Age interference of lymphokine production by lung derived lymphocytes

Young adult and aged guinea pigs, 1 and 3 years old respectively, were sensitized intranasally with Bacillus Calmette Guérin (BCG). Lung lavage cells were harvested at 2, 3, 6 and 7 weeks following sensitization and tested for migration inhibitory factor (MIF) production in Mackaness chambers with purified protein derivative (PPD). Oil induced normal pig macrophages were used as indicator cells. Aged guinea pigs, compared to young adult guinea pigs, showed significant delay and reduced levels of MIF production at 2 to 3 weeks. Delayed hypersensitivity skin reaction (DHS) to PPD was also less pronounced at 6 weeks. Senescent immune lung cells were inhibitory to migration of indicator cells in absence of PPD.     

4-O-卤代酰基-4′-去甲基表鬼臼毒素类似物的合成与抗肿瘤活性

为考察4′-去甲表鬼臼毒素C₄位上联结含卤素原子的酯化侧链时对化合物抗肿瘤活性的影响,设计并采用选择性酯化方法合成了9个新的4′-去甲基表鬼臼毒素酯化产物。其中标题化合物在L₁₂₁₀白血病肿瘤细胞与KB细胞的体外生长抑制试验中普遍表现出显著的抑制活性,大部分化合物活性超过依托泊甙。而普通脂酸酯的活性较弱。     

A polymorphism in the NPPA gene associates with asthma

Background Atrial natriuretic peptide (ANP) plays an important role in the lung and in augmenting allergic inflammation in asthma. The gene encoding ANP, NPPA , is located on chromosome 1p36, a region that has been linked to asthma.
Objectives Determine associations between asthma and four common SNPs on the NPPA gene: C/G (rs13305986) in the promoter; G/A (rs5063) in Exon 1 resulting in NPPAMet32 →Val substitution; T/C (rs5065) in Exon 3 resulting in an Arg152→Ter substitution; and T/C in the 3'UT region (rs5067).
Methods A case–control design was used in White participants. The screening cohort consisted of 336 asthmatic cases who participated in a large clinical trial and 154, non-asthmatic controls. The replicate cohort consisted of 172 asthmatic cases from a second clinical trial and 115 healthy controls. Demographic characteristics were well matched for cases and controls in the screening cohort. Adjusted (age, gender, body mass index) odds ratio (OR) were calculated by χ² and logistic regression; a P -value of 0.0167 defined the threshold of significance.
Results The C allele of rs5067 was associated with asthma in the screening and replicate cohorts: adjusted ORs (95% confidence intervals) 0.5 (0.29–0.84; P =0.009) and 0.24 (0.11–0.53; P <0.0001), respectively. The C allele of rs5065 was associated with asthma in the screening cohort but not in the replicate. The population-attributable risk for asthma in carriers of the C allele for rs5067 was 23.3%.
Conclusions For rs5067, the risks of asthma in carriers of the C allele in the screening and replicate cohorts were reduced by 50% and 76%, respectively. NPPA may be an important susceptibility gene for asthma.     

Antibacterial and immunostimulatory properties of chemotactic N-formyl peptide conjugates of ampicillin and amoxicillin.

N-Formyl dipeptide conjugates of ampicillin and amoxicillin related to the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine were synthesized and assessed for antibacterial activity and affinity for the chemotactic peptide receptor of differentiated human promyelocytic leukemia (HL-60) cells. The conjugates and parent beta-lactam antibiotics showed similar antibacterial activities against Escherichia coli and Staphylococcus aureus. The affinity of each conjugate for the chemotactic peptide receptor was determined in a competitive binding assay, using 3H-labeled N-formyl-L-methionyl-L-leucyl-L-phenylalanine. All conjugates bound to the receptor, but with affinities ranging from 1/3 to 1/100 that of the tritiated substrate. There was good correlation between receptor affinity and stimulation of chemotaxis. The peptide-antibiotic conjugates also stimulated the oxidative metabolism of the HL-60 cells by inducing the production of superoxide and hydrogen peroxide as determined by Luminol- and Lucigenin-enhanced chemiluminescence. These conjugates, based on N-formyl-L-methionyl-L-leucyl-L-phenylalanine, thus combine both potent antibacterial and immunostimulatory properties within the same molecule.     

Present and Potential Therapy for Allergic Rhinitis

Allergic rhinitis can affect up to one-fifth of the population and the economic impact is increasing. H(1) receptor antagonists were the first major pharmacologic treatment, but the associated sedation limited their use. The 2 initial second generation less sedating antihistamines, astemizole and terfenadine, were found to prolong the cardiac QT(c) interval, especially when administered with other medications metabolised by the same cytochrome (CYP) P450 isoenzyme, CYP3A4. Other second generation antihistamines, fexofenadine, loratadine and cetirizine, do not cause clinically significant cardiac QT(c) interval prolongation. Two newer agents, ebastine and mizolastine, are also effective in the treatment of allergic rhinitis. Ebastine, however, prolongs the cardiac QT(c) interval in laboratory animals and humans, the clinical significance of which is unknown. Desloratadine and norastemizole, metabolites of loratadine and astemizole, respectively, are 2 other second generation antihistamines found to be effective treatments for seasonal allergic rhinitis. Unlike their parent compounds, they do not prolong the cardiac QT(c) interval. All clinically available intranasal corticosteroids are effective in the treatment of allergic rhinitis, but studies to evaluate possible long term systemic adverse effects are limited. Mometasone furoate and fluticasone propionate have lower oral bioavailability compared with other corticosteroids that are given intranasally. This may be important, since it is likely that some of the intranasal corticosteroid is ingested. Two 1-year growth studies in children indicated that intranasal beclomethasone dipropionate given twice daily reduces growth velocity, whereas intranasal mometasone furoate given once daily in the morning does not. Other studies are needed. Most but not all studies have shown that leukotriene antagonists are effective in the treatment of allergic rhinitis. H(1) receptor antagonists are not very effective in reducing nasal congestion, but leukotriene antagonists do attenuate this symptom. Furthermore, one study demonstrates an additive benefit in treating allergic rhinitis with the combination of a H(1) receptor and leukotriene antagonist. Clinical trials have demonstrated that anti-immunoglobulin (Ig) E is effective in the treatment of seasonal allergic rhinitis when free IgE is reduced to <25 microg/L. The reduction of total IgE is dose dependent and subcutaneous and intravenous administration are both effective. Immunotherapy is also an effective treatment for allergic rhinitis. CpG oligonucleotides is a novel adjuvant for allergen immunotherapy. This adjuvant used in a murine model shifts the immune response away from the allergic or TH2 phenotype. Studies in humans have not been performed.     

HIV vaccine rationale, design and testing

A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic diversity has been addressed by vaccine design. For example, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific B-cell and T-cell responses, are reviewed.     

Multi-envelope HIV-1 vaccine devoid of SIV components controls disease in macaques challenged with heterologous pathogenic SHIV

A central obstacle to the design of a global HIV-1 vaccine is virus diversity. Pathogen diversity is not unique to HIV-1, and has been successfully conquered in other fields by the creation of vaccine cocktails. Here we describe the testing of an HIV-1 envelope cocktail vaccine. Six macaques received the vaccine, delivered by successive immunizations with recombinant DNA, recombinant vaccinia virus and recombinant envelope proteins. Following vaccination, animals developed a diversity of anti-envelope antibody binding and neutralizing activities toward proteins and viruses that were not represented by sequence in the vaccine. T-cells were also elicited, as measured by gamma-interferon production assays with envelope-derived peptide pools. Vaccinated and control animals were then challenged with the heterologous pathogenic SHIV, 89.6P. Vaccinated monkeys experienced significantly lower virus titers and better maintenance of CD4+ T-cells than unvaccinated controls. The B- and T-cell immune responses were far superior post-challenge in the vaccinated group. Four of six vaccinated animals and only one of six control animals survived a 44-week observation period post-challenge. The present report is the first to describe pathogenic SHIV disease control mediated by a heterologous HIV-1 vaccine, devoid of 89.6 or SIV derivatives.     

Natriuretic peptides and genesis of asthma: an emerging paradigm?

Exposure to allergens and infections contribute to early immune development. However, knowledge of the role of cellular metabolic, physiologic, and endocrinologic factors in controlling immune development and asthma is limited. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for atrial natriuretic peptide (ANP) both in the fetal and neonatal lymphoid organs. ANP has garnered much attention for its cardiovascular effects, but its apparently significant role in the physiology and immunity of the lung has been underappreciated. Studies indicate that ANP also plays a significant role in shaping the early immune responses to environmental antigens. The C-terminal prohormone natriuretic peptide ANP (or NP(99-126)), which possesses bronchodilatory properties, is involved in polarizing dendritic cells to produce a T(H)2 response. Also, de novo overexpression of another pro-ANP peptide, NP(73-102), provides persistent bronchoprotection and induces significant anti-inflammatory activities in the lung epithelial cells. Thus natriuretic peptides appear to play a pivotal role in the genesis and control of asthma, and they might provide an important target to modulate allergen-induced immune responses in allergic patients.     

The effects of jet fuel on immune cells of fuel system maintenance workers

Jet fuel is a common occupational exposure among commercial and military maintenance workers. JP-8 jet fuel, a military formulation, has shown immunotoxic effects in mice, but little data exist for humans. The aim of this cross-sectional study was to determine whether immune cell counts in the peripheral blood were altered among tank entry workers at three Air Force bases. After adjusting for covariates, fuel system maintenance personnel (n = 45) were found to have significantly higher counts of white blood cells (P = 0.01), neutrophils (P = 0.05), and monocytes (P = 0.02) when compared with a low-exposure group (n = 78), but no differences were noted in the numbers of total lymphocytes, T-cells, T-helper cells, T-suppressor cells, natural killer cells, and B-cells. Investigations are needed to evaluate the functional ability of these cells to produce lymphokines and cytokines and modulate the immune system.     

Pre-hospital trauma care: systems and delivery

The first 150 words of the full text of this article appear below. Key points Victims of trauma often spend a significant periodof time in the pre-hospital phase. There is wide variationin the practice of pre-hospital care internationally. The term‘paramedic’ covers a wide range of skills and abilities. Incountries other than the UK, physician-led pre-hospital careis well established. Where pre-hospital anaesthesia is performed,in-hospital standards should apply.   When the literature on pre-hospital trauma care is examined,it becomes apparent that a significant period of time is oftenspent between the time of accident and arrival in the emergencydepartment. Although the ‘Golden Hour’ is an arbitraryconcept, it is often applied to trauma care and emphasizes theimportance of life-saving interventions soon after injury. Inthe UK and elsewhere, the majority of the first hour has passedbefore the hospital-based physician has contact with the patient.Time at the scene can be much longer if the patient is . . . [Full Text of this Article]