roots of Angelica sinensis
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Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes over 90 genes and 25 microRNAs (miRNAs). The KSHV life cycle is tightly regulated to ensure persistent infection in the host. In particular, miRNAs, which primarily exert their effects by binding to the 3′ untranslated regions (3′UTRs) of target transcripts, have recently emerged as key regulators of KSHV life cycle. Although studies with RNA cross-linking immunoprecipitation approach have identified numerous targets of KSHV miRNAs, few of these targets are of viral origin because most KSHV 3′UTRs have not been characterized. Thus, the extents of viral genes targeted by KSHV miRNAs remain elusive. Here, we report the mapping of the 3′UTRs of 74 KSHV genes and the effects of KSHV miRNAs on the control of these 3′UTR-mediated gene expressions. This analysis reveals new bicistronic and polycistronic transcripts of KSHV genes. Due to the 5′-distal open reading frames (ORFs), KSHV bicistronic or polycistronic transcripts have significantly longer 3′UTRs than do KSHV monocistronic transcripts. Furthermore, screening of the 3′UTR reporters has identified 28 potential new targets of KSHV miRNAs, of which 11 (39%) are bicistronic or polycistronic transcripts. Reporter mutagenesis demonstrates that miR-K3 specifically targets ORF31-33 transcripts at the lytic locus via two binding sites in the ORF33 coding region, whereas miR-K10a-3p and miR-K10b-3p and their variants target ORF71-73 transcripts at the latent locus through distinct binding sites in both 5′-distal ORFs and intergenic regions. Our results indicate that KSHV miRNAs frequently target the 5′-distal coding regions of bicistronic or polycistronic transcripts and highlight the unique features of KSHV miRNAs in regulating gene expression and life cycle.
Genomewide Mapping and Screening of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) 3′ Untranslated Regions Identify Bicistronic and Polycistronic Viral Transcripts as Frequent Targets of KSHV MicroRNAs
Zhiqiang Bai,a,b Yufei Huang,c Wan Li,a Ying Zhu,d Jae U. Jung,d Chun Lu,corresponding authora and Shou-Jiang Gaocorresponding authorb,d
Minocycline is an oral antibiotic used for acne vulgaris. Its use has lessened due to safety concerns (including potentially irreversible pigmentation), a relatively high cost, and no evidence of any greater benefit than other acne treatments. A modified‐release version of minocycline is being promoted as having fewer side‐effects.
To assess new evidence on the effects of minocycline for acne vulgaris.
Searches were updated in the following databases to November 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We also searched trials registers and checked reference lists for further references to relevant randomised controlled trials (RCTs).
The Cochrane Skin Group’s Trials Search Co‐ordinator undertook searches exploring minocycline’s adverse effects in EMBASE and MEDLINE in February 2012.
We selected randomised controlled trials (RCTs) comparing minocycline, at any dose, to an active or a placebo control, in participants with inflammatory acne vulgaris. For adverse effects, we selected additional studies that reported the number of adverse effects and the number of participants treated.
Data collection and analysis
Outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors’ and participants’ global assessments, adverse effects, and dropout rates. Two authors independently assessed the quality of each study. Effect sizes were calculated, and meta‐analyses were undertaken where possible.
Sixteen studies met the inclusion criteria for the review of adverse effects.
We included 12 new RCTs for this update, giving a total of 39 RCTs (6013 participants). These additional 12 RCTs have not changed the original conclusions about the clinical efficacy of minocycline.
The identified RCTs were generally small and poor quality. Meta‐analysis was rarely possible because of the lack of data and different outcome measures and trial durations. Although minocycline was shown to be an effective treatment for moderate to moderately‐severe acne vulgaris, there was no evidence that it is better than any of the other commonly‐used acne treatments. One company‐sponsored RCT found minocycline to be less effective than combination treatment with topical erythromycin and zinc. No trials have been conducted using minocycline in those participants whose acne is resistant to other therapies. Also, there is no evidence to guide what dose should be used.
The adverse effects studies must be interpreted with caution. The evidence suggests that minocycline is associated with more severe adverse effects than doxycycline. Minocycline, but not other tetracyclines, is associated with lupus erythematosus, but the risk is small: 8.8 cases per 100,000 person‐years. The risk of autoimmune reactions increases with duration of use. The evidence does not support the conclusion that the more expensive extended‐release preparation is safer than standard minocycline preparations.
Minocycline is an effective treatment for moderate to moderately‐severe inflammatory acne vulgaris, but there is still no evidence that it is superior to other commonly‐used therapies. This review found no reliable evidence to justify the reinstatement of its first‐line use, even though the price‐differential is less than it was 10 years ago. Concerns remain about its safety compared to other tetracyclines.
Minocycline for acne vulgaris: efficacy and safety
Monitoring Editor: Sarah E Garner,corresponding author Anne Eady, Cathy Bennett, John Norman Newton, Karen Thomas, Catalin Mihai Popescu, and Cochrane Skin Group
Exercise programmes are a relatively inexpensive, low‐risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent claudication (IC)). This is the fourth update of a review first published in 1998.
Our goal was to determine whether an exercise programme was effective in alleviating symptoms and increasing walking treadmill distances and walking times in people with intermittent claudication. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events, and improving quality of life.
For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 15 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) via the Cochrane Register of Studies Online, along with trials registries.
Randomised controlled trials of an exercise regimen versus control or versus medical therapy for people with IC due to peripheral arterial disease (PAD). We included any exercise programme or regimen used for treatment of IC, such as walking, skipping, and running. Inclusion of trials was not affected by duration, frequency, or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain‐free walking distance and maximum walking time or maximum walking distance), ankle brachial index (ABI), quality of life, morbidity, or amputation; if none of these was reported, we did not include the trial in this review.
Data collection and analysis
For this update (2017), RAL and AH selected trials and extracted data independently. We assessed study quality by using the Cochrane ‘Risk of bias’ tool. We analysed continuous data by determining mean differences (MDs) and 95% confidence intervals (CIs), and dichotomous data by determining risk ratios (RRs) and 95% CIs. We pooled data using a fixed‐effect model unless we identified significant heterogeneity, in which case we used a random‐effects model. We used the GRADE approach to assess the overall quality of evidence supporting the outcomes assessed in this review.
We included two new studies in this update and identified additional publications for previously included studies, bringing the total number of studies meeting the inclusion criteria to 32, and involving a total of 1835 participants with stable leg pain. The follow‐up period ranged from two weeks to two years. Types of exercise varied from strength training to polestriding and upper or lower limb exercises; supervised sessions were generally held at least twice a week. Most trials used a treadmill walking test for one of the primary outcome measures. The methodological quality of included trials was moderate, mainly owing to absence of relevant information. Most trials were small and included 20 to 49 participants. Twenty‐seven trials compared exercise versus usual care or placebo, and the five remaining trials compared exercise versus medication (pentoxifylline, iloprost, antiplatelet agents, and vitamin E) or pneumatic calf compression; we generally excluded people with various medical conditions or other pre‐existing limitations to their exercise capacity.
Meta‐analysis from nine studies with 391 participants showed overall improvement in pain‐free walking distance in the exercise group compared with the no exercise group (MD 82.11 m, 95% CI 71.73 to 92.48, P < 0.00001, high‐quality evidence). Data also showed benefit from exercise in improved maximum walking distance (MD 120.36 m, 95% CI 50.79 to 189.92, P < 0.0007, high‐quality evidence), as revealed by pooling data from 10 studies with 500 participants. Improvements were seen for up to two years.
Exercise did not improve the ABI (MD 0.04, 95% CI 0.00 to 0.08, 13 trials, 570 participants, moderate‐quality evidence). Limited data were available for the outcomes of mortality and amputation; trials provided no evidence of an effect of exercise, when compared with placebo or usual care, on mortality (RR 0.92, 95% CI 0.39 to 2.17, 5 trials, 540 participants, moderate‐quality evidence) or amputation (RR 0.20, 95% CI 0.01 to 4.15, 1 trial, 177 participants, low‐quality evidence).
Researchers measured quality of life using Short Form (SF)‐36 at three and six months. At three months, the domains ‘physical function’, ‘vitality’, and ‘role physical’ improved with exercise; however this was a limited finding, as it was reported by only two trials. At six months, meta‐analysis showed improvement in ‘physical summary score’ (MD 2.15, 95% CI 1.26 to 3.04, P = 0.02, 5 trials, 429 participants, moderate‐quality evidence) and in ‘mental summary score’ (MD 3.76, 95% CI 2.70 to 4.82, P < 0.01, 4 trials, 343 participants, moderate‐quality evidence) secondary to exercise. Two trials reported the remaining domains of the SF‐36. Data showed improvements secondary to exercise in ‘physical function’ and ‘general health’. The other domains ‐ ‘role physical’, ‘bodily pain’, ‘vitality’, ‘social’, ‘role emotional’, and ‘mental health’ ‐ did not show improvement at six months.
Evidence was generally limited in trials comparing exercise versus antiplatelet therapy, pentoxifylline, iloprost, vitamin E, and pneumatic foot and calf compression owing to small numbers of trials and participants.
Review authors used GRADE to assess the evidence presented in this review and determined that quality was moderate to high. Although results showed significant heterogeneity between trials, populations and outcomes were comparable overall, with findings relevant to the claudicant population. Results were pooled for large sample sizes ‐ over 300 participants for most outcomes ‐ using reproducible methods.
High‐quality evidence shows that exercise programmes provided important benefit compared with placebo or usual care in improving both pain‐free and maximum walking distance in people with leg pain from IC who were considered to be fit for exercise intervention. Exercise did not improve ABI, and we found no evidence of an effect of exercise on amputation or mortality. Exercise may improve quality of life when compared with placebo or usual care. As time has progressed, the trials undertaken have begun to include exercise versus exercise or other modalities; therefore we can include fewer of the new trials in this update.
Exercise for intermittent claudication
Monitoring Editor: Risha Lane,corresponding author Amy Harwood, Lorna Watson, Gillian C Leng, and Cochrane Vascular Group