicrobial susceptibility test. Polymerase chain reaction (PCR) was used in the detection of integrons. Pulsed-field gel electrophoresis (PFGE) was applied in the homology studies. Result: Serotype 2a accounted for the largest proportion in S. flexneri, namely 26.4 %. Notably, an increasing trend was detected in the resistance to common antimicrobial agents during the period 2001–2011. In recent years, more than 80.0 % isolates of S. flexneri have proved to be resistant to ampicillin, nalidixic acid, and tetracycline. The positive rates of class 1, class 2, and the atypical class 1 integrons in S. flexneri are 69.3 %, 87.8 %, and 89.2 % respectively. Most integrons detected in our research carry genes encoding resistance to trimethoprim and streptomycin. Conclusion: Antimicrobial resistance in S. flexneri has demonstrated a continuous rising trend in Jiangsu Province. A high prevalence of integrons and gene cassettes play an important role in the transmission of drug resistance in S. flexneri. Effective measures are urgently needed to control the spread of multi-drug-resistant S. flexneri, and more continuing active surveillance of antimicrobial resistance should be established worldwide, especially in developing countries.     

Surveillance of antimicrobial resistance—what, how and whither?

Objective   To express the views of a working party held to consider antibiotic resistance surveillance systems, their strengths and weaknesses, and their current and future applications.
Methods   The participants, all of whom were experienced in this field, discussed the development of surveillance systems in relation to the increasing prevalence of resistance to antibacterial agents and the current interest in surveillance systems shown by many official bodies, in both the human and veterinary fields. The problems inherent in surveillance systems were considered together with the applications of different systems.
Results   The properties of good antibiotic resistance surveillance systems were defined. Surveillance systems vary widely from those with a narrow base, focusing on few organisms in one disease area, to those covering many diseases, many organisms (including normal flora) and many compounds. Whatever their design, they should be able to detect significant differences and shifts in susceptibility to various antibacterial agents, and the information derived from them should reach as many interested parties as possible in a timely manner. In using this information to decide strategies, criteria for action need to be determined by pragmatic consensus. Funding remains a major problem, with few large studies being supported by official bodies in spite of their professed enthusiasm for surveillance. In consequence, many current systems are funded by the pharmaceutical industry and are of necessity restricted in their focus.
Conclusions   Antibiotic resistance surveillance studies should and can be well planned and well executed. Many current systems suffer from well-recognized but uncorrected biases. Consortium funding will be necessary for large schemes to be successful. There is no 'ideal' surveillance system.     

The effects of S1319, a novel marine sponge-derived β<Subscript>2</Subscript>-adrenoceptor agonist,on IgE-mediated activation of human cultured mast cells

OBJECTIVE: This study aimed to evaluate the ability of S1319 (4-hydroxy-7-[1-(1-hydroxy-2-methylamino) ethyl]-1,3-benzothiazol-2(3H)-one acetate), a novel beta2-adrenoceptor selective agonist derived from marine sponge, to inhibit IgE-mediated activation of human cultured mast cells (HCMC) in vitro. MATERIALS AND METHODS: We examined the effect of S1319 (racemate) on tryptase release and tumor necrosis factor-alpha (TNF-alpha) production in HCMC generated from human cord blood cells, after cross-linking of high affinity immunoglobulin E receptors (FcepsilonRI), compared with those of the nonselective beta-adrenoceptor agonist, isoproterenol (R-isomer), the selective beta2-adrenoceptor agonist, salbutamol (racemate), and the selective and long-acting beta2-adrenoceptor agonist, formoterol (racemate). We also evaluated the effect of S1319 on the intracellular cAMP level, inositol phosphate production and protein tyrosine phosphorylation in HCMC. RESULTS: S1319 and beta-adrenoceptor agonists inhibited the IgE-mediated release of tryptase. Approximate IC50 values of S1319, formoterol, isoproterenol and albuterol for the inhibition of tryptase release were 0.51+/-0.12, 0.15+/-0.1, 0.80+/-0.09, and 28+/-32.4 nM, respectively. S1319 and beta-adrenoceptor agonists also inhibited TNF-alpha production by HCMC in a concentration-dependent manner. Approximate IC50 values of S1319, formoterol and isoproterenol for the inhibition of TNF-alpha production were 0.19+/-0.03, 0.28+/-0.02 and 0.32+/-0.03 nM, respectively. S1319 caused a concentration-dependent increase in total cell cyclic AMP levels in HCMC. On the other hand, S1319 inhibited the accumulation of inositol 1,4,5-triphosphate and IgE-mediated protein tyrosine phosphorylation of 42-kDa protein, p42 mitogen activated protein (MAP) kinase (ERK-2). CONCLUSION: These results indicate that S 1319 and beta-adrenoceptor agonists are potent inhibitors of the IgE-mediated release of mediators from HCMC.     

‘True’ antimitochondrial antibody‐negative primary biliary cirrhosis,low sensitivity of the routine assays,or both?

Anti-mitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cirrhosis (PBC), but may be missing in a proportion of these patients. We assessed sensitivity and specificity of the currently available techniques for AMA detection in a large series of PBC patients and controls, and analysed their clinical and immunological features according to the AMA status. By indirect immunofluorescence on rat tissue sections and HEp-2 cells, Western immunoblot with bovine submitochondrial particles, and two ELISAs with AMA-specific recombinant proteins, we evaluated the presence of AMA in 127 PBC patients, 166 patients with type 1 autoimmune hepatitis and 100 with non alcoholic fatty liver disease. In PBC patients Western immunoblot detects AMA significantly more often than indirect immunofluorescence on HEp-2 cells (85%versus 72%, P = 0.02) or rodent tissue sections (71%, P = 0.01); both ELISAs are only slightly less sensitive than Western immunoblot (81% and 78%). Ten patients with non alcoholic fatty liver disease were AMA-positive by indirect immunofluorescence, but none recognized AMA-specific epitopes in Western immunoblot or in ELISAs. Twelve patients with type 1 autoimmune hepatitis were AMA-positive by indirect immunofluorescence, but only 6 (3.6%) reacted by Western immunoblot and ELISAs. Western immunoblot or ELISA should be regarded as first-line assay for the detection of AMA. Up to 15% of PBC patients are consistently AMA-negative, yet they share the same clinical, biochemical and histological features of AMA-positive PBC. Detection of AMA in type 1 autoimmune hepatitis might identify a subset of patients at risk of developing a hepatitic/cholestatic syndrome.     

Evaluation of the Safety,Tolerability, and Pharmacokinetics of Gammaplex<Superscript>®</Superscript> 10% Versus Gammaplex<Superscript>®</Superscript> 5% in Subjects with Primary Immunodeficiency

Purpose

This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs).

Methods

Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only.

Results

The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC_0–28) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%.

Conclusions

In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

     

Prevalence of <Emphasis Type="Italic">Toxocara</Emphasis>-induced liver granulomas,detected by immunohistochemistry,in a series of autopsies at a Children’s Reference Hospital in Vitoria,ES, Brazil

The aim of this investigation was to study the frequency of visceral larva migrans (VLM) granulomas in autopsies at a Children’s Reference Hospital in Vitoria, ES Brazil, where anti-Toxocara antibodies are frequently detected in the serum of children admitted at the hospital. Two liver fragments from 310 autopsies of children aged between 1 and 15 years were paraffin embedded, and sections were stained with hematoxylin and eosin and submitted to detection of Toxocara antigens using a rabbit anti-Toxocara serum. Among the 24 cases with granulomatous lesions, ten had eosinophil-rich granulomas positively stained with the anti-Toxocara serum. Some were typical epithelioid granulomas, with a positive reaction in multinucleated giant cells, epithelioid cells, or necrotic debris. The results showed that VLM granulomas are the most frequent granulomatous hepatitis in children in our county. This agrees with the high prevalence of anti-Toxocara antibodies in the serum of children admitted to the Children’s Reference Hospital. The 3.2% frequency of liver VLM granulomas in autopsies is less than the 30–39% frequency of positive serology in these children, probably reflecting the low larval burden in infected children.     

Insecticidal activity of major lichen compounds, (−)- and (+)-usnic acid,against the larvae of house mosquito, <Emphasis Type="Italic">Culex pipiens</Emphasis> L.

In this research, (−)-usnic acid and (+)-usnic acid, commonly encountered lichen secondary metabolites, were evaluated for their insecticidal effects against the larvae of Culex pipiens L. (Diptera: Culicidae) under laboratory conditions. Both compounds showed strong larvicidal activity and caused 100% mortality on third–fourth larval stages of the species at 24 h at the doses of 5 and 10 ppm. Bioassays with (−)- and (+)-usnic acids against larvae of C. pipiens revealed that the LC₅₀ values were 0.8 and 0.9 ppm, respectively. The results suggest that lichen compounds could be useful in the search of new insecticides.     

Assessment of <Emphasis Type="Italic">Echinococcus granulosus</Emphasis> polymorphism in Qinghai Province,People’s Republic of China

Cystic echinococcosis (CE) is highly endemic in the Chinese province of Qinghai, located on the Tibetan Plateau. The Echinococcus granulosus sheep strain has already been reported in this focus. To improve our understanding of the role the parasite plays in the high prevalence observed in humans, we assessed the genetic polymorphism of 55 E. granulosus samples (37 from humans) using three discriminative mitochondrial markers: coxI, nadI and atp6. We obtained a total of 13 distinct genotypes which were all related to the common sheep G1 strain. Six of these genotypes have already been reported in China and other foci around the world. The remaining seven genotypes were new variants of the strain. The parasite population which was studied in the present work did not differ substantially from those observed in other foci of CE. Environmental conditions and human behaviour could explain the high incidence of the parasitic disease, particularly in the Tibetan population in the south of Qinghai, most of whom are livestock farmers.     

Determinants of CD4 Counts Among HIV-Negative Ethiopians: Role of Body Mass Index,Gender, Cigarette Smoking,Khat (<Emphasis Type="Italic">Catha Edulis</Emphasis>) Chewing,and Possibly Altitude?

To study the determinants of CD4% and CD4 counts among HIV-negative Ethiopians, and to identify factors susceptible to explain the low CD4 counts observed among Ethiopian subjects. Cohort studies among factory workers in Akaki and Wonji, Ethiopia. Clinical and laboratory examinations, including determination of HIV serological status and T-cell subsets, were performed during follow-up visits every six months. In addition, micronutrients (retinol, carotenoids, tocopherol, transferrin receptor, and selenium) plasma concentrations were determined in a subset of 38 HIV-positive and 121 HIV-negative participants. HIV-negative participants with at least one CD4 count measurement were 157 females in Akaki, 203 males in Akaki, and 712 males in Wonji. CD4 counts were independently and positively associated with body mass index (through an increase in lymphocyte counts), female gender (through an increase in CD4%), cigarette smoking (through an increase in CD4%), khat chewing (through an increase in both lymphocyte counts and CD4%), and Akaki study site (through a large increase in lymphocyte counts compensating a decrease in CD4%). Intestinal parasitic infections were not associated with CD4% or CD4 counts. Retinol, carotenoids, and -tocopherol plasma concentrations decreased with HIV infection and advancing immunosuppression, but were not associated with CD4 counts among HIV-negative subjects. Low body mass index among Ethiopians may have contributed to their overall low CD4 counts. Other factors remain to be elucidated.     

Evaluation of recombinant HP6-Tsag,an 18 kDa <Emphasis Type="Italic">Taenia saginata</Emphasis> oncospheral adhesion protein,for the diagnosis of cysticercosis

With the objective of providing inexpensive and reproducible assays for the detection of antibodies indicating exposure to Taenia saginata and Taenia solium, we have evaluated the diagnostic utility of the T. saginata oncosphere adhesion protein (HP6-Tsag), expressed in baculovirus (HP6-Bac) and bacteria (HP6-GST [glutathione S-transferase]), employing enzyme-linked immunosorbent assays (ELISAs) and sera from T. saginata infected cattle, T. solium infected pigs and serum and cerebrospinal fluid (CSF) samples from clinically defined T. solium neurocysticercosis (NCC) patients. The two recombinant proteins were antigenic in all three systems, with the signal to background ratio of the HP6-Bac ELISA slightly higher than that for the HP6-GST ELISA. Assay performance in cattle was similar to previously described peptide-based ELISA assays, although NCC sample sensitivity/specificity was marginally better. The sensitivity of the HP6-Bac and HP6-GST ELISAs was close for active human NCC (77.4 and 80.6% for serum and 76.9 and 73.1% for CSF samples, respectively). In inactive human NCC, however, the sensitivity of the HP6-Bac ELISA was almost twice that of the HP6-GST ELISA. Because peptides are relatively expensive and recombinant proteins are simple and economical to produce, the latter may provide useful reagents for antibody detection in countries with endemic cysticercosis/NCC.     

Emerging roles of extracellular vesicles in COVID‐19, a double‐edged sword?

The sudden outbreak of SARS‐CoV‐2‐infected disease (COVID‐19), initiated from Wuhan, China, has rapidly grown into a global pandemic. Emerging evidence has implicated extracellular vesicles (EVs), a key intercellular communicator, in the pathogenesis and treatment of COVID‐19. In the pathogenesis of COVID‐19, cells that express ACE2 and CD9 can transfer these viral receptors to other cells via EVs, making recipient cells more susceptible for SARS‐CoV‐2 infection. Once infected, cells release EVs packaged with viral particles that further facilitate viral spreading and immune evasion, aggravating COVID‐19 and its complications. In contrast, EVs derived from stem cells, especially mesenchymal stromal/stem cells, alleviate severe inflammation (cytokine storm) and repair damaged lung cells in COVID‐19 by delivery of anti‐inflammatory molecules. These therapeutic beneficial EVs can also be engineered into drug delivery platforms or vaccines to fight against COVID‐19. Therefore, EVs from diverse sources exhibit distinct effects in regulating viral infection, immune response, and tissue damage/repair, functioning as a double‐edged sword in COVID‐19. Here, we summarize the recent progress in understanding the pathological roles of EVs in COVID‐19. A comprehensive discussion of the therapeutic effects/potentials of EVs is also provided.