Magnetic Resonance Liver Iron Concentration Can Guide Venesection Decision-Making in Hyperferritinemia.

BACKGROUND: The clinical benefit of venesection in suspected iron overload can be unclear and serum ferritin may overestimate the degree of iron overload. AIMS: To help inform practice, we examined magnetic resonance liver iron concentration (MRLIC) in a cohort investigated for haemochromatosis. METHODS: One hundred and six subjects with suspected haemochromatosis underwent HFE genotyping and MRLIC with time-matched serum ferritin and transferrin saturation values. For those treated with venesection, volume of blood removed was calculated as a measure of iron overload. RESULTS: Forty-seven C282Y homozygotes had median ferritin 937 µg/l and MRLIC 4.83 mg/g; MRLIC was significantly higher vs non-homozygotes for any given ferritin concentration. No significant difference in MRLIC was observed between homozygotes with and without additional risk factors for hyperferritinemia. Thirty-three compound heterozygotes (C282Y/H63D) had median ferritin 767 µg/l and MRLIC 2.58 mg/g; ferritin < 750 µg/l showed 100% specificity for lack of significant iron overload (< 3.2 mg/g). 79% of C282Y/H63D had additional risk factors-mean MRLIC was significantly lower in this sub-group (2.4 mg/g vs 3.23 mg/g). 26 C282Y heterozygous or wild-type had median ferritin 1226 µg/l and MRLIC 2.13 mg/g; 69% with additional risk factors had significantly higher ferritin concentrations (with comparable MRLIC) and ferritin < 1000 µg/l showed 100% specificity for lack of significant iron overload. In 31 patients (26 homozygotes, 5 C282Y/H63D) venesected to ferritin < 100 µg/l, MRLIC and total venesection volume correlated strongly (r = 0.749), unlike MRLIC and serum ferritin. CONCLUSION: MRLIC is an accurate marker of iron overload in haemochromatosis. We propose serum ferritin thresholds in non-homozygotes which, if validated, could tailor cost-effective use of MRLIC in venesection decision-making.

Juvenile haemochromatosis.

Juvenile haemochromatosis is a severe inherited iron-loading disorder that can present in children and adolescents. Typical manifestations include heart failure, endocrine failure (including diabetes and hypogonadism), cirrhosis, and arthropathy. Compared with HFE haemochromatosis, juvenile haemochromatosis affects female and male individuals similarly, presents at a younger age, and causes multiple organ dysfunction; the principle of iron loading into tissues from the gut is shared by both forms, but the process is far more rapid in juvenile haemochromatosis. Juvenile haemochromatosis is initially recognised by extreme increases of serum ferritin and transferrin saturation, which is supported by an MRI showing iron deposition in the heart and liver. MRI software techniques allow quantification of iron in these organs, and can therefore be used to monitor progress. Juvenile haemochromatosis is autosomal recessive and is generally associated with mutations in HJV (type 2A) or HAMP (type 2B). Mutations in TFR2 cause an intermediate severity phenotype (type 3), but this phenotype can cross over into the juvenile haemochromatosis spectrum so it might need to be additionally considered during diagnosis. Treatment needs to be administered without delay, in the form of aggressive iron chelation, and a multidisciplinary approach is essential. Because iron is removed, organ function is restored, which could obviate the need for cardiac or liver transplantation. Substantial restoration of health can ensue, but patients require life-long monitoring. Family screening is an important component of the management of juvenile haemochromatosis. Genetic advances which underpin the haemochromatosis types also clarify the role of iron metabolism in health and disease, particularly the role of hepcidin in regulating iron homoeostasis. Therefore, juvenile haemochromatosis is an important condition to understand; it can present insidiously in children and adolescents, and awareness of the diagnosis is needed to inform early recognition and treatment.

Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.

Resilience of seamount benthic communities to trawling disturbance.

Despite bottom trawling being the most widespread, severe disturbance affecting deep-sea environments, it remains uncertain whether recovery is possible once trawling has ceased. Here, we review information regarding the resilience of seamount benthic communities to trawling. We focus on seamounts because benthic communities associated with these features are especially vulnerable to trawling as they are often dominated by emergent, sessile epifauna, and trawling on seamounts can be highly concentrated. We perform a meta-analysis to investigate whether any taxa demonstrate potential for recovery once trawling has ceased. Our findings indicate that mean total abundance can gradually increase after protection measures are placed, although taxa exhibit various responses, from no recovery to intermediate/high recovery, resistance, or signs of early colonisation. We use our results to recommend directions for future research to improve our understanding of the resilience of seamount benthic communities, and thereby inform the management of trawling impacts on these ecosystems.

A case of successful surgical management of primary retroperitoneal mucinous cystadenoma.

Primary retroperitoneal mucinous cystadenoma (PRMC) is a rare tumour. It was first reported in 1965, and since then, less than 100 cases have been reported. It is cystic in nature and most commonly affects the female population. It becomes symptomatic in later stages due to its mass effect, making the diagnosis challenging in its early asymptomatic stage. We report a case of a 32-year-old female who presented with abdominal pain and a mass in left iliac fossa. Diagnostic imaging revealed a large cystic lesion in retroperitoneum. A midline laparotomy was performed, and a complete surgical excision was accomplished without any spillage. Surgical histology confirmed the diagnosis of PRMC. The patient was discharged on postoperative day 2. There was no evidence of tumour recurrence on repeat imaging at 90-day follow-up. Surgical approach, with complete resection and without any spillage, remains the most effective and appropriate treatment for this tumour.

An unusual variation of gallbladder duplication originating from the right hepatic duct.

INTRODUCTION: Duplication of the gallbladder is a rare congenital biliary anomaly and may present with similar pathology to that seen in a single gallbladder. We present a previously unreported case of a symptomatic duplex gallbladder arising directly from a long segment of the right hepatic duct. PRESENTATION: A 23 years old female was referred to our team with right upper quadrant pain suggestive of biliary colic. Ultrasound, contrast enhanced CT and magnetic resonance cholangiopancreatography revealed a normal gallbladder and a separate cystic lesion containing multiple gallstones and communicating with the right main hepatic duct. Surgical management involved cholecystectomy, resection of the cystic lesion from the right hepatic duct and reconstruction with hepaticojejunostomy. The patient made a good recovery from surgery, reporting complete resolution of symptoms. Histology of the cystic lesion confirmed duplicate gallbladder with features of severe chronic cholecystitis. DISCUSSION: Symptomatic duplicate gallbladders warrant cholecystectomy and in more straightforward variations, in which a shared, single cystic duct is encountered, a laparoscopic approach is feasible. Surgical management may be more complicated for anomalies in which the duplicate gallbladder is connected separately and more proximally in the biliary tree. CONCLUSION: Trabecular duplicate gallbladder, in which a second gallbladder originates from the right or left hepatic duct is extremely rare. We report a previously undescribed variation, in which the gallbladder is attached over a wide area to the right hepatic duct and outline the successful surgical management undertaken.

Chronic genotype 1 hepatitis E infection from immunosuppression for ileo-colonic Crohn's disease.

We report a case of a 33-year-old man with a background of longstanding ileo-colonic Crohn's disease and primary sclerosing cholangitis. Following a trip to India he developed diarrhoea which was treated as an exacerbation of Crohn's disease. Liver tests became chronically deranged after increasing immunosuppression, which comprised mercaptopurine, adalimumab and prednisolone. Chronic genotype 1 hepatitis E was diagnosed and successfully treated with reduction of immunosuppression followed by a 24-week course of ribavirin. We believe that this is the first reported case of chronic hepatitis E in genotype 1. Deranged liver tests should prompt testing for hepatitis E infection in the context of immunosuppression for inflammatory bowel disease.

Earthquakes drive large-scale submarine canyon development and sediment supply to deep-ocean basins.

Although the global flux of sediment and carbon from land to the coastal ocean is well known, the volume of material that reaches the deep ocean-the ultimate sink-and the mechanisms by which it is transferred are poorly documented. Using a globally unique data set of repeat seafloor measurements and samples, we show that the moment magnitude (Mw) 7.8 November 2016 Kaikoura earthquake (New Zealand) triggered widespread landslides in a submarine canyon, causing a powerful "canyon flushing" event and turbidity current that traveled >680 km along one of the world's longest deep-sea channels. These observations provide the first quantification of seafloor landscape change and large-scale sediment transport associated with an earthquake-triggered full canyon flushing event. The calculated interevent time of ~140 years indicates a canyon incision rate of 40 mm year-1, substantially higher than that of most terrestrial rivers, while synchronously transferring large volumes of sediment [850 metric megatons (Mt)] and organic carbon (7 Mt) to the deep ocean. These observations demonstrate that earthquake-triggered canyon flushing is a primary driver of submarine canyon development and material transfer from active continental margins to the deep ocean.

Quantitative BOLD imaging at 3T: Temporal changes in hepatocellular carcinoma and fibrosis following oxygen challenge.

PURPOSE: To evaluate the utility of oxygen challenge and report on temporal changes in blood oxygenation level-dependent (BOLD) contrast in normal liver, hepatocellular carcinoma (HCC) and background fibrosis. MATERIALS AND METHODS: Eleven volunteers (nine male and two female, mean age 33.5, range 27-41 years) and 10 patients (nine male and one female, mean age 68.9, range 56-87 years) with hepatocellular carcinoma on a background of diffuse liver disease were recruited. Imaging was performed on a 3T system using a multiphase, multiecho, fast gradient echo sequence. Oxygen was administered via a Hudson mask after 2 minutes of free-breathing. Paired t-tests were performed to determine if the mean pre- and post-O2 differences were statistically significant. RESULTS: In patients with liver fibrosis (n = 8) the change in T2* following O2 administration was elevated (0.88 ± 0.582 msec, range 0.03-1.69 msec) and the difference was significant (P = 0.004). The magnitude of the BOLD response in patients with HCC (n = 10) was larger, however the response was more variable (1.07 ± 1.458 msec, range -0.93-3.26 msec), and the difference was borderline significant (P = 0.046). The BOLD response in the volunteer cohort was not significant (P = 0.121, 0.59 ± 1.162 msec, range -0.81-2.44 msec). CONCLUSION: This work demonstrates that the BOLD response following oxygen challenge within cirrhotic liver is consistent with a breakdown in vascular autoregulatory mechanisms. Similarly, the elevated BOLD response within HCC is consistent with the abnormal capillary vasculature within tumors and the arterialization of the blood supply. Our results suggest that oxygen challenge may prove a viable BOLD contrast mechanism in the liver. J. Magn. Reson. Imaging 2016;44:739-744.

Diversity in a Cold Hot-Spot: DNA-Barcoding Reveals Patterns of Evolution among Antarctic Demosponges (Class Demospongiae, Phylum Porifera).

BACKGROUND: The approximately 350 demosponge species that have been described from Antarctica represent a faunistic component distinct from that of neighboring regions. Sponges provide structure to the Antarctic benthos and refuge to other invertebrates, and can be dominant in some communities. Despite the importance of sponges in the Antarctic subtidal environment, sponge DNA barcodes are scarce but can provide insight into the evolutionary relationships of this unique biogeographic province. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the standard barcoding COI region for a comprehensive selection of sponges collected during expeditions to the Ross Sea region in 2004 and 2008, and produced DNA-barcodes for 53 demosponge species covering about 60% of the species collected. The Antarctic sponge communities are phylogenetically diverse, matching the diversity of well-sampled sponge communities in the Lusitanic and Mediterranean marine provinces in the Temperate Northern Atlantic for which molecular data are readily available. Additionally, DNA-barcoding revealed levels of in situ molecular evolution comparable to those present among Caribbean sponges. DNA-barcoding using the Segregating Sites Algorithm correctly assigned approximately 54% of the barcoded species to the morphologically determined species. CONCLUSION/SIGNIFICANCE: A barcode library for Antarctic sponges was assembled and used to advance the systematic and evolutionary research of Antarctic sponges. We provide insights on the evolutionary forces shaping Antarctica's diverse sponge communities, and a barcode library against which future sequence data from other regions or depth strata of Antarctica can be compared. The opportunity for rapid taxonomic identification of sponge collections for ecological research is now at the horizon.

Sex differences in whole body gait kinematics at preferred speeds.

Studies on human perception have identified pelvis and torso motion as key discriminators between male and female gaits. However, while most observers would advocate that men and women walk differently, consistent findings and explanations of sex differences in gait kinematics across modern empirical studies are rare. In the present study we evaluated sex differences in whole body gait kinematics from a large sample of subjects (55 men, 36 women) walking at self selected speeds. We analyzed the data through comparisons of discrete metrics and whole curve analyses. Results showed that in the frontal plane, women walked with greater pelvic obliquity than men, but exhibited a more stable torso and head. Women had greater transverse plane pelvis and torso rotation as well as greater arm swing. Additional sex differences were noted at the hip and ankle. These kinematic results are in line with anectdotal observations and qualitative studies. In order to understand these observations and substantiate some of the explanations previously set forth in the biomechanics literature, we also explored possible reasons for dynamic sex effects, and suggested applications that may benefit from their consideration.

An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant.

Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

Diversity and distribution of deep-sea shrimps in the Ross Sea region of Antarctica.

Although decapod crustaceans are widespread in the oceans, only Natantia (shrimps) are common in the Antarctic. Because remoteness, depth and ice cover restrict sampling in the South Ocean, species distribution modelling is a useful tool for evaluating distributions. We used physical specimen and towed camera data to describe the diversity and distribution of shrimps in the Ross Sea region of Antarctica. Eight shrimp species were recorded: Chorismus antarcticus; Notocrangon antarcticus; Nematocarcinus lanceopes; Dendrobranchiata; Pasiphaea scotiae; Pasiphaea cf. ledoyeri; Petalidium sp., and a new species of Lebbeus. For the two most common species, N. antarcticus and N. lanceopes, we used maximum entropy modelling, based on records of 60 specimens and over 1130 observations across 23 sites in depths from 269 m to 3433 m, to predict distributions in relation to environmental variables. Two independent sets of environmental data layers at 0.05° and 0.5° resolution respectively, showed how spatial resolution affected the model. Chorismus antarcticus and N. antarcticus were found only on the continental shelf and upper slopes, while N. lanceopes, Lebbeus n. sp., Dendrobranchiata, Petalidium sp., Pasiphaea cf. ledoyeri, and Pasiphaea scotiae were found on the slopes, seamounts and abyssal plain. The environmental variables that contributed most to models for N. antarcticus were depth, chlorophyll-a concentration, temperature, and salinity, and for N. lanceopes were depth, ice concentration, seabed slope/rugosity, and temperature. The relative ranking, but not the composition of these variables changed in models using different spatial resolutions, and the predicted extent of suitable habitat was smaller in models using the finer-scale environmental layers. Our modelling indicated that shrimps were widespread throughout the Ross Sea region and were thus likely to play important functional role in the ecosystem, and that the spatial resolution of data needs to be considered both in the use of species distribution models.

An investigation into the effects of temporal resolution on hepatic dynamic contrast-enhanced MRI in volunteers and in patients with hepatocellular carcinoma.

This study investigated the effect of temporal resolution on the dual-input pharmacokinetic (PK) modelling of dynamic contrast-enhanced MRI (DCE-MRI) data from normal volunteer livers and from patients with hepatocellular carcinoma. Eleven volunteers and five patients were examined at 3 T. Two sections, one optimized for the vascular input functions (VIF) and one for the tissue, were imaged within a single heart-beat (HB) using a saturation-recovery fast gradient echo sequence. The data was analysed using a dual-input single-compartment PK model. The VIFs and/or uptake curves were then temporally sub-sampled (at interval ▵t = [2-20] s) before being subject to the same PK analysis. Statistical comparisons of tumour and normal tissue PK parameter values using a 5% significance level gave rise to the same study results when temporally sub-sampling the VIFs to HB < ▵t <4 s. However, sub-sampling to ▵t > 4 s did adversely affect the statistical comparisons. Temporal sub-sampling of just the liver/tumour tissue uptake curves at ▵t ≤ 20 s, whilst using high temporal resolution VIFs, did not substantially affect PK parameter statistical comparisons. In conclusion, there is no practical advantage to be gained from acquiring very high temporal resolution hepatic DCE-MRI data. Instead the high temporal resolution could be usefully traded for increased spatial resolution or SNR.

Cold seep epifaunal communities on the Hikurangi margin, New Zealand: composition, succession, and vulnerability to human activities.

Cold seep communities with distinctive chemoautotrophic fauna occur where hydrocarbon-rich fluids escape from the seabed. We describe community composition, population densities, spatial extent, and within-region variability of epifaunal communities at methane-rich cold seep sites on the Hikurangi Margin, New Zealand. Using data from towed camera transects, we match observations to information about the probable life-history characteristics of the principal fauna to develop a hypothetical succession sequence for the Hikurangi seep communities, from the onset of fluid flux to senescence. New Zealand seep communities exhibit taxa characteristic of seeps in other regions, including predominance of large siboglinid tubeworms, vesicomyid clams, and bathymodiolin mussels. Some aspects appear to be novel; however, particularly the association of dense populations of ampharetid polychaetes with high-sulphide, high-methane flux, soft-sediment microhabitats. The common occurrence of these ampharetids suggests they play a role in conditioning sulphide-rich sediments at the sediment-water interface, thus facilitating settlement of clam and tubeworm taxa which dominate space during later successional stages. The seep sites are subject to disturbance from bottom trawling at present and potentially from gas hydrate extraction in future. The likely life-history characteristics of the dominant megafauna suggest that while ampharetids, clams, and mussels exploit ephemeral resources through rapid growth and reproduction, lamellibrachid tubeworm populations may persist potentially for centuries. The potential consequences of gas hydrate extraction cannot be fully assessed until extraction methods and target localities are defined but any long-term modification of fluid flow to seep sites would have consequences for all chemoautotrophic fauna.

Radiology of eating disorders: a pictorial review.

Eating disorders are a major challenge for health professionals, with many patients receiving ineffective care due to underdiagnosis or poor compliance with treatment. The incidence of eating disorders is increasing worldwide, producing an increasing burden on healthcare systems, and they most often affect young patients, with significant long-term complications. The effects of long-term malnutrition manifest in almost every organ system, and many can be detected radiologically, even without overt clinical findings. Musculoskeletal complications including osteoporosis result in a high incidence of insufficiency fractures, with long-term implications for bone health and growth, while respiratory complications are often recognized late due to disordered physiologic responses to infection. Gastrointestinal complications are numerous and in extreme cases may result in fatal outcomes after acute gastric dilatation and rupture subsequent to binge eating. In patients with severely disordered eating, in particular anorexia nervosa, marked derangement of electrolyte levels may result in refeeding syndrome, which requires emergent management. Recognition of such complications is critical to effective patient care and requires radiologists to be aware of the spectrum of imaging abnormalities that may be seen. Since many patients are reluctant to disclose their underlying condition, radiologists also play a critical role in identifying previously undiagnosed eating disorders.

Molecular epidemiology of hepatitis B in the Indigenous people of northern Australia.

BACKGROUND AND AIM: The hepatitis B surface antigen was first described in the blood of an Indigenous Australian man, yet little is known about its molecular epidemiology in this population, in which it is endemic. The study aimed to determine the clinical and molecular epidemiology of hepatitis B virus (HBV) in Indigenous people from northern Australia. METHODS: Following ethics approval and informed consent, blood specimens and clinical details from Indigenous adults known to be infected with HBV and who were born and raised in Indigenous communities in northern Australia were obtained. HBV genotypes were determined in isolates with sufficient HBV DNA by polymerase chain reaction by sequencing of the polymerase/surface gene. RESULTS: Between June 2010 and June 2012, 65 patients were recruited from six different regions of northern Australia. Thirty-two patients (49%) were hepatitis B e-antigen-positive, and 48% were hepatitis B e-antibody-positive. No patients were found to be coinfected with hepatitis C virus or human immunodeficiency virus. Of the 49 samples with sufficient viral load for genotyping, 100% were infected with genotype C4, previously only reported from two Indigenous Australians. All isolates had wild-type polymerase gene sequences despite 14 currently or previously receiving antiviral treatment. The canonical sG145R vaccine-escape variant was detected in the surface antigen of virus from two patients. CONCLUSIONS: The exclusive HBV genotype in this ancient population is genotype C4. Whole genome sequencing and clinical follow-up of this cohort are in progress, with the aim of exploring the clinical significance of these findings.

Angiogenesis imaging in neoplasia.

Angiogenesis plays a key role in physiological and pathophysiological processes and is recognized as being essential for tumor growth and metastases. The recent oncological development of anti-angiogenic drugs brings with it a need for angiogenesis quantification and monitoring of response. The nature of these agents means that traditional anatomical methods of assessing morphologic change are outmoded and functional imaging techniques and/or agents are necessary. Herein, we describe the various imaging techniques that can be employed to assess angiogenesis, along with their inherent advantages and disadvantages and discuss the current and future developments in the field.