bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenesis of proteinuria in minimal change disease and focal segmental glomerulosclerosis
Authors: Niaudet Patrick , Meyrier Alain
Published: June 2018

It is now well established that the podocyte, and in particular the slit diaphragm structure, are critical to the barrier to serum albumin entering glomerular filtrate in large quantities. In minimal change disease there is proteinuria without podocyte death, whereas in focal segmental glomerulosclerosis there is not only podocyte dysfunction but also podocyte loss.
Membranous glomerulonephritis
Authors: Cattran Daniel C. , Reich Heather N.
Published: June 2018

It has been clear for several decades from comparison with the rodent model disease Heymann nephritis that membranous glomerulonephritis (MGN) is an immune condition in which antibodies, usually autoantibodies, bind to targets on the surface of podocytes. However, the antigen in Heymann nephritis, megalin, is not present on human podocytes.
The first potential antigen was identified by studying rare examples of maternal alloimmunization, leading to congenital membranous nephropathy in the infant caused by antibodies to neutral endopeptidase. More recently, the target of autoantibody formation in most patients with primary MGN has been identified to be the phospholipase A2 receptor, PLA2R.
Genome-wide association studies identify predisposing genetic loci at HLADQ and at the locus encoding the autoantigen itself. So antibodies to at least two different molecular targets can cause MGN, and it seems likely that there may be other targets in secondary types of MGN, and possibly haptenized or otherwise modified molecules are implicated in drug- and toxin-induced MGN.
Once antibodies are fixed, animal models and human observations suggest that complement is involved in mediating tissue damage. However, immunoglobulin G4, not thought to fix complement, is the predominant isotype in human MGN, and the mechanisms are not fully unravelled. Podocyte injury is known to cause proteinuria. In MGN, antibody fixation or cell damage may stimulate production of extracellular matrix to account for the increased GBM thickness with ‘podocyte type’ basement membrane collagen isoforms, and ultimately cell death and glomerulosclerosis.
Immunoglobulin A nephropathy
Authors: Lai Kar Neng , Tang Sydney C. W.
Published: June 2018

Immunoglobulin A nephropathy is characteristically slowly evolving, and studies from autopsies and kidney donors show that deposition of immunoglobulin A is quite common and not necessarily associated with overt disease. However, series of biopsy-diagnosed patients that extend to 20 or 30 years report rates of end-stage renal failure of up to 40–50%. A very approximate overall rate of end-stage renal disease of 1% per year has been suggested. Proteinuria, glomerular filtration rate (GFR), and possibly some features on renal biopsies enable risk stratification, but all patients need long-term monitoring.
Treatment is based on the use of angiotensin converting-enzyme inhibitors for patients with proteinuria, and blood pressure control, and of course during most of the previous long-term studies patients would not have been treated with these agents or to modern blood pressure standards.
For patients who show loss of GFR despite this, or other markers of high risk, the best evidence is for treatment with high-dose corticosteroids over a limited period of months. There is little convincing evidence for additional benefit from cytotoxic or other immunomodulatory agents, except possibly in the most aggressive disease, when there is weak evidence for cyclophosphamide. Some studies claim benefit from tonsillectomy, but this is not clear, and most nephrologists only recommend this for patients with recurrent tonsillitis.
Antiglomerular basement membrane disease
Authors: Cui Zhao , Turner Neil , Zhao Ming-hui
Published: June 2018

Cyclophosphamide and plasma exchange are the standard of care in rapidly progressive glomerulonephritis or lung haemorrhage caused by antiglomerular basement membrane (anti-GBM) disease, and it is unusual to encounter patients at earlier stages. Steroids are universally used in addition. There is some evidence that plasma exchange may not be a critical part of treatment at an earlier stage. There is no more than anecdotal evidence for other therapies. Slower-onset therapies such as antibodies to B cells are rarely appropriate.
If untreated, patients with severe anti-GBM disease will not recover renal function and are at risk of pulmonary haemorrhage. Evidence for the pathogenicity of circulating anti-GBM antibodies provides rationale for removal of circulating antibodies as rapidly as possible, whilst simultaneously inhibiting their synthesis. This was behind the introduction of the combination of plasma exchange with immunosuppressive therapy in mid 1970s, which revolutionized outcomes. Plasmapheresis aims to remove circulating pathogenic antibodies against GBM and possibly other mediators; cyclophosphamide prevents further synthesis of autoantibodies; and steroids act as anti-inflammatory agents to attenuate the glomerular inflammatory response initiated by anti-GBM antibodies. It is clear from experimental models and occasional observations in man that the anti-cell mediated effects of current therapies are important too.
Outcomes vary, but in general patient survival is now good, while renal survival remains poor, in many series less than 50% at 1 year. Treatment is toxic and after an early peak in deaths due to pulmonary haemorrhage, secondary infections are the next threat. It may therefore be best not to immunosuppress patients with a very poor renal prognosis who appear to be at low risk of pulmonary haemorrhage.
Treatment can usually be curtailed after 3 months without recurrence. ANCA and anti-GBM antibodies occur together in some patients. This is typically an older group which often has features of vasculitis, and the anti-GBM response may often be secondary. Longer treatment as for small vessel vasculitis is usually indicated.
Antiglomerular basement membrane disease
Authors: Cui Zhao , Turner Neil , Zhao Ming-hui
Published: June 2018

Individuals appear to be predisposed to antiglomerular basement membrane (anti-GBM) disease by carrying a predisposing human leucocyte antigen type, DRB1*1501 being identified as the highest risk factor, and there are likely to be other predisposing genes or influences on top of which a relatively rare ‘second hit’ leads to the development of autoimmunity. In anti-GBM disease this appears to have a self-perpetuating, accelerating component, that may be to do with antibodies and altered antigen presentation. Lymphocyte depletion may also predispose to the disease.
A number of second hits have been identified and they seem to share a theme of damage to the glomerulus. There may be a prolonged (months to years) and usually subclinical phase in anti-GBM disease in which usually relatively low level antibody titres are associated with variable haematuria, sometimes minor pulmonary haemorrhage, but often no symptoms.
Damage to the lung seems to determine whether there is a pulmonary component to the disease. Without pulmonary damage caused typically by smoking, inhalation of other fumes, and potentially infection or oxygen toxicity, the disease remains an isolated kidney disease.
Antibodies appear to be an important component of the disease, but cell-mediated immunity is also critical to the clinical picture. In animal models, cell-mediated immunity triggered by the GBM antigen can cause severe renal damage in the absence of pathogenic antibody. The development of specific antibody also requires T-cell sensitization and help, and suppressing the response is likely to require suppressing both antibody and cell-mediated immunity.
Antibodies recognize one major and some other epitopes, which are now well described. T-cell epitopes are becoming better understood. Evidence from animal models also suggests that the damage in anti-GBM disease is dependent on complement, macrophages, and neutrophils.
Malnutrition, obesity, and undernutrition in chronic kidney disease
Authors: Kumar Navneet , Henderson Heather , Cameron Beverly D. , McCullough Peter A.
Published: June 2018

Both overnutrition resulting in obesity and undernutrition leading to protein energy wasting contribute to chronic kidney disease-related morbidity and adverse outcomes. Early in the course of chronic kidney disease, goals should be set for a healthy body weight and lifelong efforts should be encouraged to attain and keep this goal.
For patients with progressive chronic kidney disease, the development of weight loss and protein energy wasting is an ominous sign and is a clinical signal for a myriad of adverse catabolic processes that have been associated with poor outcomes including hospitalization and death, particularly for those with end-stage renal disease. Renal nutrition consultation at all stages of chronic kidney disease with frequent visits and education and counselling is needed to intercede early in both ends of the nutrition continuum in patients with chronic kidney disease.
Kidney/eye syndromes
Authors: Salvetti Anna Paola , Mackensen Friederike , Schwenger Vedat , Billing Heiko
Published: June 2018

Ophthalmologists and nephrologists should know of the diseases that touch both their specialties. Some are very rare, but the diagnosis can only be made if awareness of them exists. This chapter covers diseases that affect eye and kidney and tries to create a scaffolding of thought to remember them more easily and also to help in rapidly finding the affected structures when looking up diseases and syndromes in this textbook.
Dengue and other viral haemorrhagic fevers
Authors: Chang Jung-San , Chen Hung-Chun
Published: June 2018

Human infections of dengue viruses are mediated by mosquito bites. The disease spectrum ranges from asymptomatic infection to severe dengue haemorrhagic fever, and dengue shock syndrome. Dengue virus infects a wide range of immune cells that lead to plasma leakage and dengue haemorrhagic fever. Dengue haemorrhagic fever can be complicated with renal involvement, including haematuria, proteinuria, glomerulonephritis, acute kidney injury, and haemolytic uraemic syndrome. Diagnosis can be made by serology, detection of viral proteins by Western blot assay, or detection of the dengue viral genome by reverse transcription-polymerase chain reaction. Treatment is mainly supportive. Renal involvement associated with other viral haemorrhagic fevers has mostly been described as case reports and causality has not been established.
Medical management of nephrocalcinosis and nephrolithiasis
Authors: Sinnott Bridget , Maalouf Naim M. , Sakhaee Khashayar , Moe Orson W.
Published: June 2018

Conditions associated with nephrocalcinosis and nephrolithiasis are described. Some (cystinuria, urate) have specific therapies, and there are some general measure, particular for calcium-containing stones (urine volume, dietary salt, urinary citrate, thiazide diuretics). In the absence of a primary aetiology, urinary biochemical predisposing factors can be manipulated. Properly directed medical therapy is highly effective in preventing recurrence.
Overall outcomes of acute kidney injury
Authors: Lameire Norbert , Van Biesen Wim , Vanholder Raymond
Published: June 2018

This chapter describes the overall short- and long-term, mainly non-renal outcomes of patients who suffer from acute kidney injury (AKI). Despite increasing age and greater burden of co-morbidity at the occurrence of AKI, patient mortality shows an overall decline over time. However, relatively ‘mild’ forms of AKI (i.e. defined as an absolute increase in serum creatinine of at least 0.3 mg/dL (26.4 µmol/L)) are associated with statistically significant decreased patient survival. The absolute mortality rates of AKI vary according to the different patient groups studied (intensive care unit, hospital, and population based), differences in parameters used for the criteria of AKI, differences in acquisition of baseline serum creatinine, differences between need of renal replacement therapy or not, and timing of endpoints (in-hospital mortality, 30 days, 60 days, or longer). In many instances, particularly in critically ill patients, AKI occurs in the setting of other diseases, such as sepsis, which are associated with a significant mortality risk. In such cases, AKI appears to amplify the risk of death associated with the underlying disease.
Acute kidney injury and hantavirus disease
Authors: Clement Jan
Published: June 2018

Hantavirus disease or at least its renal form, the so-called haemorrhagic fever with renal syndrome is the only globally emerging acute kidney injury (AKI) form, and currently without doubt the most underestimated form of community-acquired AKI. Hantavirus disease is a viral zoonosis, caused by inhalation of infectious aerosolized excreta from chronically infected rodents, which are both the reservoir and the vector of different hantavirus species. Clinical presentation consists of sudden flu-like symptoms (fever, headache, myalgia), followed by gastrointestinal discomfort and AKI, often with anuria or oliguria. More rarely, acute myopia and/or non-cardiogenic acute lung oedema or injury is the presenting or complicating symptom. Laboratory hallmarks are initial thrombocytopenia and proteinuria, raised C-reactive protein and lactate dehydrogenase, left-shift leucocytosis, and typical but transient serum lipid disturbances. Spontaneous remission occurs within 2–3 weeks without sequelae. Case fatality rate is between 0.1% and 15% according to the infecting hantavirus species, but most infections show in fact an asymptomatic or paucisymptomatic presentation. Treatment is only supportive, but may necessitate life-saving intensive care techniques. Together with leptospirosis, haemorrhagic fever with renal syndrome is the only form of AKI against which different vaccines are in use, but a World Health Organization-licensed hantavirus vaccine is still lacking.
Community-acquired pneumonia and acute kidney injury
Authors: Lameire Norbert
Published: June 2018

It is known that in one-half of the patients hospitalized for community-acquired pneumonia, severe sepsis develops, with non-pulmonary organ dysfunction developing in more than one-third and septic shock in 4.5%. Some years ago, it was found that acute kidney injury was common in community-acquired pneumonia even in patients who appeared to have an uncomplicated course of community-acquired pneumonia and where acute kidney injury was observed in one-quarter of them.
Acute kidney injury in severe sepsis
Authors: Prowle John , Bellomo Rinaldo
Published: June 2018

Septic acute kidney injury (S-AKI) accounts for close to 50% of all cases of AKI in ICU and, in its various forms, affects between 15% and 20% of ICU patients. Patients typically present with clinical evidence of severe sepsis and septic shock, developing oliguria or anuria, and rapidly rising serum creatinine concentration. The pathophysiology of S-AKI is poorly understood. Although haemodynamic factors might play a role in the loss of glomerular filtration rate, this may not be through the induction of renal ischaemia. Inflammation, microvascular shunting, and changes in glomerular arteriolar tone may play important roles. Much evidence suggests that clinically urinalysis fails to provide useful diagnostic or prognostic information in this setting but novel biomarkers and urine microscopy may provide more useful prognostic information.

The treatment of S-AKI remains based on the treatment of the aetiology of sepsis with source control and appropriate antibiotics, supportive treatment of systemic illness including, in severe cases, renal replacement therapy (RRT). Because most patients with S-AKI requiring RRT are critically ill and haemodynamically unstable, RRT in these patients is best provided as continuous RRT.

Approximately 50% of patients with severe S-AKI survive to hospital discharge and, among those who survive, approximately 85–90% recover to dialysis independence. However, those patients who recover appear to be at increased risk of developing chronic kidney disease over the following years.
Autosomal dominant polycystic kidney disease
Authors: Sandford Richard
Published: June 2018

Autosomal dominant polycystic kidney disease (ADPKD) is a diagnosis typically made following imaging of the renal tract. The characteristic features of enlarged bilateral polycystic kidneys with or without liver cysts and a positive family history allow a secure diagnosis to be made for the majority of affected individuals. Other conditions may mimic ADPKD and features of these diseases should always be sought before making a diagnosis. Genetic testing for ADPKD is now widely available and its use in clinical practice is being evaluated. It is likely to have a role in cases with diagnostic uncertainty, living related donor assessment, and pre-symptomatic testing in addition to reproductive planning.
Management of cystic liver disease
Authors: van Aerts René M. M. , Gevers Tom J. G. , Drenth Joost P. H.
Published: June 2018

In a subset of autosomal dominant polycystic kidney disease patients, hepatic cysts dominate the clinical picture. These patients may develop polycystic liver disease, and enlargement of the liver leads to compression of adjacent abdominal and thoracic organs. The main risk factors for growth of liver cysts are female sex, exogenous oestrogen use, multiple pregnancies, and severity of renal disease. Treatment is only indicated in those with symptoms, and choice of treatment depends on total liver volume, size, and location of the liver cysts. Current radiological and surgical therapies include aspiration-sclerotherapy, fenestration, segmental hepatic resection, and liver transplantation. They all are palliative in nature and are partially effective and have non-negligible morbidity and mortality. Somatostatin analogues are still in development for polycystic liver disease.
The molecular basis of glomerular basement membrane disorders
Authors: Lennon Rachel , Turner Neil
Published: June 2018

The glomerular basement membrane (GBM) is a condensed network of extracellular matrix molecules which provides a scaffold and niche to support the function of the overlying glomerular cells. Within the glomerulus, the GBM separates the fenestrated endothelial cells, which line capillary walls from the epithelial cells or podocytes, which cover the outer aspect of the capillaries. In common with basement membranes throughout the body, the GBM contains core components including collagen IV, laminins, nidogens, and heparan sulphate proteoglycans. However, specific isoforms of these proteins are required to maintain the integrity of the glomerular filtration barrier.

Across the spectrum of glomerular disease there is alteration in glomerular extracellular matrix (ECM) and a number of histological patterns are recognized. The GBM can be thickened, expanded, split, and irregular; the mesangial matrix may be expanded and glomerulosclerosis represents a widespread accumulation of ECM proteins associated with loss of glomerular function. Whilst histological patterns may follow a sequence or provide diagnostic clues, there remains limited understanding about the mechanisms of ECM regulation and how this tight control is lost in glomerular disease. Monogenic disorders of the GBM including Alport and Pierson syndromes have highlighted the importance of both collagen IV and laminin isoforms and these observations provide important insights into mechanisms of glomerular disease.
WT1 and its disorders
Authors: Hastie Nick , Miller-Hodges Eve
Published: June 2018

Mutations in the Wilms tumour suppressor gene, WT1, are associated with Wilms tumour in childhood. However, in addition WT1 has a key role in renal development, emerging roles in podocyte function, and a potential role in tissue regeneration. An understanding of WT1 is of increasing importance to clinical practice. WT1 is a complex gene with multiple isoforms. It is crucial for normal embryonic development, especially kidney development, where it is necessary for mesenchymal-to-epithelial transition to form the nephron. WT1 mutations lead to abnormalities in renal and genitourinary development, causing diseases such as Denys–Drash syndrome and Frasier syndrome as well as Wilms tumour. Recently, WT1 mutations have been recognized as a significant cause of isolated steroid-resistant nephrotic syndrome in children and young adults, without other associated syndromic features. WT1 continues to be expressed in adult podocytes, where it acts as a transcriptional activator of many podocyte genes. However, the specific role of WT1 in adult podocyte function remains poorly understood.
Anatomy of the hyper-runaway star LP 40–365 with Gaia
Authors: Raddi R , Hollands M A , Gänsicke B T , Townsley D M , Hermes J J , Gentile Fusillo N P , Koester D
Published: June 2018

LP 40–365 (aka GD 492) is a nearby low-luminosity hyper-runaway star with an extremely unusual atmospheric composition, which has been proposed as the remnant of a white dwarf that survived a peculiar Type Iax supernova (SN Iax) in a single-degenerate scenario. Adopting the Gaia Data Release 2 (DR2) parallax, ϖ = 1.58 ± 0.03 mas, we estimate a radius of 0.18 ± 0.01 R⊙, confirming LP 40–365 as a subluminous star that is ≃ 15 times larger than a typical white dwarf and is compatible with the SN Iax remnant scenario. We present an updated kinematic analysis, making use of the Gaia parallax and proper motion, and confirm that LP 40–365 is leaving the Milky Way at about 1.5 times the escape velocity of the Solar neighbourhood with a rest-frame velocity of 852 ± 10 km s−1. Integrating the past trajectories of LP 40–365, we confirm that it crossed the Galactic disc 5.3 ±  0.5 Myr ago in the direction of Carina, likely coming from beneath the plane. Finally, we estimate that LP 40–365 was ejected from its progenitor binary with a velocity of at least 600 km s−1, which is compatible with theoretical predictions for close binaries containing a white dwarf and a helium-star donor.
Contact Lens Solutions and Contact Lens Discomfort: Examining the Correlations Between Solution Components, Keratitis, and Contact Lens Discomfort
Authors: Kuc Christopher J. , Lebow Kenneth A.
Published: June 2018

Objectives:

This article will examine the current literature, as it relates to contact lens discomfort (CLD) secondary to contact lens solutions. The reader will better understand the characteristics of contact lenses, as they uniquely interact with each type of contact lens solution and also gain a better comprehension of the components of contact lens solution such as preservatives, surfactants, and chelating agents, which may contribute to discomfort. By investigating corneal staining theory and the mechanisms that contribute to its presence, the reader will gain insight into this clinical finding, which relates to selection of contact lens solutions. The FDA standards for testing solutions and how this relates to contact lens keratitis will also be appraised in regards to current ISO recommendations. Finally, better selection of multipurpose contact lens solution (MPS) and hydrogen peroxide–based solutions for patients should be accessible to the clinician based on this review and preexisting clinical findings or diagnoses.

Methods:

A review of current published literature from peer reviewed journals and online journals was conducted to gain an understanding of contact lens solution's impact on contact lens discomfort.

Conclusions:

Many studies have been conducted comparing comfort between various types of contact lens solutions. It is challenging to decipher this information and apply it clinically when selecting solutions for patients. By comparing solution components, how contact lens solutions interact with different types of lenses, keratitis related to contact lenses, and preexisting ocular conditions, this review will improve a clinician's ability to eliminate CLD.
Imaging Investigation of Thyroid Eye Disease
Authors: Siakallis Loizos C. , Uddin Jimmy M. , Miszkiel Katherine A.
Published: June 2018

Introduction:

Thyroid eye disease (TED), is a term referring to the extrathyroidal manifestation of Grave's disease, a disorder which is currently the most common cause of hyperthyroidism and is characterised by underlying autoimmunity.

The pathogenic course of the disease can be broadly classified into two stages, an early inflammatory and a late fibrotic stage. These stages are reflected in clinical severity and activity classifications, such as Clinical Activity Score and Class 0: No signs or symptoms, 1: Only signs, no symptoms (e. g. lid retraction), 2: Soft tissue involvement, 3: Proptosis, 4: Extraocular muscle involvement, 5: Corneal involvement, 6: Sight loss (NOSPECS). Classifications based on the latter, have important implications in treatment decisions since patients in the early active stage of the disease are more likely to respond to anti-inflammatory and immunosuppressive therapies, whereas patients in the late fibrotic stage require different therapeutic approaches, including rehabilitative surgery.

Methods:

We reviewed cases of TED investigated with CT and Magnetic Resonance Imaging (MRI) in our department. We assessed the findings of imaging studies and their role in the clinical investigation of patients with TED as well as in the differential diagnosis from other disorders.

Results:

Imaging has a significant role in the investigation of TED, however a consensus on the use of different imaging modalities in the course of disease has yet to be reached. Nevertheless, imaging and specifically CT and MRI can have a vital role in the initial diagnosis of clinically atypical presentation of TED, in surgical planning, as well as in the differential diagnosis from other orbital disorders.

Conclusion:

In this review, we attempt to present current trends in imaging investigation of TED. Rather than focusing on the findings of each imaging modality separately, we present the two main imaging modalities focusing on CT and MRI, in the context of pathogenic stages of the disease.
Cultural influences on parental responses to children's pain
Authors: Kristjansdottir Olof , McGrath Patrick J. , Finley G. Allen , Kristjansdottir Gudrun , Siripul Pulsuk , Mackinnon Sean P. , Yoshida Yoko
Published: June 2018

There is a scarcity of work examining the relationship between culture and pain-related caregiver behaviors. Moreover, no pediatric pain studies have examined the relationship between caregiver cultural values and pain-related caregiver behaviors nor discern if this process is mediated by caregiver parenting styles and moderated by ecosocial context. Based on cross-cultural developmental theories, this study hypothesized that ecosocial context would moderate the relationship between cultural values, parenting styles, and pain-related caregiver behaviors; and that parenting styles mediate the effect of cultural values on pain-related caregiver behaviors. A cross-cultural survey design was employed using a convenience sample of 547 caregivers of 6 to 12 year olds living in Canada (n = 183), Iceland (n = 184), and Thailand (n = 180). Multigroup structural equation modeling showed that ecosocial context did not affect which cultural model of parenting the caregiver adopted. Parenting styles mediated the relationship between cultural values and pain-related caregiver behavior. Vertical/horizontal individualism, collectivism, and authoritative- and authoritarian-parenting styles positively predicted solicitousness. Vertical individualism and authoritarian-parenting style positively predicted discouraging behavior, whereas other predictors did not. The findings support the sociocommunication model of children's pain by showing that cultural context does affect parents' behaviors. They also corroborate with others' claims of solicitousness universality in a pediatric pain context. However, solicitousness may have different cultural meanings among individuals and may be used in conjunction with discouraging behavior. The findings from this study have implications for the theory development about culture and pediatric pain, but do not provide specific clinical recommendations.
Pain processing in the human brainstem and spinal cord before, during, and after the application of noxious heat stimuli
Authors: Stroman Patrick W. , Ioachim Gabriela , Powers Jocelyn M. , Staud Roland , Pukall Caroline
Published: June 2018

Descending regulation of spinal cord responses to nociceptive signaling has a strong influence on pain perception. Previous studies using functional magnetic resonance imaging (fMRI) have indicated that in addition to reactive responses to nociceptive signals, there is a continuous component to regulation, and that it may vary with differences in pain sensitivity. We hypothesize that this continuous regulation component occurs routinely in fMRI studies before noxious stimulation, as well as during, and after stimulation. This hypothesis was tested by analyzing data from 59 healthy participants in 4 previous fMRI studies in our laboratory using noxious heat stimuli. Analyses included structural equation modeling to identify coordinated blood oxygenation-level–dependent (BOLD) signal variations between regions (ie, connectivity) and Bayesian regression of BOLD time-series responses in relation to pain ratings and stimulus temperatures. The results demonstrate the periaqueductal gray–rostral ventromedial medulla–spinal cord descending modulation pathway, influenced by input from the hypothalamus, parabrachial nucleus, and nucleus tractus solitarius. Connectivity between specific regions is observed to vary in relation to pain sensitivity. The results support the conclusion that homeostatic autonomic control influences the net descending pain regulation, and therefore influences pain sensitivity. The results describe the overall properties of pain processing (specifically pain elicited by heat) in the healthy human brainstem and spinal cord, and mechanisms for variation across individuals. This understanding is expected to be important for studies of how pain processing is altered in chronic pain conditions.
Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances
Authors: Guilmette Julie M. , Nosé Vania
Published: June 2018

This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of “well-differentiated high-grade NET (G3)” to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.
Scavenger: A pipeline for recovery of unaligned reads utilising similarity with aligned reads
Authors: Yang Andrian , Tang Joshua Y. S. , Troup Michael , Ho Joshua W. K.
Published: June 2018

Motivation

Read alignment is an important step in RNA-seq analysis as the result of alignment forms the basis for further downstream analyses. However, recent studies have shown that published alignment tools have variable mapping sensitivity and do not necessarily align reads which should have been aligned, a problem we termed as the false-negative non-alignment problem.

Results

We have developed Scavenger, a pipeline for recovering unaligned reads using a novel mechanism which utilises information from aligned reads. Scavenger performs recovery of unaligned reads by re-aligning unaligned reads against a putative location derived from aligned reads with sequence similarity against unaligned reads. We show that Scavenger can successfully recover unaligned reads in both simulated and real RNA-seq datasets, including single-cell RNA-seq data. The reads recovered contain more genetic variants compared to previously aligned reads, indicating that divergence between personal and reference genomes plays a role in the false-negative non-alignment problem. We also explored the impact of read recovery on downstream analyses, in particular gene expression analysis, and showed that Scavenger is able to both recover genes which were previously non-expressed and also increase gene expression, with lowly expressed genes having the most impact from the addition of recovered reads. We also found that the majority of genes with >1 fold change in expression after recovery are categorised as pseudogenes, indicating that pseudogene expression can be affected by the false-negative non-alignment problem. Scavenger helps to solve the false-negative non-alignment problem through recovery of unaligned reads using information from previously aligned reads.

Availability

Scavenger is available via an open source license in https://github.com/VCCRI/Scavenger/

Contact

j.ho@victorchang.edu.au
A Data Structure for real-time Aggregation Queries of Big Brain Networks
Authors: Ganglberger Florian , Kaczanowska Joanna , Haubensak Wulf , Bühler Katja
Published: June 2018

Recent advances in neuro-imaging allowed big brain-initiatives and consortia to create vast resources of brain data that can be mined by researchers for their individual projects. Exploring the relationship between genes, brain circuitry, and behavior is one of key elements of neuroscience research. This requires fusion of spatial connectivity data at varying scales, such as whole brain correlated gene expression, structural and functional connectivity. With ever-increasing resolution, those exceed the past state-of-the art in several orders of magnitude in size and complexity. Current analytical workflows in neuroscience involve time-consuming manual aggregation of the data and only sparsely incorporate spatial context to operate continuously on multiple scales. Incorporating techniques for handling big connectivity data is therefore a necessity.

We propose a data structure to explore heterogeneous neurobiological connectivity data for integrated visual analytics workflows. Aggregation Queries, i.e. the aggregated connectivity from, to or between brain areas allow experts the comparison of multimodal networks residing at different scales, or levels of hierarchically organized anatomical atlases. Executed on-demand on volumetric gene expression and connectivity data, they enable an interactive dissection of networks, with billions of edges, in real-time, and based on their spatial context. The data structure is optimized to be accessed directly from the hard disk, since connectivity of large-scale networks typically exceed the memory size of current consumer level PCs. This allows experts to embed and explore their own experimental data in the framework of public data resources without large-scale infrastructure.

Our novel data structure outperforms state-of-the-art graph engines in retrieving connectivity of local brain areas experimentally. We demonstrate the application of our approach for neuroscience by analyzing fear-related functional neuroanatomy in mice. Further, we show its versatility by comparing multimodal brain networks linked to autism. Importantly, we achieve cross-species congruence in retrieving human psychiatric traits networks, which facilitates selection of neural substrates to be further studied in mouse models.
Transcriptome Analysis of Bael (Aegle marmelosL.) a Member of Family Rutaceae
Authors: Kaushik Prashant , Kumar Shashi
Published: June 2018

Aegle marmelosis a medicinally and horticulturally important tree member of the family Rutaceae. It is native to India where it is also known as Bael. Despite its importance; the genomic resources of this plant are scarce. This study presented the first-ever report of expressed transcripts in the leaves ofAegle marmelos. A total of 133,616 contigs were assembled to 46,335 unigenes with the minimum and maximum lengths of 201 and 14,853 bp. There were 7002 transcription factors and 94,479 simple sequence repeat (SSR) markers. TheA. marmelostranscripts were also annotated based on information from other members of Rutaceae; namelyCitrus clementineandCitrus sinensis. A total of 482 transcripts were annotated as cytochrome p450s (CYPs) and 314 transcripts were annotated as glucosyltransferases (GTs). In theA. marmelosleaves the monoterpenoid biosynthesis pathway was predominant. This study provides an important genomic resource along with useful information aboutA. marmelos.
White matter microstructural properties in bipolar disorder and its relationship to the spatial distribution of lithium in the brain
Authors: Necus Joe , Sinha Nishant , Smith Fiona Elizabeth , Thelwall Peter Edward , Flowers Carly Jay , Taylor Peter Neal , Blamire Andrew Matthew , Cousins David Andrew , Wang Yujiang
Published: June 2018

Background

Lithium treatment is associated with an increase in magnetic resonance imaging derived measures of white matter integrity, but the relationship between the spatial distribution of brain lithium and white matter integrity is unknown.

Methods

Euthymic patients with bipolar disorder receiving lithium treatment (n=12) and those on other medications but naïve to lithium (n=17) underwent diffusion imaging alongside matched healthy controls (n=16). Generalised fractional anisotropy (gFA) within white matter was compared between groups using a standard space white matter atlas. Lithium-treated patients also underwent novel multinuclear 3D lithium magnetic resonance imaging (7Li-MRI) to determine relative lithium concentration across the brain. The relationship between 7Li-MRI signal intensity and gFA was investigated at the resolution of the 7Li-MRI sequence in native space.

Results

The lithium-treated bipolar disorder and healthy control groups had higher mean gFA in white matter than the bipolar disorder group treated with other medications but naïve to lithium (t = 2.5, p < 0.05; t = 2.7, p < 0.03, respectively). No differences in gFA were found between patients taking lithium and healthy controls (t = 0.02, p = 1). These effects were seen consistently across most regions in the white matter atlas. In the lithium-treated group, a significant effect of the 7Li-MRI signal in predicting the gFA (p < 0.01) was identified in voxels containing over 50% white matter.

Conclusions

Lithium treatment of bipolar disorder is associated with higher gFA throughout brain white matter, and the spatial distribution of lithium is also positively associated with white matter gFA.
Populational Super-Resolution Sparse M/EEG Sources and Connectivity Estimation
Authors: Gonzalez-Moreira E. , Paz-Linares D. , Martinez-Montes E. , Valdes-Hernandez P. , Bosch-Bayard Jorge , Bringas-Vega M.L. , Valdés-Sosa P.
Published: June 2018

In this paper, we describe a novel methodology, BC-VARETA, for estimating the Inverse Solution (sources activity) and its Precision Matrix (connectivity parameters) in the frequency domain representation of Stationary Time Series. The aims of this method are three. First: Joint estimation of Source Activity and Connectivity as a frequency domain linear dynamical system identification approach. Second: Achieve super high resolution in the connectivity estimation through Sparse Hermitian Sources Graphical Model. Third: To be a populational approach, preventing the Inverse Solution and Connectivity statistical analysis across subjects as a postprocessing, by modeling population features of Source Activity and Connectivity. Our claims are supported by a wide simulation framework using realistic head models, realistic Sources Setup, and Inverse Crime effects evaluation. Also, a fair quantitative analysis is performed, based on a diversification of quality measures on which state of the art Inverse Solvers were tested.
Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila
Authors: Munden Alexander , Rong Zhan , Gangula Rama , Mallal Simon , Nordman Jared T.
Published: June 2018

Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified a physical interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in an SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.
Aberrant Information Transfer Interferes with Functional Axon Regeneration
Authors: Ding Chen , Hammarlund Marc
Published: June 2018

Functional axon regeneration requires regenerating neurons to restore appropriate synaptic connectivity and circuit function. To model this process, we developed a single-neuron assay inC. elegansthat links axon regeneration and synapse reformation with recovery of relevant behavior. After axon injury to the DA9 neuron, regeneration restores synapses to their pre-injury location. Surprisingly, presynapses also accumulate in the dendrite. Both axonal and dendritic synapses are functional. Dendritic synapses result in information misrouting that suppresses behavioral recovery. Formation of dendritic synapses is specifically dependent on dynein-mediated transport andjnk-1. However, even when information transfer is corrected, axonal synapses fail to adequately transmit information. Our study reveals unexpected plasticity during functional regeneration. Regeneration of the axon is not sufficient for the reformation of correct neuronal circuits after injury. Rather, synapse reformation and function are also key variables, and manipulation of circuit reformation improves behavioral recovery.
Human primitive brain displays negative mitochondrial-nuclear expression correlation of respiratory genes
Authors: Barshad Gilad , Blumberg Amit , Cohen Tal , Mishmar Dan
Published: June 2018

Oxidative phosphorylation (OXPHOS), a fundamental energy source in all human tissues, requires interactions between mitochondrial (mtDNA)- and nuclear (nDNA)-encoded protein subunits. Although such interactions are fundamental to OXPHOS, bi-genomic coregulation is poorly understood. To address this question, we analyzed ∼8500 RNA-seq experiments from 48 human body sites. Despite well-known variation in mitochondrial activity, quantity, and morphology, we found overall positive mtDNA-nDNA OXPHOS genes’ co-expression across human tissues. Nevertheless, negative mtDNA-nDNA gene expression correlation was identified in the hypothalamus, basal ganglia, and amygdala (subcortical brain regions, collectively termed the “primitive” brain). Single-cell RNA-seq analysis of mouse and human brains revealed that this phenomenon is evolutionarily conserved, and both are influenced by brain cell types (involving excitatory/inhibitory neurons and nonneuronal cells) and by their spatial brain location. As the “primitive” brain is highly oxidative, we hypothesized that such negative mtDNA-nDNA co-expression likely controls for the high mtDNA transcript levels, which enforce tight OXPHOS regulation, rather than rewiring toward glycolysis. Accordingly, we found “primitive” brain-specific up-regulation of lactate dehydrogenase B (LDHB), which associates with high OXPHOS activity, at the expense of LDHA, which promotes glycolysis. Analyses of co-expression, DNase-seq, and ChIP-seq experiments revealed candidate RNA-binding proteins and CEBPB as the best regulatory candidates to explain these phenomena. Finally, cross-tissue expression analysis unearthed tissue-dependent splice variants and OXPHOS subunit paralogs and allowed revising the list of canonical OXPHOS transcripts. Taken together, our analysis provides a comprehensive view of mito-nuclear gene co-expression across human tissues and provides overall insights into the bi-genomic regulation of mitochondrial activities.
Long-read sequencing of nascent RNA reveals coupling among RNA processing events
Authors: Herzel Lydia , Straube Korinna , Neugebauer Karla M.
Published: June 2018

Pre-mRNA splicing is accomplished by the spliceosome, a megadalton complex that assembles de novo on each intron. Because spliceosome assembly and catalysis occur cotranscriptionally, we hypothesized that introns are removed in the order of their transcription in genomes dominated by constitutive splicing. Remarkably little is known about splicing order and the regulatory potential of nascent transcript remodeling by splicing, due to the limitations of existing methods that focus on analysis of mature splicing products (mRNAs) rather than substrates and intermediates. Here, we overcome this obstacle through long-read RNA sequencing of nascent, multi-intron transcripts in the fission yeast Schizosaccharomyces pombe. Most multi-intron transcripts were fully spliced, consistent with rapid cotranscriptional splicing. However, an unexpectedly high proportion of transcripts were either fully spliced or fully unspliced, suggesting that splicing of any given intron is dependent on the splicing status of other introns in the transcript. Supporting this, mild inhibition of splicing by a temperature-sensitive mutation in prp2, the homolog of vertebrate U2AF65, increased the frequency of fully unspliced transcripts. Importantly, fully unspliced transcripts displayed transcriptional read-through at the polyA site and were degraded cotranscriptionally by the nuclear exosome. Finally, we show that cellular mRNA levels were reduced in genes with a high number of unspliced nascent transcripts during caffeine treatment, showing regulatory significance of cotranscriptional splicing. Therefore, overall splicing of individual nascent transcripts, 3′ end formation, and mRNA half-life depend on the splicing status of neighboring introns, suggesting crosstalk among spliceosomes and the polyA cleavage machinery during transcription elongation.
Corruption control and prevention in the Korean government
Authors: Choi Jin-Wook
Published: June 2018

Purpose

The purpose of this paper is to examine how corruption has changed over time in South Korea and to explore how the corruption control and prevention efforts of the Korean government have been successful and failed.

Design/methodology/approach

This paper draws on institutional theory to formulate a qualitative analysis to assess the effectiveness of anti-corruption policies and measures, and to identify the strengths and weaknesses of anti-corruption reform efforts in South Korea.

Findings

This paper argues that while the Korean government has been quite successful in building anti-corruption institutions to control low-level petty corruption, it has failed to institutionalize anti-corruption institutions to curb high-level grand corruption.

Originality/value

While many studies have attempted to identify the successful factors of fighting corruption, this paper draws a theoretical distinction between institution-building vs institutionalization to examine the success and failure of corruption control and prevention efforts in South Korea.