cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

BACKGROUND AND PURPOSE

Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet-derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo-contractile phenotype, a process requiring activation of extracellular signal-regulated kinase (ERK) and p70^S6 Kinase (p70^S6K). The effects of cAMP-elevating agents on these processes is unknown. Here, we investigated the effects of cAMP elevation by prostaglandin E₂ (PGE₂) and the activation of the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (Epac) on PDGF-induced phenotype switching in bovine tracheal smooth muscle (BTSM).

EXPERIMENTAL APPROACH

Effects of long-term treatment with the PGE₂ analogue 16,16-dimethyl-PGE₂, the selective Epac activator, 8-pCPT-2′-O-Me-cAMP and the selective PKA activator, 6-Bnz-cAMP were assessed on the induction of a hypo-contractile, proliferative BTSM phenotype and on activation of ERK and p70^S6K, both induced by PDGF.

KEY RESULTS

Treatment with 16,16-dimethyl-PGE₂ inhibited PDGF-induced proliferation of BTSM cells and maintained BTSM strip contractility and contractile protein expression in the presence of PDGF. Activation of both Epac and PKA similarly prevented PDGF-induced phenotype switching and PDGF-induced activation of ERK. Interestingly, only PKA activation resulted in inhibition of PDGF-induced phosphorylation of p70^S6K.

CONCLUSIONS AND IMPLICATIONS

Our data indicate for the first time that both Epac and PKA regulated switching of ASM phenotype via differential inhibition of ERK and p70^S6K pathways. These findings suggest that cAMP elevation may be beneficial in the treatment of long-term changes in airway disease.     

Limited Margins Using Modern Radiotherapy Techniques Does Not Increase Marginal Failure Rate of Glioblastoma

PURPOSE: We investigate the patterns of failure in the treatment of glioblastoma(GBM) based on clinical target volume(CTV) margin size,dose delivered to the site of initial failure,and the use of temozolomide and intensity-modulated radiotherapy(IMRT).METHODS: Between August 2000 and May 2010,161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide.Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique.Patterns of failure and time to progression and overall survival were compared based on CTV margin,use of temozolomide,and use of IMRT.Kaplan Meier analysis was used to estimate survival times,and χ test was used for comparison of cohorts.RESULTS: For patients treated with 5-,10-,and 15-to 20-mm CTV,79%,77%,and 86% experienced failures in the 60 Gy volume,respectively.Forty-eight percent,55%,and 66% of patients with 5-,10-,and 15-to 20-mm CTV experienced failures in the 46 Gy volume,respectively.There was no statistical difference between patients treated with 5-,10-,15-to 20-mm margins with regard to 60 Gy failure(P=0.76),46 Gy failure(P=0.51),or marginal failure(P=0.73).Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume.There was no increased likelihood of marginal failures in patients receiving IMRT(P =0.97).CONCLUSIONS: Modern treatment techniques including use of concurrent temozolmide,limited CTV margin size,and IMRT have not greatly changed the patterns of failure of GBM.     

Cellular immunity and hypersensitivity as components of periodontal destruction

BACKGROUND: Cellular immunity has been implicated in periodontal destruction for over 25 years. Studies in the 1970s used lymphocyte transformation and lympho-kine assays to establish a role for cell-mediated mechanisms in periodontal disease. lmmunohistological studies subsequently showed that the formation of gingivitis followed a similar pattern to the formation of a delayed type hypersensitivity reaction. Further functional studies suggested that a T cell/macrophage immunoregulatory imbalance may exist locally in the periodontitis lesion and that this imbalance may be antigen specific. RECENT EVIDENCE: More recently, T cell subsets have been dichotomised on the basis of their cytokine profiles. In general, Thl cells produce IL-2 and IFN-gamma while Th2 cells produce IL-4, IL-5 and IL-6. The major function of Th l cells is to mediate delayed type hypersensitivity. In contrast the major function of Th2 cells is to provide B cell help.
HYPOTHESIS: A model for periodontal disease has now been developed based on this functional dichotomy which provides a framework for the study of cytokine profiles in periodontal disease. Early studies in this context have demonstrated a higher proportion of IL-4 producing cells in periodontitis tissues suggesting a role for Th2 cells in the progressive lesion. Clonal studies have shown that the selection of a particular cytokine profile is not antigen dependent and that differences may be due to the host susceptibility although this remains to be determined.
CONCLUSION: These emerging data clearly establish a role for cell-mediated mechanisms in the control of periodontal destruction and raise the possibility that in the future cytokine therapy for the treatment of periodontal disease in susceptible subjects may become a viable option.     

Psychosocial interventions for improving engagement in care and health and behavioural outcomes for adolescents and young people living with HIV: a systematic review and meta‐analysis

IntroductionAdolescents and young people comprise a growing proportion of new HIV infections globally, yet current approaches do not effectively engage this group, and adolescent HIV‐related outcomes are the poorest among all age groups. Providing psychosocial interventions incorporating psychological, social, and/or behavioural approaches offer a potential pathway to improve engagement in care and health and behavioural outcomes among adolescents and young people living with HIV (AYPLHIV).MethodsA systematic search of all peer‐reviewed papers published between January 2000 and July 2020 was conducted through four electronic databases (Cochrane Library, PsycINFO, PubMed and Scopus). We included randomized controlled trials evaluating psychosocial interventions aimed at improving engagement in care and health and behavioural outcomes of AYPLHIV aged 10 to 24 years.Results and discussionThirty relevant studies were identified. Studies took place in the United States (n = 18, 60%), sub‐Saharan Africa (Nigeria, South Africa, Uganda, Zambia, Zimbabwe) and Southeast Asia (Thailand). Outcomes of interest included adherence to antiretroviral therapy (ART), ART knowledge, viral load data, sexual risk behaviours, sexual risk knowledge, retention in care and linkage to care. Overall, psychosocial interventions for AYPLHIV showed important, small‐to‐moderate effects on adherence to ART (SMD = 0.3907, 95% CI: 0.1059 to 0.6754, 21 studies, n = 2647) and viral load (SMD = −0.2607, 95% CI −04518 to −0.0696, 12 studies, n = 1566). The psychosocial interventions reviewed did not demonstrate significant impacts on retention in care (n = 8), sexual risk behaviours and knowledge (n = 13), viral suppression (n = 4), undetectable viral load (n = 5) or linkage to care (n = 1) among AYPLHIV. No studies measured transition to adult services. Effective interventions employed various approaches, including digital and lay health worker delivery, which hold promise for scaling interventions in the context of COVID‐19.ConclusionsThis review highlights the potential of psychosocial interventions in improving health outcomes in AYPLHIV. However, more research needs to be conducted on interventions that can effectively reduce sexual risk behaviours of AYPLHIV, as well as those that can strengthen engagement in care. Further investment is needed to ensure that these interventions are cost‐effective, sustainable and resilient in the face of resource constraints and global challenges such as the COVID‐19 pandemic.     

美国卫生组织体系20年的变革和经验

1背景与资料上世纪80和90年代,美国的医院和医生组织投入大量时间和资源进行机构重组,以实现提高组织效率、改善财务绩效水平、机构长期生存、承担社区责任和救治病人的目的。而机构重组的主要趋势是建立“有组织的服务提供体系”,包括建立横向的医院联合体,横向的医生联合体,以及纵向的医院与医生联合体等。到目前为止,在美国开展的大量研究对上述机构重组效果的认识莫衷一是。     

日本血吸虫重组22kD表膜蛋白免疫水牛的效果观察

目的 用重组日本血吸虫22kD表膜蛋白（rSj22)免疫水牛,检测特异性IgG抗体的应答水平,并观察抗血吸虫的保护效果。方法 用抗原（rSj22)加佐剂（Quil-A)肌肉注射免疫水牛,以1000条日本血吸虫尾蚴攻击感染,感染后55d剖杀,计算减虫和减卵率,用免疫印斑和ELISA方法测定抗体反应。结果 免疫组每头牛血清均能特异地识别Quil-A对照组相比,减虫率仅8.5%肝卵EPG减少12.3%,粪卵EPG减少26.8%,但均无统计学意义,结论 用rSj22kD抗原免疫水牛诱导的特异性IgG抗体不能发挥免疫保护作用。     

Transvaginal cervico-isthmic cerclage: a simple approach

In this article, we describe a relatively simple surgical option that we believe is indicated for use in cases of cervical incompetence. We discuss the advantages of this procedure to the surgeon and patient, and give details of 59 patients who have undergone this procedure one or more times over a 13-year period. A short review of the history of treatment of cervical incompetence and of recent trends for its management is also presented.     

Principles and practice of HIV-protease inhibitor pharmacoenhancement

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (C_trough or C_min) plasma concentrations, which are close to, or below, the plasma protein binding‐corrected inhibitory concentration (IC₅₀ or IC₉₅) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug–drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher C_min levels, and in most cases prolonged elimination half‐lives. The long‐term clinical benefits of PK enhancing are unknown as are the long‐term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low‐dose RTV in HIV‐infected patients. Head‐to‐head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.