BACKGROUND & AIMS: :Lymphogranuloma venereum (LGV) cases are currently re-emerging in the homosexual community, particularly in HIV-seropositive patients. The standard treatment for this infection, which is caused by Chlamydia trachomatis L1, L2 and L3 serotypes, is a 3-week doxycycline regimen. The case is reported of a male patient presenting with LGV, who was rapidly cured with moxifloxacin treatment after failure of extended treatment with cyclines. This fluoroquinolone is known to be highly active in vitro on the LGV pathogenic agent. Thus it may be a useful alternative when doxycycline treatment results in failure.

背景与目标： ：同性恋性淋巴肉芽肿（LGV）病例目前正在重新出现，尤其是在HIV血清阳性患者中。由沙眼衣原体L1，L2和L3血清型引起的这种感染的标准治疗是3周的强力霉素方案。该病例报道了一名男性患者，患有LGV，在用环素进行长期治疗失败后迅速用莫西沙星治愈。已知该氟喹诺酮在体外对LGV病原体具有高活性。因此，当强力霉素治疗导致失败时，它可能是一个有用的替代方法。

BACKGROUND & AIMS: BACKGROUND:Langerhans cells (LCs) polarize the immune milieu towards a T helper type (Th) 1 or Th2 immune response. We investigated the effects of selected tetracyclines on Th cells development mediated by LCs, and their implications for the treatment of atopic dermatitis (AD). METHODS:Mice were primed with ovalbumin (OVA) peptide-pulsed LCs, which had been treated with each antibiotic, via the hind footpad. After 5 days, the Th1/Th2 cytokine response in the popliteal lymph nodes was investigated by enzyme-linked immunosorbent assay. The expression of cell surface molecules on LCs was investigated using reverse transcriptase polymerase chain reaction. The therapeutic effects of a selected antibiotic on AD-like skin lesions of NC/Nga mice were assessed in terms of the skin severity score, histological changes in the lesioned skin, the serum level of total IgE, and expression of Th1/Th2 cytokines in lymph nodes and skin lesions. RESULTS:Antibiotic-treated, OVA peptide-pulsed LCs inhibited development of Th2 cells but not Th1 cells. This was accompanied by suppression of T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression in LCs. Doxycycline had the greatest activity against Staphylococcus aureus strains isolated from skin lesions of patients with AD, and a strong inhibitory effect on Th2 cell development. Doxycycline suppressed the increase in the skin severity score during the acute phase in NC/Nga mice similar to betamethasone. This suppressive effect was associated with a decrease in the serum IgE level and production of Th2 cytokines in auricular lymph node cells and skin lesions. CONCLUSION:Topical application of doxycycline to AD lesions would act on both superficial S. aureus colonization and epidermal LCs, thus possibly inhibiting the development of Th2 cells in vivo, with benefits for control of acute inflammation in AD.

背景与目标： 背景：朗格汉斯细胞（LC）将免疫环境极化为T辅助型（Th）1或Th2免疫应答。我们调查了选定的四环素对LC介导的Th细胞发育的影响，及其对特应性皮炎（AD）的治疗意义。
方法：用卵清蛋白（OVA）肽脉冲的LC灌注小鼠，并通过后足垫对每种LC进行了治疗。 5天后，通过酶联免疫吸附试验研究the淋巴结中的Th1 / Th2细胞因子反应。使用逆转录酶聚合酶链反应研究了细胞表面分子在LC上的表达。根据皮肤严重程度评分，病变皮肤的组织学变化，血清总IgE水平以及Th1 / Th2细胞因子的表达来评估所选抗生素对NC / Nga小鼠AD样皮肤病变的治疗效果。淋巴结和皮肤病变。
结果：经抗生素处理的OVA肽脉冲LC可抑制Th2细胞的发育，但不能抑制Th1细胞的发育。这伴随着LC中T细胞免疫球蛋白和含粘蛋白结构域的蛋白（TIM）-4表达的抑制。强力霉素对从AD患者皮肤病变中分离出的金黄色葡萄球菌菌株具有最大的活性，并且对Th2细胞发育具有很强的抑制作用。强力霉素抑制了与倍他米松相似的NC / Nga小鼠在急性期的皮肤严重程度评分的升高。这种抑制作用与耳廓淋巴结细胞和皮肤损伤中血清IgE水平的降低以及Th2细胞因子的产生有关。
结论：强力霉素在AD病灶上的局部应用将对金黄色葡萄球菌定植和表皮LC均起作用，从而可能在体内抑制Th2细胞的发育，有利于控制AD的急性炎症。

BACKGROUND & AIMS: :Actinomyces spp have been increasingly associated with endodontic infections. However, the antimicrobial susceptibility of this genus has not been studied extensively. The objective of this study was to determine the susceptibility of oral isolates of Actinomyces naeslundii, Actinomyces gerencseriae, Actinomyces israelii, Actinomyces viscosus, and Actinomyces odontolyticus to amoxicillin, clindamycin, doxycycline, metronidazole, and moxifloxacin using in vitro assays. The minimum inhibitory concentration (MIC) of each bacterial isolate was determined by using E-test strips (AB Biodisk, Solna, Sweden). The MIC(90) was 0.19 microg/mL for amoxicillin, 0.25 microg/mL for doxycycline, 0.50 microg/mL for moxifloxacin, and 1.00 microg/mL for clindamycin. However, metronidazole was not active against any of the Actinomyces spp tested (MIC(90)>256 microg/mL).

背景与目标： ：放线菌属物种已越来越多地与牙髓感染相关。但是，该属的抗菌敏感性尚未得到广泛研究。这项研究的目的是确定内生放线菌，gerencseriae放线菌，以色列放线菌，粘性放线菌和牙本质放线放线菌的口服分离株对阿莫西林，克林霉素，强力霉素，甲硝唑和莫西沙星的敏感性。通过使用E-test试纸（AB Biodisk，Solna，瑞典）确定每种细菌分离物的最小抑制浓度（MIC）。阿莫西林的MIC（90）为0.19微克/毫升，强力霉素为0.25微克/毫升，莫西沙星为0.50微克/毫升，克林霉素为1.00微克/毫升。但是，甲硝唑对测试的任何放线菌都不具有活性（MIC（90）> 256 microg / mL）。

BACKGROUND & AIMS: :Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

背景与目标： ：细菌性脑膜炎的特征在于对入侵病原体的炎症反应，最终可能导致感觉神经性听力丧失，永久性脑损伤或死亡。基质金属蛋白酶（MMP）和肿瘤坏死因子α转化酶（TACE）是促进细菌性脑膜炎中的炎症，血脑屏障破坏和脑损伤的关键介质。强力霉素是临床上使用的具有抗炎作用的抗生素，可导致细胞因子释放减少和MMP抑制。在这里，强力霉素在体外以50％的74 microM抑制剂量抑制TACE，在体内将释放到脑脊液中的肿瘤坏死因子α的量减少了90％。在肺炎球菌性脑膜炎的幼鼠模型中，感染后18 h除头孢曲松外，单剂多西环素（30 mg / kg）辅助治疗，可显着降低死亡率，血脑屏障破坏和皮质脑范围受伤。辅助多西环素（30 mg / kg皮下注射，每天一次，连续4天）也可减轻听力损失（通过听觉脑干反应测听法评估），以及感染后3周时耳蜗螺旋神经节的神经元死亡。因此，强力霉素可能是其抗炎特性的结果，对这种肺炎球菌脑膜炎模型的婴儿大鼠大脑和耳蜗具有广泛的有益作用，并提高了生存率。

BACKGROUND & AIMS: :We previously documented persistent regulation of erythropoietin (Epo) secretion in mice after a single intramuscular (i.m.) injection of a recombinant adeno-associated virus (rAAV) vector harboring both the tetracycline-dependent transactivator (rtTA) and the Epo cDNA (D. Bohl, A. Salvetti, P. Moullier, and J. M. Heard, Blood 92:1512-1517, 1998). Using the same vector harboring the cynomolgus macaque Epo cDNA instead, the present study evaluated the ability of the tetracycline-regulatable (tetR) system to establish long-term transgene regulation in nonhuman primates. The vector was administered i.m., after which 5-day induction pulses were performed monthly for up to 13 months by using doxycycline (DOX), a tetracycline analog. We show that initial inductions were successful in all individuals and that there was a tight regulation and a rapid deinduction pattern upon DOX withdrawal. For one macaque, regulation of Epo secretion was maintained during the entire experimental period; for the five remaining macaques, secreted Epo became indistinguishable from endogenous Epo upon repeated DOX inductions. We investigated the mechanism involved and showed that, except in the animal in which secretion persisted, delayed humoral and cellular immune responses were directed against the rtTA transactivator protein associated with the reduction of vector DNA in transduced muscles. This study provides some evidence that, when the immune system is not mobilized against the rtTA transactivator, the tetR-regulatable system is able to support long-term transgene regulation in the context of an rAAV in nonhuman primates. In addition, our results suggest potential improvements for vector design.

背景与目标： ：我们先前记录了单次肌内（im）注射含有四环素依赖性反式激活因子（rtTA）和Epo cDNA（D. Bohl，A.Salvetti，P.Moullier，和JM Heard，Blood 92：1512-1517，1998）。本研究使用带有食蟹猕猴Epo cDNA的相同载体，评估了四环素可调节（tetR）系统在非人类灵长类动物中建立长期转基因调控的能力。载体是在上午给药的，之后通过使用四环素类似物强力霉素（DOX）每月进行5天的诱导脉冲，长达13个月。我们显示初始诱导在所有个体中均成功，并且在DOX停用后有严格的调节和快速的诱导模式。对于一只猕猴，在整个实验期间都维持Epo分泌的调节。对于剩下的五只猕猴，在反复进行DOX诱导后，分泌的Epo与内源性Epo变得无法区分。我们研究了涉及的机制，结果表明，除了在持续存在分泌物的动物中，延迟的体液和细胞免疫应答针对的是与转导的肌肉中的载体DNA减少有关的rtTA反式激活蛋白。这项研究提供了一些证据，表明当未针对rtTA反式激活因子动员免疫系统时，可在非人类灵长类动物的rAAV情况下，tetR调控系统能够支持长期转基因调控。另外，我们的结果表明载体设计有潜在的改进。

BACKGROUND & AIMS: :The association of doxycycline and periodontal treatment in non-controlled diabetes mellitus (DM) has shown positive results on clinical and metabolic parameters. Antimicrobial photodynamic therapy (aPDT) is a local and painless antimicrobial treatment that can be applied in periodontal treatment without systemic risks. The aim of this study was to evaluate the potential improvement of aPDT on clinical and metabolic effects in patients with type 2 diabetes mellitus in conjunction with nonsurgical periodontal treatment plus doxycycline. Thirty patients with type 2 diabetes and diagnosis of chronic periodontitis were treated with scaling and root planning (SRP; N = 15) or SRP plus phenothiazine chloride photosensitizer-induced aPDT (SRP + aPDT, N = 15). Patients of both groups took doxycycline (100 mg/day) for 2 weeks and plaque index, bleeding on probe (BOP), probing pocket depth (PPD), suppuration, clinical attachment level (CAL), and glycated hemoglobin levels (HbA1c) were measured at baseline and 3 months after therapy. An improvement in clinical parameters such as PPD, CAL, S, and BOP between groups was observed but without statistical significance (p > 0.05). Intragroup analysis showed a significant reduction of HbA1c (8.5 ± 0.9 to 7.5 ± 0.1, p < 0.01) in the SRP + aPDT group. The differences of HbA1c between baseline and 3 months were greater for the SRP + aPDT (11.4 %) than SRP (10 %) (0.87 ± 0.9 and 0.4 ± 0.84 respectively; p < 0.05). A single application of the aPDT as an adjunct to periodontal treatment did not show additional benefits in the clinical parameters but resulted in a slight greater decrease in HbA1c.

背景与目标： ：在非控制性糖尿病（DM）中，强力霉素与牙周治疗的关联在临床和代谢参数方面显示出积极的结果。抗菌素光动力疗法（aPDT）是一种局部且无痛的抗菌素疗法，可用于牙周治疗而无系统性风险。这项研究的目的是评估aPDT对2型糖尿病患者结合非手术牙周治疗加强力霉素的临床和代谢作用的潜在改善作用。 30例2型糖尿病并诊断为慢性牙周炎的患者接受了结垢和牙根计划（SRP； N = 15）或SRP加上吩噻嗪氯化物光敏剂诱导的aPDT（SRP aPDT，N = 15）。两组患者均接受强力霉素（100 mg /天）治疗2周，其斑块指数，探针出血（BOP），探查袋深度（PPD），化脓，临床依从水平（CAL）和糖化血红蛋白水平（HbA1c）均为在基线和治疗后3个月进行测量。两组之间的临床参数如PPD，CAL，S和BOP均有改善，但无统计学意义（p> 0.05）。组内分析显示，SRP aPDT组的HbA1c显着降低（8.5±0.9至7.5±0.1，p <0.01）。对于SRP aPDT，基线和3个月之间HbA1c的差异（11.4％）大于SRP（10％）（分别为0.87±0.9和0.4±±0.84； p <0.05）。单独应用aPDT作为牙周治疗的辅助手段并未在临床指标上显示出其他益处，但导致HbA1c的下降幅度更大。

BACKGROUND & AIMS: :Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.

背景与目标： 亨廷顿舞蹈病（HD）是一种遗传性神经系统疾病，导致运动障碍，人格改变，痴呆症和过早死亡，目前尚无有效的治疗方法。据报道，改良的四环素抗生素米诺环素可改善HD R6 / 2小鼠模型的疾病表型。由于四环素还被报道在其他淀粉样蛋白疾病中具有抑制聚集的作用，因此我们研究了它们抑制亨廷顿蛋白聚集的能力，并进一步探索了它们在临床前小鼠试验中的功效。我们表明四环素是有效的浓度为30 microM的海马切片培养模型中的亨廷顿蛋白聚集的有效抑制剂。但是，尽管通过口服米诺环素治疗R6 / 2小鼠达到了接近该浓度的组织水平，但我们观察到它们的行为异常或死后总负荷没有明显差异。根据这些新数据，我们建议在进行米诺环素的人体临床试验时应谨慎行事。

BACKGROUND & AIMS: Background:We aimed to compare the therapeutic efficacy of prolonged macrolide (PMC), corticosteroids (CST), doxycycline (DXC), and levofloxacin (LFX) against macrolide-unresponsive Mycoplasma pneumoniae (MP) pneumonia in children and to evaluate the safety of the secondary treatment agents. Methods:We retrospectively analyzed the data of patients with MP pneumonia hospitalized between January 2015 and April 2017. Macrolide-unresponsiveness was clinically defined with a persistent fever of ≥ 38.0°C at ≥ 72 hours after macrolide treatment. The cases were divided into four groups: PMC, CST, DXC, and LFX. We compared the time to defervescence (TTD) after secondary treatment and the TTD after initial macrolide treatment in each group with adjustment using propensity score-matching analysis. Results:Among 1,165 cases of MP pneumonia, 190 (16.3%) were unresponsive to macrolides. The proportion of patients who achieved defervescence within 48 hours in CST, DXC, and LFX groups were 96.9% (31/33), 85.7% (12/14), and 83.3% (5/6), respectively. The TTD after initial macrolide treatment did not differ between PMC and CST groups (5.1 vs. 4.2 days, P = 0.085), PMC and DXC groups (4.9 vs. 5.7 days, P = 0.453), and PMC and LFX groups (4.4 vs. 5.0 days, P = 0.283). No side effects were observed in the CST, DXC, and LFX groups. Conclusion:The change to secondary treatment did not show better efficacy compared to PMC in children with macrolide-unresponsive MP pneumonia. Further studies are needed to guide appropriate treatment in children with MP pneumonia.

背景与目标： 背景：我们旨在比较延长的大环内酯（PMC），皮质类固醇（CST），强力霉素（DXC）和左氧氟沙星（LFX）对儿童对大环内酯无反应性肺炎支原体（MP）肺炎的疗效，并评估其安全性二级治疗剂。
方法：我们回顾性分析2015年1月至2017年4月住院的MP肺炎患者的数据。临床定义大环内酯无反应性，并在大环内酯治疗后≥72小时持续发烧≥38.0°C。病例分为四类：PMC，CST，DXC和LFX。我们使用倾向评分匹配分析，通过调整比较了每组中二次治疗后的去铁时间（TTD）和初始大环内酯类药物治疗后的TTD。
结果：在1,165例MP肺炎患者中，有190例（16.3％）对大环内酯类药物无反应。 CST，DXC和LFX组在48小时内达到退热的患者比例分别为96.9％（31/33），85.7％（12/14）和83.3％（5/6）。 PMC和CST组（5.1 vs.4.2天，P = 0.085），PMC和DXC组（4.9 vs. 5.7天，P = 0.453），PMC和LFX组（4.4 vs. 5.0天，P = 0.283）。在CST，DXC和LFX组中未观察到副作用。
结论：对大环内酯无反应的MP肺炎患儿，与PMC相比，二级治疗的改变没有显示出更好的疗效。需要进一步研究以指导MP肺炎患儿的适当治疗。

BACKGROUND & AIMS: :Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub-antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-MTM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 μm). Treatment of Strat-MTM with microneedle rollers resulted in a reduction in fibroblast-mediated collagen gel contraction and MMP activity compared with untreated Strat-MTM. Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds.

背景与目标： ：许多慢性伤口均表现出高基质金属蛋白酶（MMP）活性，阻碍了正常伤口的愈合过程。皮下递送（IDD）的多西环素抗微生物剂浓度（作为MMP抑制剂）可以靶向慢性伤口发展的早期阶段，并抑制伤口的进一步发展。为了在皮肤内递送强力霉素，必须破坏皮肤屏障。微针辊通过创建多个微通道作为药物扩散的临时导管，从而提供了一种微创技术来穿透皮肤。在这项研究中，使用微针辊研究了一种新颖而简便的方法，用于在多股Strat-MTM膜上递送强力霉素。多西环素扩散通过微孔的数量和速率与微针长度（250、500和750μm）的增加直接相关。与未处理的Strat-MTM相比，用微针滚轮治疗Strat-MTM减少了成纤维细胞介导的胶原凝胶收缩和MMP活性。我们的结果表明，用微针辊治疗表皮模拟物为多西环素扩散和抑制MMP活性提供了足够的通透性。我们得出的结论是，微针滚轮是一种有前途的，临床上可立即使用的工具，适合皮内输送强力霉素治疗慢性伤口。

BACKGROUND & AIMS: BACKGROUND:Onchocerciasis is a priority neglected tropical disease targeted for elimination by 2025. The standard strategy to combat onchocerciasis is annual Community-Directed Treatment with ivermectin (CDTi). Yet, high prevalence rates and transmission persist following > 12 rounds in South-West Cameroon. Challenges include programme coverage, adherence to, and acceptability of ivermectin in an area of Loa loa co-endemicity. Loiasis patients harbouring heavy infections are at risk of potentially fatal serious adverse events following CDTi. Alternative strategies are therefore needed to achieve onchocerciasis elimination where CDTi effectiveness is suboptimal. METHODS/DESIGN:We designed an implementation study to evaluate integrating World Health Organisation-endorsed alternative strategies for the elimination of onchocerciasis, namely test-and-treat with the macrofilaricide, doxycycline (TTd), and ground larviciding for suppression of blackfly vectors with the organophosphate temephos. A community-based controlled before-after intervention study will be conducted among > 2000 participants in 20 intervention (Meme River Basin) and 10 control (Indian River Basin) communities. The primary outcome measure is O. volvulus prevalence at follow-up 18-months post-treatment. The study involves four inter-disciplinary components: parasitology, entomology, applied social sciences and health economics. Onchocerciasis skin infection will be diagnosed by skin biopsy and Loa loa infection will be diagnosed by parasitological examination of finger-prick blood samples. A simultaneous clinical skin disease assessment will be made. Eligible skin-snip-positive individuals will be offered directly-observed treatment for 5 weeks with 100 mg/day doxycycline. Transmission assessments of onchocerciasis in the communities will be collected post-human landing catch of the local biting blackfly vector prior to ground larviciding with temephos every week (0.3 l/m3) until biting rate falls below 5/person/day. Qualitative research, including in-depth interviews and focus-group discussions will be used to assess acceptability and feasibility of the implemented alternative strategies among intervention recipients and providers. Health economics will assess the cost-effectiveness of the implemented interventions. CONCLUSIONS:Using a multidisciplinary approach, we aim to assess the effectiveness of TTd, alone or in combination with ground larviciding, following a single intervention round and scrutinise the acceptability and feasibility of implementing at scale in similar hotspots of onchocerciasis infection, to accelerate onchocerciasis elimination.

背景与目标： 背景：盘尾丝虫病是一种优先被忽视的热带病，目标是到2025年消除。盘尾丝虫病的标准策略是每年使用伊维菌素（CDTi）进行社区定向治疗。然而，喀麦隆西南地区进行了12轮以上的攻击后，高流行率和传播率仍然存在。挑战包括在Loa loa共流行地区的伊维菌素的覆盖率，依从性和可接受性。携带重度感染的精神病患者有CDTi后可能致命的严重不良事件的风险。因此，在CDTi效果欠​​佳的情况下，需要采取其他策略来消除盘尾丝虫病。
方法/设计：我们设计了一项实施研究，以评估世界卫生组织认可的消除盘尾丝虫病的替代策略，即用大杀线虫剂，强力霉素（TTd）进行试验和治疗，以及用杀幼虫剂抑制地蝇的方法。有机磷酸酯。 20> 2000名参与者将在20个干预（Meme河盆地）和10个控制（印度河盆地）社区中进行以社区为基础的前后干预研究。主要结局指标是在治疗后18个月进行随访时，肠弯曲菌的患病率。该研究涉及四个跨学科的组成部分：寄生虫学，昆虫学，应用社会科学和卫生经济学。盘尾丝虫病皮肤感染将通过皮肤活检来诊断，而Loa loa感染将通过手指刺血样品的寄生虫学检查来诊断。同时进行临床皮肤疾病评估。合格的皮肤剪断阳性个体将接受直接观察到的治疗，为期5周，每天100 mg强力霉素。社区中盘尾丝虫病的传播评估将在每周（0.3l / m3）用腾飞蚊进行地面幼虫之前，收集当地叮咬的粉虱媒介的人工着陆捕捞量，直到叮咬率降至5 /人/天以下。定性研究，包括深度访谈和焦点小组讨论，将用于评估干预接受者和提供者之间已实施替代策略的可接受性和可行性。卫生经济学将评估已实施干预措施的成本效益。
结论：我们采用多学科方法，旨在通过一次干预后评估TTd单独或与地面杀幼虫剂联合使用的有效性，并仔细研究在类似盘尾丝虫病热点地区大规模实施TTd的可接受性和可行性，以加速盘尾丝虫病的消除。

BACKGROUND & AIMS: :Allergic diseases, which affect up to 20-30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro. Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. In vivo, our results demonstrated that treatment with doxycycline significantly attenuated clinical symptoms of mouse models of experimental allergic conjunctivitis (EAC) with a significant decrease in inflammatory cell frequency, IgE production, histamine release, and a decrease in TNF-α and IL-4 production. Using mouse models of MCs-dependent passive systemic anaphylaxis (PSA), we further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Furthermore, our results showed that doxycycline significantly attenuate histamine-induced systemic anaphylaxis-like reaction (HISA) with a significantly downregulation of PI3K/Akt/eNOS/VE-cadherin pathway. The doxycycline-mediated anti-allergy effects during EAC, PSA and HISA were abrogated when an Akt activator, SC79, was administered. These findings suggest that doxycycline inhibits B cell, MC and histamine function and attenuates experimental allergic conjunctivitis and systemic anaphylaxis by possible modulating the PI3K/Akt pathway.

背景与目标： 过敏性疾病影响着全球20％至30％的人口，仍然是过敏症患者的治疗挑战。四环素属于一种抗生素药物家族，具有惊人的多种非抗生素特性，已成功应用于多种疾病。然而，它们在过敏性结膜炎和过敏反应中的作用及其潜在的抗过敏机制仍然难以捉摸。在这里，我们报道用强力霉素进行治疗可显着降低小鼠B细胞释放的IgE以及通过IgE依赖性方式激活的小鼠肥大细胞（MC）的脱颗粒和炎性细胞因子的产生。此外，强力霉素在体外可显着抑制组胺诱导的血管通透性过高。从机理上讲，强力霉素介导的对B细胞，MC和组胺的抑制作用可能是通过PI3K / Akt途径的调节而发生的。在体内，我们的结果表明，用强力霉素进行治疗可显着减轻实验性变应性结膜炎（EAC）小鼠模型的临床症状，炎症细胞频率，IgE产生，组胺释放以及TNF-α和IL-4的降低均显着降低生产。使用小鼠模型的MCs依赖的被动系统性过敏反应（PSA），我们进一步证实了强力霉素的抗过敏作用和强力霉素对MCs介导的抑制作用。此外，我们的结果表明，强力霉素显着减弱了PI3K / Akt / eNOS / VE-钙粘蛋白途径的组织胺诱导的全身过敏样反应（HISA）。当使用Akt激活剂SC79时，EAC，PSA和HISA中强力霉素介导的抗过敏作用被取消。这些发现表明强力霉素可通过调节PI3K / Akt途径来抑制B细胞，MC和组胺功能，并减轻实验性过敏性结膜炎和全身性过敏反应。

BACKGROUND & AIMS: BACKGROUND/AIMS:Orally administered doxycycline, a broad-spectrum antibiotic, is an established treatment for ocular surface diseases, particularly rosacea, meibomian gland dysfunction and recurrent epithelial cell erosion. In recent times, its efficacy in treating these diseases has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and interleukin-1 (IL-1) synthesis. Since these functions are concentration-dependent, the aim of this project was to determine whether sufficient doxycycline reached the tear film to fulfil these roles in vivo. METHODS:Doxycycline was extracted with 1-butanol from tear and blood plasma samples obtained from patients with ocular surface disease and healthy individuals and quantified spectrophotometrically. The MMPs present in the patients tear films before and during doxycycline treatment were analysed zymographically. RESULTS:The quantity of doxycycline detected in the blood plasma samples of patients undergoing treatment ranged from 1.83 to 13.18 microM. Although doxycycline was not detected in their tear samples, the treatment caused the disappearance of the MMPs symptomatic of disease progression. CONCLUSION:The inability to detect doxycycline in the tear film of patients undergoing treatment indicates that doxycycline does not directly inhibit MMP activity or the synthesis/secretion of these proteases and IL-1 from corneal epithelial cells.

背景与目标： 背景/目的：口服强力霉素，一种广谱抗生素，是一种针对眼表疾病，尤其是酒渣鼻，睑板腺功能障碍和复发性上皮细胞侵蚀的治疗方法。近年来，其治疗这些疾病的功效归因于抑制基质金属蛋白酶（MMP）活性以及MMP和白介素1（IL-1）合成的能力。由于这些功能是浓度依赖性的，因此本项目的目的是确定是否有足够的强力霉素到达泪液膜以在体内发挥这些作用。
方法：用1-丁醇从眼表疾病患者和健康个体的眼泪和血浆样品中提取强力霉素，并用分光光度法定量。用酶法分析了强力霉素治疗前后患者泪膜中存在的MMP。
结果：在接受治疗的患者的血浆样本中检测到的强力霉素的含量范围为1.83至13.18 microM。尽管在他们的眼泪样品中未检测到强力霉素，但这种治疗导致疾病进展的MMP消失。
结论：无法检测接受治疗的患者泪膜中的强力霉素表明，强力霉素不能直接抑制角膜上皮细胞的MMP活性或这些蛋白酶和IL-1的合成/分泌。

BACKGROUND & AIMS: :Acute lung injury is an inflammatory condition developed after severe sepsis in response to excessive secretion of pro-inflammatory cytokines. Doxycycline is widely reported to possess immunomodulatory activity through inhibition of various inflammatory pathways. Considering the broad spectrum of anti-inflammatory activity, protective effect of doxycycline was evaluated in clinically relevant murine polymicrobial sepsis model induced by caecal ligation and puncture (CLP). In this model, sepsis is accompanied with infection and therefore ceftriaxone at sub-protective dose was combined to retard the bacterial growth. Three hours after CLP challenge, mice were administered vehicle, ceftriaxone (100 mg/kg subcutaneously) alone and in combination with immunomodulatory dose of doxycycline (50 mg/kg, intraperitoneal) and survival were monitored for 5 days. Bacterial count in blood and peritoneal fluid along with cytokines [interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α] and myeloperoxidase (MPO) in plasma and lung homogenate were measured at 18 h post-CLP. Plasma glutathione (GSH) was also determined. Doxycycline in presence of ceftriaxone improved survival of septic mice by significantly reducing the plasma and lung pro-inflammatory cytokines and MPO levels. It also increased plasma GSH levels. Doxycycline did not improve antibacterial effect of ceftriaxone in combination, suggesting that the protective effect of doxycycline was due to its immunomodulatory activity. Doxycycline in the presence of ceftriaxone demonstrated improved survival of septic mice by modulating the immune response.

背景与目标： ：急性肺损伤是严重的脓毒症后，由于促炎性细胞因子的过度分泌而引起的炎性疾病。据报道，强力霉素通过抑制各种炎症途径而具有免疫调节活性。考虑到广谱的抗炎活性，在盲肠结扎和穿刺（CLP）诱导的临床相关鼠类微生物败血症模型中评估了强力霉素的保护作用。在该模型中，败血症伴有感染，因此联合使用次保护剂量的头孢曲松以延缓细菌的生长。 CLP攻击后三小时，对小鼠单独给予媒介物，头孢曲松（皮下注射100 mg / kg），并与强力霉素的免疫调节剂量（50 mg / kg，腹膜内）结合使用，并监测存活5天。在CLP后18小时，测定血浆和肺匀浆中血液和腹膜液中的细菌计数以及细胞因子[白介素（IL）-6，IL-1β，肿瘤坏死因子（TNF）-α]和髓过氧化物酶（MPO）。还测定了血浆谷胱甘肽（GSH）。在存在头孢曲松钠的情况下，强力霉素可通过显着降低血浆和肺部促炎性细胞因子及MPO水平来提高败血症小鼠的存活率。它还增加了血浆谷胱甘肽水平。多西环素并不能改善头孢曲松的抗菌作用，表明多西环素的保护作用是由于其免疫调节活性。在头孢曲松存在的情况下，强力霉素可通过调节免疫应答来提高败血性小鼠的存活率。

BACKGROUND & AIMS: :Tetracycline (TC)-sensing bioreporters using green fluorescent protein (GFP) were generated in Escherichia coli and solvent-tolerant Acinetobacter oleivorans. A TC-inducible promoter, tetH promoter, and a TetR repressor of the pAST2 plasmid recovered from sludge were used to construct plasmid-based and chromosome-based bioreporters. Two host plasmids with a broad range, pRK415 and pBBR1MCS2, and three randomly chosen chromosomal sites were used to create the reporter strains. Although the copy numbers of the two plasmids in A. oleivorans were greater than those in E. coli, GFP expression from the tetH promoter and growth under TC were significantly higher in E. coli. Thus, the E. coli bioreporter had higher GFP expression driven by TC, and the two plasmids differed in terms of their sensitivity. Our data reflected mosaic evolution of the constructed plasmids, suggesting that the plasmid replication efficiency and the tetH promoter strength differed in the two different hosts. Among the tested TC compounds, doxycycline (DC) was the most effective in promoting GFP expression. qRT-PCR data confirmed that the expression of the tetH promoter in the original pAST2 plasmid produced the most rapid response to DC. E. coli- and A. oleivorans-based plasmid reporters could detect 5 and 30 nM DC, respectively. Insertion of the GFP reporter into different positions of the A. oleivorans chromosome resulted in variations of GFP expression. Our stable A. oleivorans chromosomal bioreporter was functional in the presence of toxic organic solvents. Furthermore, the field test showed that strain A. oleivorans DR1-Tet1 could act as a sensitive bioreporter in activated sludge for DC detection.

背景与目标： ：使用绿色荧光蛋白（GFP）的四环素（TC）感应生物报告在大肠杆菌和耐溶剂不动油杆菌中产生。从污泥中回收的pAST2质粒的TC诱导型启动子，tetH启动子和TetR阻遏物用于构建基于质粒和基于染色体的生物报告基因。使用两个具有广泛范围的宿主质粒pRK415和pBBR1MCS2，以及三个随机选择的染色体位点来创建报告株。尽管在油曲霉中两个质粒的拷贝数大于在大肠杆菌中的拷贝数，但是在大肠杆菌中，来自tetH启动子的GFP表达和TC下的生长明显更高。因此，大肠杆菌生物报道基因具有较高的由TC驱动的GFP表达，并且两种质粒的敏感性不同。我们的数据反映了构建质粒的镶嵌进化，表明在两个不同宿主中质粒复制效率和tetH启动子强度不同。在测试的TC化合物中，强力霉素（DC）在促进GFP表达方面最有效。 qRT-PCR数据证实，原始pAST2质粒中tetH启动子的表达产生了对DC的最快速反应。基于大肠杆菌和油曲霉的质粒报告子分别可以检测5和30 nM DC。 GFP报告基因插入到油曲霉染色体的不同位置会导致GFP表达的变化。在有毒有机溶剂的存在下，我们稳定的油橄榄曲霉染色体生物报告剂可发挥功能。此外，现场测试表明，油曲霉DR1-Tet1菌株可作为活性污泥中的敏感生物报告物用于DC检测。

BACKGROUND & AIMS: BACKGROUND:Anaerobic organisms are important pathogens in acute pelvic inflammatory disease (PID). The currently recommended PID regimen of a single dose of ceftriaxone and doxycycline for 14 days has limited anaerobic activity. The need for broader anaerobic coverage is unknown and concerns have been raised about metronidazole tolerability. METHODS:We conducted a randomized, double-blind placebo-controlled trial comparing ceftriaxone 250 mg IM single dose and doxycycline for 14 days, with or without 14 days of metronidazole in women with acute PID. The primary outcome was clinical improvement at 3 days following enrollment. Additional outcomes at 30 days following treatment were the presence of anaerobic organisms in the endometrium, clinical cure (absence of fever and reduction in tenderness), adherence and tolerability. RESULTS:We enrolled 233 women (116 to metronidazole and 117 to placebo). Clinical improvement at 3 days was similar between the two groups. At 30 days following treatment, anaerobic organisms were less frequently recovered from the endometrium in women treated with metronidazole than placebo (8% vs 21%, p<0.05) and cervical Mycoplasma genitalium was reduced (4% vs. 14%, p<0.05). Pelvic tenderness was also less common among women receiving metronidazole (9% vs 20%, p<0.01). Adverse events and adherence were similar in each treatment group. CONCLUSIONS:In women treated for acute PID, the addition of metronidazole to ceftriaxone and doxycycline was well tolerated and resulted in reduced endometrial anaerobes, decreased M. genitalium and reduced pelvic tenderness compared to ceftriaxone and doxycycline. Metronidazole should be routinely added to ceftriaxone and doxycycline for the treatment of women with acute PID.

背景与目标： 背景：厌氧菌是急性盆腔炎的重要病原体。目前推荐的单剂量头孢曲松和强力霉素的PID治疗方案持续14天，其厌氧活性有限。尚无更广泛的厌氧覆盖范围的需求，人们对甲硝唑的耐受性提出了关注。
方法：我们进行了一项随机，双盲，安慰剂对照试验，比较了急性PID患者中头孢曲松250 mg IM单剂量和强力霉素14天，有或无14天甲硝唑的情况。主要结果是入选后3天的临床改善。治疗后30天的其他结局是子宫内膜中存在厌氧菌，临床治愈（无发热和压痛减轻），依从性和耐受性。
结果：我们招募了233名妇女（116名甲硝唑和117名安慰剂）。两组在3天时的临床改善相似。在治疗后30天，甲硝唑治疗的妇女子宫内膜中厌氧菌的恢复率低于安慰剂（8％对21％，p <0.05），生殖器宫颈支原体减少（4％vs. 14％，p <0.05） ）。接受甲硝唑的女性盆腔压痛也较少见（9％vs 20％，p <0.01）。每个治疗组的不良事件和依从性相似。
结论：与头孢曲松钠和强力霉素相比，在接受急性PID治疗的妇女中，对头孢曲松和多西环素添加甲硝唑的耐受性良好，可导致子宫内膜厌氧菌减少，生殖器支原体减少和盆腔压痛。甲硝唑应常规添加到头孢曲松和强力霉素中，以治疗患有急性PID的女性。