The role of the immune system in the pathogenesis of interstitial cystitis

Interstitial cystitis (IC) is a chronic debilitating condition predominantly affecting middle-aged females which presents with suprapubic pain and urinary frequency. At cystoscopy the bladder capacity is usually reduced and the urothelium may appear red and ulcerated - the Runner's ulcer. Chronic inflammatory cell infiltrate within bladder biopsies suggests an immunological aetiopathogenesis for IC but this has not previously been investigated in great detail. A series of 51 cases of IC, 48 female and 3 male have been studied. To determine if there is a genetic predisposition to IC ABO and rhesus blood groups and 102 different HLA tissue types were determined for IC cases and 140 normal controls. The incidence of ABO and rhesus blood groups were similar in the two groups but there was a significant association between HLA-DR6 and IC, with a relative risk factor of 4.91. The presence of chronic inflammation without evidence of an infective agent, the high incidence in middle-aged females and association with conditions such as Hashimoto's thyroiditis are features shared by IC and autoimmune diseases. The binding of IgA, IgG and IgM class antibodies from the serum of IC cases to bladder of normal controls of blood group O was examined and compared with serum from four female cases of chronic bacterial cystitis (BC) and eight normal female controls. Antibody binding to the urothelium was detected in 82% of IC, 75 % of BC and 13% of normal controls, and the titres were significantly higher in IC than in BC and normals. There was a similar prevalence of antibodies to detrusor sarcoplasm and sarcolemma in IC. In autoimmune diseases target cell destruction is initiated by abnormal surface expression of class II (HLA-DR) molecules with antigen which activates CD4+ T cells which in turn starts the cascade of immune autoreactivity, ultimately leading to destruction of target cells. Aberrant urothelial HLA-DR expression was found in all but one of the IC cases in which the urothelium was not denuded. Furthermore, the urothelium and submucosa in IC was infiltrated by CD4+, CD8+ and γδT cells, plasma cells, mast cells and macrophages. A search for infection with mycobacteria and viruses as an aetiological factor in IC using specific DNA probes produced negative results. Extra-vesical denervation (EVD) relieves pain in IC. Morphometric analysis of bladder wall PGP 9.5 immunoreactive nerve fibres has demonstrated nerve fibre proliferation in IC and depletion of nerve fibres within the submucosal plexus but not the detrusor muscle after EVD. This finding explains how EVD improves bladder pain without impairment of detrusor function, as demonstrated by urodynamic studies. The precise aetiology of IC remains obscure although this study has revealed a genetic predisposition to the development of IC and has demonstrated immunological autoreactive mechanisms in the pathogenesis of this condition

When Face Recognition Meets with Deep Learning: an Evaluation of Convolutional Neural Networks for Face Recognition

Deep learning, in particular Convolutional Neural Network (CNN), has achieved promising results in face recognition recently. However, it remains an open question: why CNNs work well and how to design a 'good' architecture. The existing works tend to focus on reporting CNN architectures that work well for face recognition rather than investigate the reason. In this work, we conduct an extensive evaluation of CNN-based face recognition systems (CNN-FRS) on a common ground to make our work easily reproducible. Specifically, we use public database LFW (Labeled Faces in the Wild) to train CNNs, unlike most existing CNNs trained on private databases. We propose three CNN architectures which are the first reported architectures trained using LFW data. This paper quantitatively compares the architectures of CNNs and evaluate the effect of different implementation choices. We identify several useful properties of CNN-FRS. For instance, the dimensionality of the learned features can be significantly reduced without adverse effect on face recognition accuracy. In addition, traditional metric learning method exploiting CNN-learned features is evaluated. Experiments show two crucial factors to good CNN-FRS performance are the fusion of multiple CNNs and metric learning. To make our work reproducible, source code and models will be made publicly available.Comment: 7 pages, 4 figures, 7 table

Case report: Malignant teratoma of the uterine corpus

<p>Abstract</p> <p>Background</p> <p>Teratomas are the commonest germ cell tumours and are most frequently found in the testes and ovary. Extragonadal teratomas are rare and mainly occur in midline structures. Uterine teratomas are extremely rare with only a few previous case reports, usually involving mature teratomas of the uterine cervix.</p> <p>Case Presentation</p> <p>We report an 82-year-old lady presenting with post-menopausal bleeding. Initial investigations revealed a benign teratoma of the uterus which was removed. Her symptoms persisted and a recurrent, now malignant, teratoma of the uterine corpus was resected at hysterectomy. Six months after surgery she relapsed with para-aortic lymphadenopathy and was treated with a taxane, etoposide and cisplatin-containing chemotherapy regimen followed by retroperitoneal lymph node dissection.</p> <p>Conclusion</p> <p>In this report we discuss the aetiology, diagnosis and management of uterine teratomas, and review previous case studies.</p

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Site preparation impacts on soil biotic and abiotic properties, weed control, and native grass establishment

In severely degraded systems active restoration is required to overcome legacies of past land use and to create conditions that promote the establishment of target plant communities. While our understanding of the importance of soil microbial communities in ecological restoration is growing, few studies have looked at the impacts different site preparation techniques have on these communities. We trialed four methods of site preparation: fire, top-soil removal (TSR; removal of top 50 mm of soil), slashing (vegetation cut to 30 mm, biomass removed), and carbon (C; as sugar and saw-dust) addition, and quantified resulting soil bacterial communities using DNA metabarcoding. We compared the effectiveness of these techniques to reduce weed biomass, improve native grass establishment, and induce changes in soil nutrient availability. TSR was the most effective technique, leading to a reduction in both available nutrients and competition from weeds. In comparison, the remaining methods had little or no effect on weed biomass, native grass establishment, or soil nutrient availability. Both TSR and C addition resulted in changes in the soil bacterial community. These changes have the potential to alter plant community assembly in many ways, such as via nutrient acquisition, pathogenic effects, nutrient cycling, and decomposition. We recommend TSR for ecological restoration of old-fields and suggest it is a much more effective technique than burning, slashing, or C addition. Restoration practitioners should consider how their management techniques may influence the soil biota and, in turn, affect restoration outcomes

Intraorbital Implants After Enucleation and Their Complications: A 10-Year Review

BACKGROUND Many different types of orbital implants have been used after enucleation. Associated complications such as infection, exposure, extrusion, and ptosis have been reported. OBJECTIVE To describe 342 consecutive patients who underwent enucleation with intraorbital implant placement at the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla, during the past 10.5 years and their complications. METHODS Medical records of orbital implantation after enucleation performed by 3 surgeons (T.G.M., D.T., and T.J.) were reviewed retrospectively. Demographic data, ocular diagnosis, previous ophthalmic surgery, implant characteristics, and postoperative complications were described in all patients, with a minimum of 2 months' follow-up, using a standardized format. RESULTS Eleven complications were observed in 7 patients. Four patients had exposure of the implant, and 1 of these patients developed associated infection. Three patients developed pyogenic granulomas, 1 patient developed ptosis requiring surgical intervention, 1 patient had long-term orbital discomfort, and 1 patient developed an inclusion cyst. CONCLUSION Complications after enucleation with orbital implant placement are minimal and are observed with both porous and acrylic orbital implants.Arch Ophthalmol. 1998;116:1199-1203--

Evaluation of Efficacy and Complications: Primary Pediatric Orbital Implants After Enucleation

BACKGROUND Orbital implants are used routinely in pediatric patients at the time of enucleation. Complications, such as exposure, ptosis, and infection, may occur after implantation. Controversy continues regarding the rate of complications with newer implants in the pediatric population. OBJECTIVE To examine the effects of orbital implants on children whose eyes have been enucleated. METHODS Records of orbital implantation after enucleation performed by 5 surgeons on 120 pediatric patients (123 eyes) over a 10.5-year period were reviewed retrospectively. Demographic data, ocular diagnosis, prior ophthalmic surgery, implant characteristics, and postoperative complications were described using a standardized format for all patients, with a minimum of 6 months of follow-up (mean, 3 years). RESULTS Complications were observed in 7 eyes (5.7%). Implant exposure (1 [0.8%]), implant extrusion (0 [0%]), and implant migration (3 [2.4%]) were rare. One hundred eighteen eyes (96%) had good cosmesis and 120 (98%) had good motility. CONCLUSIONS Orbital implantation after enucleation is successful in the pediatric population. Complications are minimal. Hydroxyapatite implants were not associated with unacceptable complications in this pediatric population.Arch Ophthalmol. 2000;118:503-506--