Tubulointerstitial nephritis and uveitis in Northern Ireland.

OBJECTIVES: This paper looks at patients with a diagnosis of tubulointerstitial nephritis and uveitis (TINU) presenting to the Northern Ireland regional adult and paediatric uveitis service in the Belfast Health and Social Care Trust. The demographic distribution, treatment required and the visual and renal outcomes of these patients are documented. METHODS: Data were collected retrospectively on 24 patients with TINU using the Northern Ireland Electronic Care Record, central pathology records alongside the adult and paediatric uveitis databases from 2011 to 2021. Patients were categorised into two groups using the Mandeville classification system. Standard Uveitis Nomenclature (SUN) was used to classify the uveitis. RESULTS: The population prevalence is at least 12.6 cases per million based on a population of 1.9 million. Nineteen of 24 cases were definite TINU and five of 24 probable. Seventeen out of 24 had biopsy-positive TIN, all of which met all of the Mandeville clinical diagnostic features required for a definite diagnosis. All but one presented with acute bilateral anterior uveitis. The paediatric cases ranged from age 12 to 18 at age of onset with a mean age of 14. Of the 18 adult onset cases, the age ranged from 20 to 76 years. The mean age of onset for the adult cases was 53 years. Of these patients 71% were female; 42% required second-line immunosuppression for ocular disease. Visual acuity was maintained. Follow-up time ranged from 3 months to 16 years. No patient developed long-term renal impairment. CONCLUSIONS: TINU is a cause of uveitis in both the paediatric and adult populations. In Northern Ireland average age with TINU was older than much of the published literature. Long-term immunosuppression for uveitis may be required as ongoing ocular, rather than renal inflammation seemed to require treatment.

Diagnostic Limitations in Congenital Zika Virus Infection.

This is the first documented case of an infant with congenital Zika virus infection (ZVI) born in Ireland. A term infant was delivered with an antenatal diagnosis of severe microcephaly. First trimester bloods confirmed maternal ZVI and although the infant did not have Zika virus RNA or Zika-specific IgM in her blood or urine, she had multiple clinical features of congenital ZVI and Zika virus RNA was present in the placenta.

Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

High-resolution melt curve analysis to confirm the presence of co-circulating isolates of avian nephritis virus in commercial chicken flocks.

Avian Nephritis Virus (ANV) has been implicated in poor growth and renal disease of young chickens. This paper describes the development of a reverse-transcriptase polymerase chain reaction for the detection of ANV in commercial meat chickens and the use of high-resolution melt curves to detect the presence of genetically different ANVs. Pooled cloacal swabs from both healthy and ill commercial chicken broiler flocks were tested for the presence of ANV using a combination of polymerase chain reaction, molecular cloning, high-resolution melt curve analysis and sequencing. Except for one, all specimens were found to contain two genetically different ANVs. Phylogenetic analysis of the capsid amino acid sequences revealed the presence of four of six groups of ANV identified previously in other countries as well as in two novel groups of ANV. Phylogenetic analysis of nucleotide sequences of partial polymerase, capsid and 3' untranslated regions reveal that the genes of individual ANV virus isolates have different ancestors. This was shown to be due to a template-switching event in the capsid gene that resulted in the 3' end of the capsid gene and the 3' untranslated region of one ANV isolate being transferred to another ANV. These results reveal that infection of chicken flocks with multiple ANV isolates is common and this needs to be taken into consideration in diagnosis of ANV using molecular techniques and in future epidemiological investigations.

The C-terminal end of the capsid protein of Avian Nephritis Virus is antigenic and induces broadly cross-reactive antibodies.

Avian nephritis virus (ANV) has been isolated frequently from commercial broilers in many countries. The prevalence and economic impact of ANV however has been difficult to ascertain due to the lack of convenient serological techniques. In this study the full-length and fragments of the ANV capsid protein were expressed in Baculovirus and affinity purified recombinant proteins used for the detection of ANV antibodies in ELISA. The crystal structure of Human Astrovirus (HAstV) was used as a model to determine potential homologous C-terminal antigenic regions in ANV. The rp37 fragment from three ANV strains NSW_3, ANV-1 and ANV-2, and a shorter NSW_3 fragment (rp33) were compared for their ability to detect ANV antibodies in seven reference chicken sera. The ANV-1 rp37 antigen was the most strain specific whereas the NSW_3 rp37 and rp33 antigens detected antibodies in all heterologous sera, including ANV-1 serum. Irrespective of the strain used, the two NSW_3 protein fragments rp37 and rp33 were found to be superior as antigens for ELISA when compared to the full-length capsid protein rp75. An ELISA designed using the NSW_3 rp33 could reliably differentiate between uninfected and infected commercial broiler flocks, as demonstrated by statistically significant differences between the OD values. This study identified an ANV immunogenic region and successfully used recombinant protein expression of this region to detect cross-reactive ANV antibodies. The results of this study facilitate future studies into the epidemiology and importance of ANV infections in commercial poultry.

Prognostic Value of Dynamic Susceptibility Contrast-Enhanced and Diffusion-Weighted MR Imaging in Patients with Glioblastomas.

BACKGROUND AND PURPOSE: Prediction of survival in patients with glioblastomas is important for individualized treatment planning. This study aimed to assess the prognostic utility of presurgical dynamic susceptibility contrast and diffusion-weighted imaging for overall survival in patients with glioblastoma. MATERIALS AND METHODS: MR imaging data from pathologically proved glioblastomas between June 2006 to December 2013 in 58 patients (mean age, 62.7 years; age range, 22-89 years) were included in this retrospective study. Patients were divided into long survival (≥15 months) and short survival (<15 months) groups, depending on overall survival time. Patients underwent dynamic susceptibility contrast perfusion and DWI before surgery and were treated with chemotherapy and radiation therapy. The maximum relative cerebral blood volume and minimum mean diffusivity values were measured from the enhancing part of the tumor. RESULTS: Maximum relative cerebral blood volume values in patients with short survival were significantly higher compared with those who demonstrated long survival (P < .05). No significant difference was observed in the minimum mean diffusivity between short and long survivors. Receiver operator curve analysis demonstrated that a maximum relative cerebral blood volume cutoff value of 5.79 differentiated patients with low and high survival with an area under the curve of 0.93, sensitivity of 0.89, and specificity of 0.90 (P < .001), while a minimum mean diffusivity cutoff value of 8.35 × 10(-4)mm(2)/s had an area under the curve of 0.55, sensitivity of 0.71, and specificity of 0.47 (P > .05) in separating the 2 groups. CONCLUSIONS: Maximum relative cerebral blood volume may be used as a prognostic marker of overall survival in patients with glioblastomas.

Infant botulism due to C. butyricum type E toxin: a novel environmental association with pet terrapins.

We describe two cases of infant botulism due to Clostridium butyricum producing botulinum type E neurotoxin (BoNT/E) and a previously unreported environmental source. The infants presented at age 11 days with poor feeding and lethargy, hypotonia, dilated pupils and absent reflexes. Faecal samples were positive for C. butyricum BoNT/E. The infants recovered after treatment including botulism immune globulin intravenous (BIG-IV). C. butyricum BoNT/E was isolated from water from tanks housing pet 'yellow-bellied' terrapins (Trachemys scripta scripta): in case A the terrapins were in the infant's home; in case B a relative fed the terrapin prior to holding and feeding the infant when both visited another relative. C. butyricum isolates from the infants and the respective terrapin tank waters were indistinguishable by molecular typing. Review of a case of C. butyricum BoNT/E botulism in the UK found that there was a pet terrapin where the infant was living. It is concluded that the C. butyricum-producing BoNT type E in these cases of infant botulism most likely originated from pet terrapins. These findings reinforce public health advice that reptiles, including terrapins, are not suitable pets for children aged <5 years, and highlight the importance of hand washing after handling these pets.

Diagnostic utility of diffusion tensor imaging in differentiating glioblastomas from brain metastases.

BACKGROUND AND PURPOSE: Differentiation of glioblastomas and solitary brain metastases is an important clinical problem because the treatment strategy can differ significantly. The purpose of this study was to investigate the potential added value of DTI metrics in differentiating glioblastomas from brain metastases. MATERIALS AND METHODS: One hundred twenty-eight patients with glioblastomas and 93 with brain metastases were retrospectively identified. Fractional anisotropy and mean diffusivity values were measured from the enhancing and peritumoral regions of the tumor. Two experienced neuroradiologists independently rated all cases by using conventional MR imaging and DTI. The diagnostic performances of the 2 raters and a DTI-based model were assessed individually and combined. RESULTS: The fractional anisotropy values from the enhancing region of glioblastomas were significantly higher than those of brain metastases (P < .01). There was no difference in mean diffusivity between the 2 tumor types. A classification model based on fractional anisotropy and mean diffusivity from the enhancing regions differentiated glioblastomas from brain metastases with an area under the receiver operating characteristic curve of 0.86, close to those obtained by 2 neuroradiologists using routine clinical images and DTI parameter maps (area under the curve = 0.90 and 0.85). The areas under the curve of the 2 radiologists were further improved to 0.96 and 0.93 by the addition of the DTI classification model. CONCLUSIONS: Classification models based on fractional anisotropy and mean diffusivity from the enhancing regions of the tumor can improve diagnostic performance in differentiating glioblastomas from brain metastases.

Trypsin and rosmarinic acid reduce the toxicity of Micrurus fulvius venom in mice.

UNLABELLED: CONTEXT. Antivenom is expensive and not always available, so alternative treatments are being investigated. OBJECTIVE. The efficacy of trypsin or rosmarinic acid (RA) in treating Micrurus fulvius in a murine model is determined. MATERIALS AND METHODS. DESIGN: randomized controlled blinded study. SUBJECTS: Fifty mice (20-30 g). Study groups: Intraperitoneal injections of: 1) 2 mg/kg M. fulvius venom (approximately twice the LD50 for mice; n = 10); 2) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with RA at a 1:10 ratio (n = 17); 3) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with 1 mg of trypsin (n = 17); 4)1 mg trypsin IP without venom (n = 3); and 5) RA IP without venom (n = 3). MAIN OUTCOME: time to toxicity (respiratory distress (< 25 breaths/min.), loss of spontaneous locomotor activity, or inability to upright self). STATISTICAL ANALYSIS: Time to toxicity using Tukey-Kramer HSD; Survival to 4, 6, and 12 h using Chi-square analysis. RESULTS. Onset of toxicity: venom + saline, 120.3 + 64.4 min; venom + rosmarinic acid, 238.1 ± 139.2 min (p = 0.15 relative to venom + saline); venom + trypsin, 319.7 + 201.0 min (p = 0.007 relative to venom + saline). Venom + trypsin but not venom + RA survival to 4 h was significant compared to venom + saline (p = 0.023). Two mice in the venom + trypsin group and one mouse in the venom + RA group survived to 12 h. Mice receiving trypsin without venom or RA without venom survived to 12 h without toxicity. Discussion. This work suggests that trypsin and RA may have efficacy in treatment M. fulvius envenomation. CONCLUSION. In vitro neutralization of M. Fulvius venom by trypsin justifies progressing to an in vivo model in future studies.

Rasmussen's encephalitis presenting as focal cortical dysplasia.

Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD) and discuss the literature on this topic.

Primary plasmacytoma of the kidney.

Primary renal plasmacytomas are an extremely rare clinical condition. Their management is particularly challenging due to the paucity of evidence, with only just over a dozen previously reported cases. We report a case of a primary extramedullary plasmacytoma of the kidney and performed a review of the literature. The case is presented as a learning point that it is imperative to keep plasmacytic tumours in mind and to include them in the differential diagnosis of anaplastic tumours, even in unusual locations, such as the kidney.

Differentiation between oligodendroglioma genotypes using dynamic susceptibility contrast perfusion-weighted imaging and proton MR spectroscopy.

BACKGROUND AND PURPOSE: Oligodendrogliomas with 1p/19q chromosome LOH are more sensitive to chemoradiation therapy than those with intact alleles. The usefulness of dynamic susceptibility contrast-PWI-guided ¹H-MRS in differentiating these 2 genotypes was tested in this study. MATERIALS AND METHODS: Forty patients with oligodendrogliomas, 1p/19q LOH (n = 23) and intact alleles (n = 17), underwent MR imaging and 2D-¹H-MRS. ¹H-MRS VOI was overlaid on FLAIR images to encompass the hyperintense abnormality on the largest cross-section of the neoplasm and then overlaid on CBV maps to coregister CBV maps with ¹H-MRS VOI. rCBVmax values were obtained by measuring the CBV from each of the selected ¹H-MRS voxels in the neoplasm and were normalized with respect to contralateral white matter. Metabolite ratios with respect to ipsilateral Cr were computed from the voxel corresponding to the rCBVmax value. Logistic regression and receiver operating characteristic analyses were performed to ascertain the best model to discriminate the 2 genotypes of oligodendrogliomas. Qualitative evaluation of conventional MR imaging characteristics (patterns of tumor border, signal intensity, contrast enhancement, and paramagnetic susceptibility effect) was also performed to distinguish the 2 groups of oligodendrogliomas. RESULTS: The incorporation of rCBVmax value and metabolite ratios (NAA/Cr, Cho/Cr, Glx/Cr, myo-inositol/Cr, and lipid + lactate/Cr) into the multivariate logistic regression model provided the best discriminatory classification with sensitivity (82.6%), specificity (64.7%), and accuracy (72%) in distinguishing 2 oligodendroglioma genotypes. Oligodendrogliomas with 1p/19q LOH were also more associated with paramagnetic susceptibility effect (P < .05). CONCLUSIONS: Our preliminary results indicate the potential of combing PWI and ¹H-MRS to distinguish oligodendroglial genotypes.

Management of maple syrup urine disease in the peri-operative period.

Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.

Survival analysis of patients with high-grade gliomas based on data mining of imaging variables.

BACKGROUND AND PURPOSE: The prediction of prognosis in HGGs is poor in the majority of patients. Our aim was to test whether multivariate prediction models constructed by machine-learning methods provide a more accurate predictor of prognosis in HGGs than histopathologic classification. The prediction of survival was based on DTI and rCBV measurements as an adjunct to conventional imaging. MATERIALS AND METHODS: The relationship of survival to 55 variables, including clinical parameters (age, sex), categoric or continuous tumor descriptors (eg, tumor location, extent of resection, multifocality, edema), and imaging characteristics in ROIs, was analyzed in a multivariate fashion by using data-mining techniques. A variable selection method was applied to identify the overall most important variables. The analysis was performed on 74 HGGs (18 anaplastic gliomas WHO grades III/IV and 56 GBMs or gliosarcomas WHO grades IV/IV). RESULTS: Five variables were identified as the most significant, including the extent of resection, mass effect, volume of enhancing tumor, maximum B0 intensity, and mean trace intensity in the nonenhancing/edematous region. These variables were used to construct a prediction model based on a J48 classification tree. The average classification accuracy, assessed by cross-validation, was 85.1%. Kaplan-Meier survival curves showed that the constructed prediction model classified malignant gliomas in a manner that better correlates with clinical outcome than standard histopathology. CONCLUSIONS: Prediction models based on data-mining algorithms can provide a more accurate predictor of prognosis in malignant gliomas than histopathologic classification alone.

Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies.

Dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway. Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence. No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease. This is the first reported case of recurrent dense deposit disease being managed with eculizumab. Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident. A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease. Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function. There was a marked clinical and biochemical response following the administration of eculizumab. This case provides the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease. More information is necessary to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging. The results of clinical trials of eculizumab in this condition are eagerly awaited.

Application of high-resolution melting curve analysis for typing of fowl adenoviruses in field cases of inclusion body hepatitis.

OBJECTIVE: Fowl adenoviruses (FAdVs) cause inclusion body hepatitis (IBH) in chickens. In this study, clinical cases of IBH from Australian broiler flocks were screened for the presence and genotype of FAdVs. METHODS: Twenty-six IBH cases from commercial poultry farms were screened. Polymerase chain reaction (PCR) coupled with high-resolution melt (HRM) curve analysis (PCR/HRM genotyping) was used to determine the presence and genotype of FAdVs. For comparison, field isolates were also assessed by virus microneutralisation and nucleotide sequence analysis of the hexon loop 1 (Hex L1) gene. PCR detection of chicken anaemia virus (CAV) and infectious bursal disease virus (IBDV) was also employed. RESULTS: FAdV-8b and FAdV-11 were identified in 13 cases each. In one case, FAdV-1 was also identified. Cross-neutralisation was observed between the FAdV-11 field strain and the reference FAdV-2 and 11 antisera, a result also seen with the type 2 and 11 reference FAdVs. Field strains 1 and 8b were neutralised only by their respective type antisera. The FAdV-8b field strain was identical to the Australian FAdV vaccine strain (type 8b) in the Hex L1 region. The Hex L1 sequence of the FAdV-11 field strain had the highest identity to FAdV-11 (93.2%) and FAdV-2 (92.7%) reference strains. In the five cases tested for CAV and IBDV, neither virus was detected. The evidence suggested the presence of sufficient antibodies against CAV and IBD in the parent flocks and there was no indication of immunosuppression caused by these viruses. CONCLUSION: These results indicate that PCR/HRM genotyping is a reliable diagnostic method for FAdV identification and is more rapid than virus neutralisation and direct sequence analysis. Furthermore, they suggest that IBH in Australian broiler flocks is a primary disease resulting from two alternative FAdV strains from different species.

Epidemiology of recent outbreaks of infectious laryngotracheitis in poultry in Australia.

OBJECTIVE: Over the past 3 years, numerous outbreaks of infectious laryngotracheitis (ILT) have occurred in poultry in Australia. The objectives of this study were to identify the viral strains involved in the recent outbreaks and to determine possible epidemiological links between these outbreaks. PROCEDURE: A combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses of several genes of the ILT virus was used to identify genetic differences in field/vaccine ILT virus isolates. In a previous study, these procedures had demonstrated five classes (1-5) in Australia. RESULTS: Analysis of 92 field ILT viruses demonstrated four new classes: 6, 7, 8 and 9. Class 6 was responsible for four outbreaks in one Victorian broiler company and demonstrated to be distinct from other Australian strains of ILT. Class 7 was the Nobilis ILT vaccine (Intervet Pty Ltd). Class 8 was responsible for the majority of the outbreaks in New South Wales and was phylogenetically close to class 7. On one occasion, classes 7 and 8 were identified in an outbreak on a Victorian farm that had used the Nobilis ILT vaccine. Class 9, also phylogenetically close to classes 7 and 8, was found only in New South Wales. The previously identified class 2 was also found to be responsible for a large number of outbreaks, mainly in Victoria. CONCLUSION: The results demonstrate that, epidemiologically, most outbreaks of ILT in New South Wales are unrelated to those in Victoria and suggest a link between classes 8 and 9 and the Nobilis ILT vaccine (class 7).