Multidisciplinary team discussion: the emerging gold standard for management of cardiopulmonary complications of connective tissue disease.

Cardiopulmonary complications of connective tissue diseases (CTDs), particularly pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), are major determinants of morbidity and mortality. Multidisciplinary meetings may improve diagnostic accuracy and optimise treatment. We review the literature regarding multidisciplinary meetings in CTD-ILD and PAH and describe our tertiary centre experience of the role of the multidisciplinary meeting in managing CTD-PAH.

Eye Removal in Living Zebrafish Larvae to Examine Innervation-dependent Growth and Development of the Visual System.

Zebrafish exhibit remarkable life-long growth and regenerative abilities. For example, specialized stem cell niches established during embryogenesis support continuous growth of the entire visual system, both in the eye and the brain. Coordinated growth between the retinae and the optic tectum ensures accurate retinotopic mapping as new neurons are added in the eyes and brain. To address whether retinal axons provide crucial information for regulating tectal stem and progenitor cell behaviors such as survival, proliferation, and/or differentiation, it is necessary to be able to compare innervated and denervated tectal lobes within the same animal and across animals. Surgical removal of one eye from living larval zebrafish followed by observation of the optic tectum achieves this goal. The accompanying video demonstrates how to anesthetize larvae, electrolytically sharpen tungsten needles, and use them to remove one eye. It next shows how to dissect brains from fixed zebrafish larvae. Finally, the video provides an overview of the protocol for immunohistochemistry and a demonstration of how to mount stained embryos in low-melting-point agarose for microscopy.

Tissue-Specific Requirement for the GINS Complex During Zebrafish Development.

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages.

Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation.

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the 'limited oocyte pool' hypothesis and the 'two-hit' hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy.

Nasolacrimal Sac Diverticulum: A Case Series and Literature Review.

PURPOSE: To describe the demographics, presentation, treatment, and outcome in 10 cases of lacrimal sac diverticulum and to review the literature on this topic, and to determine the incidence of diverticula from a series of dacryocystograms. METHODS: Data were collected for all consecutive patients with lacrimal sac diverticulum seen between 2003 and 2015, including patient demographics, clinical presentation, imaging findings, treatment, and follow-up. A systematic literature review was performed for cases of lacrimal sac diverticulum. A retrospective review of 400 consecutive dacryocystograms was performed to determine the incidence of lacrimal sac diverticulum. RESULTS: Ten cases (9 patients) of lacrimal sac diverticulum are described, and a further 36 cases were discovered through a literature review. Epiphora, swelling, and dacryocystitis and/or diverticulitis were the most common presenting complaints. When all 46 cases are combined, lacrimal patency was demonstrated in 50% of cases. Dacryocystography diagnosed only 57% of patients with diverticulum, not helped by the addition of ultrasound or CT. The incidence of diverticulum was 3.2% on review of 400 consecutive dacryocystograms (1.6% per lacrimal system). Surgical management with dacryocystorhinostomy and/or diverticulum excision was effective in all 34 operated cases at resolving symptoms in the case series and literature review. CONCLUSIONS: Lacrimal sac diverticula present with epiphora, medial canthal swelling, dacryocystitis, and/or diverticulitis. Dacryocystography, despite being the most sensitive radiologic test, is only 59% sensitive, and adjunctive CT and ultrasound have limited use. Surgical management is recommended because conservative management often fails. Dacryocystorhinostomy, diverticulum excision, or a combination thereof appears to be equivalent in achieving resolution of symptoms.

Implications of the diagnostic criteria of idiopathic pulmonary fibrosis in clinical practice: Analysis from the Australian Idiopathic Pulmonary Fibrosis Registry.

BACKGROUND AND OBJECTIVE: Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry. METHODS: All patients enrolled in the registry undergo a diagnostic review whereby international IPF guidelines are applied via a registry MDD. We investigated the clinical applicability of these guidelines with regard to: (i) adherence to guidelines, (ii) Natural history of IPF diagnostic categories and (iii) Concordance for diagnostic features. RESULTS: A total of 417 participants (69% male, 70.6 ± 8.0 years) with a clinical diagnosis of IPF underwent MDD. The 23% of participants who did not meet IPF diagnostic criteria displayed identical disease behaviour to those with confirmed IPF. Honeycombing on radiology was associated with a worse prognosis and this translated into poorer prognosis in the 'definite' IPF group. While there was moderate agreement for IPF diagnostic categories, agreement for specific radiological features, other than honeycombing, was poor. CONCLUSION: In clinical practice, physicians do not always follow IPF diagnostic guidelines. We demonstrate a cohort of IPF patients who do not meet IPF diagnostic guideline criteria, based largely on their radiology and lack of lung biopsy, but who have outcomes identical to those with IPF.

Quantifying change in pulmonary function as a prognostic marker in systemic sclerosis-related interstitial lung disease.

OBJECTIVES: Clinically meaningful change in systemic sclerosis (SSc) related interstitial lung (SSc-ILD) disease is unknown. The aim of this study was to quantify change in pulmonary function as a predictor of outcome in SSc-ILD. METHODS: All patients had SSc-ILD defined by HRCT chest. All PFTs during follow-up, including FVC (L), DLCO (ml/min/mmHg) and KCO (DLCO/alveolar volume ratio; DLCO/VA) (ml/min/mmHg/L) were retrieved. The rate of change over the first four years, and percentage change in the first year of follow-up were used in ROC curve analysis to determine the best cut-off points to predict adverse outcome (home oxygen, lung transplantation, or death). RESULTS: Among 264 patients, there were 49 events (38 deaths, 10 supplemental oxygen, one lung transplant) over a mean (±SD) follow-up of 3.0 (±1.7) years. The rates of decline over time and percentage change over one year in each of FVC, DLCO and KCO were predictive of adverse outcome. Stable PFTs over four years gave the optimal negative predictive values (NPVs) of 88-96%. The best sensitivity-specificity trade-off was a decline in FVC of 10% and in DLCO and KCO of 15% with NPVs of 92-93%. CONCLUSIONS: The course that SSc-ILD takes is evident within the first 1-4 years of follow up. Patients who have no decline in PFTs over 4 years have better outcomes. A decline within one year in DLCO or KCO of 15% or more is a poor prognostic factor, and identifies patients who should be monitored more closely and considered for therapy.

Examining the sensitivity of ultrasound-guided large core biopsy for invasive breast carcinoma in a population screening programme.

INTRODUCTION: To evaluate the sensitivity of ultrasound-guided core-needle biopsy (UCB) in invasive breast carcinoma and to establish causes of false-negative biopsy in a population screening programme. METHOD: We identified 571 consecutive women diagnosed with surgically proven invasive breast cancer. Histology from 14-gauge UCB was compared with surgical histology to identify true-positive and false-negative ultrasound core biopsies. True-positive and false-negative groups were compared for tumour size and histology. On blinded review of UCB images and pathology reports from false negative (n = 20) and a random sample of true-positive cases (n = 80), we compared core sample number and needle visualisation in the lesion. RESULTS: Of 571 carcinomas sampled with UCB, 551 (96.5%) were true positive and 20 (3.5%) were false negative. The mean core number was 2.0 (range 1-3) for false negatives and 2.25 (range 1-4) for true positives (P = 0.27). Mean tumour sizes were 13.3 and 16.2 mm for the false-negative and true-positive groups, respectively (P = 0.25). Tubular carcinomas represented 30% (6/20) of false-negative cases compared with 5.1% (28/551) of the true-positive cases (P < 0.001). On blinded review, needle visualisation within the lesion was demonstrated in 47.4% (9/19) of false-negative cases and 76.3% (61/80) of true-positive cases (P = 0.02). CONCLUSION: We demonstrated a sensitivity of 96.5% with a mean of 2.21 cores. False-negative results were more likely in the absence of post-fire needle position verification and with tubular carcinomas. Neither tumour size nor core number predicted diagnostic accuracy.

Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease.

OBJECTIVES: In a multi-centre study, we sought to determine whether extent of disease on high-resolution CT (HRCT) lung, reported using a simple grading system, is predictive of decline and mortality in SSc-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables. METHODS: SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All HRCTs and PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease: >20%: extensive; <20%: limited; unclear: indeterminate. Indeterminate HRCTs were converted to limited or extensive using a forced vital capacity threshold of 70%. The composite outcome variable was deterioration (need for home oxygen or lung transplantation), or death. RESULTS: Among 172 patients followed for mean (s.d.) of 3.5 (2.9) years, there were 30 outcome events. In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) = 3.0, 95% CI 1.2, 7.5 and P = 0.02. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in 172 patients), serial diffusing capacity of the lung for carbon monoxide by alveolar volume ratio (ml/min/mmHg/l) (aHR = 0.4; 95% CI 0.3, 0.7; P = 0.001) and forced vital capacity (dl) (aHR = 0.9; 95% CI 0.8, 0.97; P = 0.008), were also strongly predictive of outcome. CONCLUSION: Extensive disease (>20%) on HRCT at baseline, reported using a semi-quantitative grading system, is associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited disease. Serial PFTs are informative in follow-up of patients.

Imaging features of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome.

OBJECTIVE: The purpose of this study was to analyze the radiologic features of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome. The syndrome is a phenomenon characterized by clinical deterioration of the condition of HIV-positive patients after initiation of highly active antiretroviral therapy. MATERIALS AND METHODS: The study included four patients at our institution who fulfilled the diagnostic criteria for pulmonary Kaposi sarcoma-associated immune reconstitution syndrome from 2001 to 2006. All patients were men (mean age, 43 years; range, 31-59 years). Images reviewed included chest radiographs obtained before highly active antiretroviral therapy, radiographs and chest CT scans obtained at appearance of the symptoms of Kaposi sarcoma-associated immune reconstitution syndrome, and follow-up radiographs and chest CT scans during immune reconstitution syndrome. RESULTS: The radiographic findings of Kaposi sarcoma-associated immune reconstitution syndrome included reticular and reticulonodular opacities (n = 4), areas of consolidation (n = 3), septal lines (n = 3), and pleural effusion (n = 3). The CT findings in all four patients were ill-defined pulmonary nodules and interlobular septal thickening. Three of the patients had a CT halo sign, areas of consolidation, ground-glass opacities, lymphadenopathy, and pleural effusion. The areas of consolidation in three subjects who did not receive chemotherapy increased markedly after 14-20 days. CT performed during the initial symptoms of immune reconstitution syndrome in these three subjects showed less than 5% parenchymal involvement. Follow-up CT showed 26-50% involvement in two patients and more than 50% involvement in one patient. CONCLUSION: The radiologic findings of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome are similar to the findings described in patients with Kaposi sarcoma without the syndrome, but the extent of abnormalities tends to increase with the development of the syndrome.