LC3 has been used as a marker to locate autophagosomes. However, it is also well established that LC3 can localize on various membranous structures other than autophagosomes. We recently demonstrated ...that the LC3 conjugation system (ATG7, ATG3, and ATG12-ATG5-ATG16L1) is required to target LC3 and IFNG (interferon, gamma)-inducible GTPases to the parasitophorus vacuole membrane (PVM) of a protist parasite Toxoplasma gondii and consequently for IFNG to control T. gondii infection. Here we show that not only LC3, but also its homologs (GABARAP, GABARAPL1, and GABARAPL2) localize on the PVM of T. gondii in a conjugation-dependent manner. Knockout/knockdown of all LC3 homologs led to a significant reduction in targeting of the IFNG-inducible GTPases to the PVM of T. gondii and the IFNG-mediated control of T. gondii infection. Furthermore, when we relocated the ATG12-ATG5-ATG16L1 complex, which specifies the conjugation site of LC3 homologs, to alternative target membranes, the IFNG-inducible GTPases were targeted to the new target membranes rather than the PVM of T. gondii. These data suggest that the localization of LC3 homologs onto a membrane by the LC3 conjugation system is necessary and sufficient for targeting of the IFNG-inducible GTPases to the membrane, implying Targeting by AutophaGy proteins (TAG). Our data further suggest that the conjugation of ubiquitin-like LC3 homologs to the phospholipids of membranes may change the destiny of the membranes beyond degradation through lysosomal fusion, as the conjugation of ubiquitin to proteins changes the destiny of the proteins beyond proteasomal degradation.
All viruses with positive-sense RNA genomes replicate on membranous structures in the cytoplasm called replication complexes (RCs). RCs provide an advantageous microenvironment for viral replication, ...but it is unknown how the host immune system counteracts these structures. Here we show that interferon-gamma (IFNG) disrupts the RC of murine norovirus (MNV) via evolutionarily conserved autophagy proteins and the induction of IFN-inducible GTPases, which are known to destroy the membrane of vacuoles containing bacteria, protists, or fungi. The MNV RC was marked by the microtubule-associated-protein-1-light-chain-3 (LC3) conjugation system of autophagy and then targeted by immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) upon their induction by IFNG. Further, the LC3 conjugation system and the IFN-inducible GTPases were necessary to inhibit MNV replication in mice and human cells. These data suggest that viral RCs can be marked and antagonized by a universal immune defense mechanism targeting diverse pathogens replicating in cytosolic membrane structures.
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•IFN-gamma inhibits murine norovirus replication complexes via the LC3 conjugation system•Degradative autophagy is not required to affect LC3-mediated RC restriction•LC3 and IFN-inducible GTPases are targeted to the RC membrane•IFN-inducible GTPases are required to inhibit MNV replication in mice and humans
The replication complexes (RCs) of positive-sense RNA viruses have been considered impenetrable to antiviral responses. Biering et al. discovered that viral RCs can be marked by the LC3 conjugation system of autophagy and targeted by IFN-inducible GTPases, demonstrating a universal effector mechanism against cytosolic vacuoles containing viruses, bacteria, protists, or fungi.
Pelvic inflammatory disease commonly occurs in adults and is most frequently caused by sexually-transmitted organisms. When left untreated, it can progress to abscess formation and subsequent ...infertility due to tubal scarring. This condition rarely occurs in the pediatric population and even less frequently in the absence of sexual activity. The cases presented here depict 3 cases of pyosalpinx due to noncommunicable infectious agents. Since children are typically not subjected to transvaginal ultrasound, they are particularly at risk for delays in diagnosis and appropriate treatment. Cases described here also demonstrate the value of the pediatric interventional radiology service in treating this gynecological source of infection. Both transabdominal and transrectal approached to ultrasound-guided drainage are described.
Branchio-oto-renal syndrome is a rare genetic disorder that affects multiple organ systems. Temporal bone abnormalities include the unwound appearance of the cochlea which is common in this syndrome. ...This appearance can prompt renal imaging and evaluation. Presented here are two cases of branchio-oto-renal syndrome with dysplastic cochleae. A branchial cleft sinus and renal dysplasia were also present in one of the cases.
The optimal cord management strategy at birth for each preterm baby is still unknown, despite more than 100 randomized controlled trials (RCTs) undertaken on this question. To address this, we ...brought together all RCTs examining cord management strategies at preterm birth in the iCOMP (individual participant data on COrd Management at Preterm birth) Collaboration, to perform an individual participant data network meta-analysis. In this paper, we describe the trials and tribulations around obtaining individual participant data to resolve controversies around cord clamping, and we derive key recommendations for future collaborative research in perinatology. To reliably answer outstanding questions, future cord management research needs to be collaborative and coordinated, by aligning core protocol elements, ensuring quality and reporting standards are met, and carefully considering and reporting on vulnerable sub-populations. The iCOMP Collaboration is an example of the power of collaboration to address priority research questions, and ultimately improve neonatal outcomes worldwide.
The role of clothing in the management of eczema (also called atopic dermatitis or atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments ...(in addition to standard care) for the management of eczema in children with moderate to severe disease.
This was a parallel-group, randomised, controlled, observer-blind trial. Children aged 1 to 15 y with moderate to severe eczema were recruited from secondary care and the community at five UK medical centres. Participants were allocated using online randomisation (1:1) to standard care or to standard care plus silk garments, stratified by age and recruiting centre. Silk garments were worn for 6 mo. Primary outcome (eczema severity) was assessed at baseline, 2, 4, and 6 mo, by nurses blinded to treatment allocation, using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). A safety outcome was number of skin infections. Three hundred children were randomised (26 November 2013 to 5 May 2015): 42% girls, 79% white, mean age 5 y. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights 25th to 75th centile 57% to 96% and 34% of days 25th to 75th centile 10% to 76%). Geometric mean EASI scores at baseline, 2, 4, and 6 mo were, respectively, 9.2, 6.4, 5.8, and 5.4 for silk clothing and 8.4, 6.6, 6.0, and 5.4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age, and centre: adjusted ratio of geometric means 0.95, 95% CI 0.85 to 1.07, (p = 0.43). This confidence interval is equivalent to a difference of -1.5 to 0.5 in the original EASI units, which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) of children in the silk clothing and standard care groups, respectively. Even if the small observed treatment effect was genuine, the incremental cost per quality-adjusted life year was £56,811 in the base case analysis from a National Health Service perspective, suggesting that silk garments are unlikely to be cost-effective using currently accepted thresholds. The main limitation of the study is that use of an objective primary outcome, whilst minimising detection bias, may have underestimated treatment effects.
Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema.
Current Controlled Trials ISRCTN77261365.
Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo.
To explore the clinical ...effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo.
Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up.
Sixteen UK hospitals - participants were recruited from primary and secondary care and the community.
Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area.
Topical corticosteroids mometasone furoate 0.1% (Elocon
, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based.
The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment).
In total, 517 participants were randomised (adults,
= 398; and children,
= 119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%;
= 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%;
= 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective).
Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase.
Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed.
Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed.
Current Controlled Trials ISRCTN17160087.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.
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