APIs matter in software development, but determining how to use them can be challenging. Developers often refer to a small set of API usage examples, analysing the information there to understand and adapt them to their own context. Generalization over many examples may aid in understanding commonalities and differences, reducing information overload while including greater variety. We propose ASGard, a novel approach that generates API usage templates from examples. Approximating the formal problem of E -generalization, ASGard generalizes all syntactic and some semantic information within the examples to arrive at pseudocode representations that retain the commonality of the usage examples but abstract the varying aspects. We evaluate the templates from our approach and the patterns generated from PAM and MUDetect (two existing tools for API data mining), using a total of 1954 API usage examples across 59 different APIs. We measure the quality of the resulting templates: ASGard's templates have superior completeness and compression. We perform a user study on ASGard with 12 participants to compare the use of these templates in solving programming tasks, compared to MUDetect. We find that participants solved the programming tasks in significantly less time with ASGard. Participants expressed a general preference for using ASGard templates.

This chapter focuses on the advantages and limitations of nematodes as pharmacological models, neurotransmitter receptor systems and intracellular signaling cascades and Caenorhabditis elegans and drug discovery. The efficacy of some experimental approaches developed to understand the effects of drugs and chemicals that are used to treat parasitic nematode infections of animals and plants is also discussed.

Both cognitive function and cerebral blood flow (CBF) decline across the lifespan. However, the relation between them remains unclear, particularly in the context of aging. Furthermore, fitness improves both cognition and CBF, and may be associated with preserved cognitive and cerebrovascular function in an older population.PurposeThe aims of this study were to 1) clarify the effect of CBF on cognition across healthy adulthood, and the extent to which age‐related reductions are modulated by the usually‐observed impairment in cerebrovascular function, and 2) examine the association of aerobic fitness on baseline CBF and cognitive performance in healthy young and older adults.MethodUsing a placebo‐controlled, single‐blinded, randomized cross‐over design, we tested the hypothesis that an acute reduction in CBF (using indomethacin [1.2 mg/kg oral dose]) would impair cognition in both young (n = 13; 25 ± 4y) and older (n = 12; 58 ± 6y) adults. Cerebrovascular function was assessed using blood velocity in the middle cerebral artery (MCAv; Transcranial Doppler Ultrasound). Cerebrovascular CO2 reactivity (CVRCO2) was calculated as the change in MCAv for a given change in end‐tidal CO2 (mm Hg). Cognitive function was measured using visuomotor, inhibitory, and mental switching response time tasks. Aerobic fitness was predicted using a submaximal exercise test (i.e., V̇O2peak). Linear and rank‐based mixed models were used to assess the individual and interactive effects of cerebrovascular function and cognition, while accounting for age, sex, and aerobic fitness.ResultsOlder adults had 11% lower MCAv and 15% worse response time overall (all p ≤ 0.049), but not reliably lower CVRCO2 (p ≥ 0.16). Indomethacin decreased MCAv by 26 ± 11% and CVRCO2 by 69 ± 25% (all p < 0.01), regardless of age. The degree of indomethacin‐induced reductions in CVRCO2 was strongly associated with baseline CVRCO2 (r = 0.87, p < 0.01). Visuomotor response time was 6 ± 13% slower after indomethacin (p = 0.04), but this impairment was not linearly associated with decreases of MCAv (r = −0.26). Finally, aerobic fitness was not associated with baseline CBF in either group (r ≤ 0.14), and was only weakly associated with response time performance in young (r ≤ −0.34), but not older (r ≤ 0.21) adults.ConclusionThe impairments in cognitive function from indomethacin were not evidently associated with the 26% reduction in cerebral perfusion, even in older adults. Compared to young, older adults had worse cognitive performance and decreased CBF but did not have impaired cerebrovascular function. Aerobic fitness was only weakly associated with resting CBF and cognition in both young and older adults. Therefore, cognitive performance may not be influenced by a ≤26% reduction in CBF per se in healthy young and older adults.Support or Funding InformationFunding support from the School of Physical Education, Sport and Exercise Sciences, and Department of Medicine.

It is now more than fifty years since Burg made a signal advance in the study of renal physiology by reporting a method of isolating and perfusing tubules from selected regions of the kidney (1). Prior to this, knowledge of renal tubular function had been derived either from micropuncture experiments, limited to the superficial regions of the kidney (2) , from kidney slices (3-6), which were subject to injury and represented an aggregate of tubular function, or from renal cells in tissue culture (7-9).

Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population.

Change is inevitable for software systems to deal with the evolving environment surrounding them, and applying changes requires careful design and implementation not to break existing functionalities. Evolution in software product lines (SPLs) is more complex compared to evolution for individual products: a change applied to a single feature might affect all the products in the whole product family. In this paper we present an approach for change impact analysis in delta-oriented programming (DOP), an existing language aimed at supporting SPLs. We propose the CIAHelper tool to identify dependencies within a DOP program, by analyzing the semantics of both the code artifacts and variability models to construct a directed dependency graph. We also consider how the source code history could be used to enhance the recall of detecting the affected artifacts given a change proposal. We evaluate our approach by means of five case studies on two different DOP SPLs.

Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic male Cyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet, without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude (I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite being transgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependent hypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d), we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) in the diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ± 19 mm Hg after 3 mo, with no adverse phenotypic features observed. In conclusion, Cyp1a1-Ren2 rats are a useful animal model to investigate hypertension-induced end-organ damage and potential new therapeutic targets to manage hypertension.

Context: Pragmatic software reuse is a common activity in industry, involving the reuse of software artifacts not designed to anticipate that reuse. Objective: There are two key issues in such tasks that have not been previously explored. (1) Subtle bugs can be inserted due to mistakes on the part of a developer performing the pragmatic reuse. The reused code, integrated in the target system, should be (re-)validated there. But it is not clear what validation strategies would be employed by professional developers, and which of these strategies would be most effective to detect and to repair these inserted bugs. (2) Although semi-automated reuse of the associated test suite has been previously proposed as a strategy to detect such inserted bugs, it is unknown if the reused test suite would be maintainable in practice and how its maintenance characteristics would compare against alternative strategies. Method: We present two empirical studies with industrial developers to address these open issues. Results: We find that industrial developers use a few strategies including test suite reuse, but that test suite reuse is more reliably effective at discovering and repairing bugs inserted during pragmatic reuse. We also find that, in general, semi-automatically reused test suites are slightly more maintainable than manually reused test suites, in pragmatic reuse scenarios; specific situations can vary wildly however. Participants suggested specific extensions to tool support for semi-automated reuse of test suites. Conclusions: While various validation strategies are employed by industrial developers in the context of pragmatic reuse, none is as reliable and effective as test case reuse at discovering and repairing bugs inserted during pragmatic reuse. Despite the fact that semi-automatically reused test cases contain non-trivial adaptive code, their maintainability is equivalent to or exceeds that of manually reused test suites. The approach could be improved, however, by adopting the suggestions of our participants to increase usability.

ABSTRACTAimWhile the prevalence of end stage kidney disease in New Zealand (NZ) is well defined, the prevalence of chronic kidney disease (CKD) in NZ is unknown. To estimate the prevalence of and risk factors for CKD in the southern region of New Zealand.MethodsA retrospective electronic health record cohort study using data from the Southern Primary Care register covering 94% of the population. Patients, 20 years or older were identified and linked to laboratory results for serum creatinine and urinary albumin excretion. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2 (G3‐5) or the presence of albuminuria of greater than 3 mg/mmol (A2‐3). Diabetes was identified from a national virtual diabetes database. From this, we estimated the prevalence of CKD by age, gender, ethnicity, deprivation and the presence of diabetes mellitus.ResultsOf a total adult population of 211 980, 159 799 had a serum creatinine checked and 27 905 had an estimate of albuminuria. The estimated prevalence of CKD was 11.8%. 6.3% of total population had CKD stage G3a, 2.4% G3b, 0.8% G4, 0.2% G5, 1.8% A2 albuminuria and 0.3% A3 albuminuria. Increasing age, female sex, ethnic group, social deprivation and diabetes mellitus were associated with an increased risk of CKD. 11 351 patients had a diagnosis of diabetes mellitus and were almost universally tested (99.3%) for CKD. The presence of albuminuria was strongly correlated with ethnic group, male sex and living in a deprived area. The retrospective electronic health record study with associated selection and testing bias are potential limitations of the present study.ConclusionChronic kidney disease prevalence in this region appears to be similar to other reported populations. The majority of those at risk for CKD were tested for reduced eGFR. The presence of albuminuria, an integral component of CKD diagnostic criteria, was under utilized in the non‐diabetic population.

AimLong-term administration of lithium has been associated with the development of a chronic interstitial fibrosis in addition to nephrogenic diabetes insipidus (NDI). Earlier studies have demonstrated that amiloride, by blocking the epithelial sodium channel ENaC and thus preventing lithium uptake into the principal cells of the collecting ducts, can partially reverse lithium-induced NDI. However, there are no long-term studies examining whether or not amiloride also modifies the progressive chronic interstitial fibrosis and tubular atrophy often evident with long-term lithium exposure. MethodsUsing an established animal model of lithium-induced chronic interstitial fibrosis, rats were treated with amiloride and lithium for 5months following 1month of exposure to lithium alone and compared with control animals and those given only lithium. Results and ConclusionsIn this study, the 5months of amiloride therapy partially mitigated the lithium-induced NDI and limited the further progression of lithium-induced kidney fibrosis. This improvement was associated with decreased expression of the pro-fibrotic connective tissue growth factor (CTGF), along with reduced myofibroblast infiltration and decreased collagen deposition around the distended cortical collecting ducts. This may, in part, be mediated by modifying lithium-induced alterations in -catenin activity through its effects on GSK-3 beta.

Change is inevitable for software systems to deal with the evolving environment surrounding them, and applying changes requires careful design and implementation not to break existing functionalities. Evolution in software product lines (SPLs) is more complex compared to evolution for individual products: a change applied to a single feature might affect all the products in the whole product family. In this paper we present an approach for change impact analysis in delta-oriented programming (DOP), an existing language aimed at supporting SPLs. We propose the CIAHelper tool to identify dependencies within a DOP program, by analyzing the semantics of both the code artifacts and variability models to construct a directed dependency graph. We also consider how the source code history could be used to enhance the recall of detecting the affected artifacts given a change proposal. We evaluate our approach by means of five case studies on two different DOP SPLs.

We are told of the significant benefits of automated approaches to testing over manual approaches. However, it is unclear what automated testing practices exist, and how efficient or widespread such practices are within open source software. Although some organizations rigorously apply automated testing to their software, this rich pool of test code is not utilized to serve existing source code with poor or no test suites. To investigate how automated testing is performed in practice, we attempted a thorough, large-scale analysis of open source repositories. Alongside this analysis, we propose a novel approach to reuse such existing tests within projects that lack test code, hence leveraging the quality of such projects with minimal developer intervention. While such an analysis seems to be a straightforward task, we report on various practical challenges that hindered applying our proposed approach for tests' reuse. We present the challenges we have addressed so far, and those we expect to appear in the near future, in applying our approach for test reuse with open source projects. We outline potential solutions to the projected future challenges.

The focus of this article is to define goals and resulting action plans that can be collectively embraced by interested stakeholders to facilitate new therapeutic approaches to mitigate chronic kidney disease progression. The specific goals include identifying druggable targets, increasing the capacity for preclinical and early clinical development, broadening the availability of new therapeutic approaches, and increasing investment in the development of new therapies to limit chronic kidney disease. Key deliverables include the establishment of new regional, national, and global consortia; development of clinical trial networks; and creation of programs to support the temporary mutual movement of scientists between academia and the biotechnology and pharmaceutical sector. Other deliverables include cataloging and maintaining up-to-date records to collate progress in renal research and development, inventorying the capacity of research and clinical networks, and describing methods to ensure novel drug development. Copyright (C) 2017, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Oxalate nephropathy represents formation of tubular oxalate crystals with progressive renal dysfunction. A 66year old Caucasian male presented with a 3month history of malaise, nausea, lethargy and polyuria associated with steatorrhoea on a background of prior extensive alcohol intake. He had acute on chronic kidney disease with his plasma creatinine peaking at 568μmol/L. Urine examination and ultrasound imaging were unhelpful beyond dilatation of the pancreatic duct. A renal biopsy demonstrated birefringent tubular crystals with interstitial inflammatory infiltrate and interstitial fibrosis with background hypertensive change (Fig. 1). The appearances were consistent with oxalate nephropathy. Magnetic resonance cholangiopancreatography demonstrated fatty replacement of the pancreas, and exocrine pancreatic deficiency was confirmed (faecal elastase <15mg/g). An endoscopic retrograde cholangiopancreatogram was unsuccessful. Endoscopic ultrasound did not show an obstructing lesion. Pancreatic enzyme replacement, oral potassium citrate and low oxalate diet was commenced. Renal function stabilized with a creatinine of 320–350μmol/L (eGFR 18mL/min/1.73m) after 4months. Exocrine pancreatic insufficiency is failure of the pancreas to secrete an appropriate amount of digestive enzymes, presenting with steatorrhoea and weight loss. Impaired enzyme secretion causes maldigestion of fats with an increased intestinal fatty acid load, which binds calcium leaving oxalate uncomplexed. The increased solute gradient with resultant increased paracellular permeability (large intestine) causes passive hyperabsorption of oxalate and hyperoxalaemia with hyperoxaluria. Oxalate nephropathy can present as acute tubulointerstitial nephritis because of calcium oxalate tubular deposition, confirmed on biopsy with birefringent crystals under polarized light. The incidence of oxalate nephropathy is unknown. In a case series, 40% progressed to end-stage kidney disease within 2 years. Early therapeutic measures to replace pancreatic enzymes and alkalinize the urine may help delay or prevent the progression of the kidney injury. We report a rare case of rapidly progressive renal insufficiency as a result of biopsy confirmed oxalate nephropathy in the setting of pancreatic insufficiency due to chronic pancreatitis. Manipulation of the oxalate handling by the gut and measures to alter the solubility of oxalate crystals appear to have resulted in a degree of recovery/stabilization of kidney function in this case.

BACKGROUNDSubjects with hypertension are frequently obese or insulin resistant, both conditions in which hyperuricemia is common. Obese and insulin-resistant subjects are also known to have blood pressure that is more sensitive to changes in dietary sodium intake. Whether hyperuricemia is a resulting consequence, moderating or contributing factor to the development of hypertension has not been fully evaluated and very few studies have reported interactions between sodium intake and serum uric acid.METHODSWe performed further analysis of our randomized controlled clinical trials (Australian New Zealand Clinical Trials Registry #12609000161224 and #12609000292279) designed to assess the effects of modifying sodium intake on concentrations of serum markers, including uric acid. Uric acid and other variables (including blood pressure, renin, and aldosterone) were measured at baseline and 4 weeks following the commencement of low (60 mmol/day), moderate (150 mmol/day), and high (200-250 mmol/day) dietary sodium intake.RESULTSThe median aldosterone-to-renin ratio was 1.90 [pg/ml]/[pg/ml] (range 0.10-11.04). Serum uric acid fell significantly in both the moderate and high interventions compared to the low sodium intervention. This pattern of response occurred when all subjects were analyzed, and when normotensive or hypertensive subjects were analyzed alone.CONCLUSIONSAlthough previously reported in hypertensive subjects, these data provide evidence in normotensive subjects of an interaction between dietary sodium intake and serum uric acid. As this interaction is present in the absence of hypertension, it is possible it could play a role in hypertension development, and will need to be considered in future trials of dietary sodium intake.CLINICAL TRIALS REGISTRATIONThe trials were registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224 and ACTRN1260.

In order to change the current state of chronic kidney disease knowledge and therapeutics, a fundamental improvement in the understanding of genetic and environmental causes of chronic kidney disease is essential. This article first provides an overview of the existing knowledge gaps in our understanding of the genetic and environmental causes of chronic kidney disease, as well as their interactions. The second part of the article formulates goals that should be achieved in order to close these gaps, along with suggested timelines and stakeholders that are to be involved. A better understanding of genetic and environmental factors and their interactions that influence kidney function in healthy and diseased conditions can provide novel insights into renal physiology and pathophysiology and result in the identification of novel therapeutic or preventive targets to tackle the global public health care problem of chronic kidney disease.

Real product families need to evolve in ways that are not always anticipated by a pre-planned design. Any given approach for software product lines will likely lead to both positive and negative consequences during unanticipated software evolution. Unfortunately, we know little about the evolvability characteristics of SPL approaches that concern both modelling and implementation, limiting our ability to make rational and disciplined decisions about adoption. We conduct a case study into the unanticipated evolution of a software product family using two approaches: separate products versus a common codebase using delta-oriented programming (DOP). We compare the ease of change within the two versions through a set of quantitative measurements and qualitative observations. We find that both versions have strengths and weaknesses: complexity and incomplete support from DOP tools versus significant duplication and error-proneness in the separate products.

Abstract The microscopic free-living nematode worm Caenorhabditis elegans was the first metazoan to have its genome sequenced and for many decades has served as a genetically tractable model for the investigation of neural mechanisms of behavioral plasticity. Many of its behaviors involve the detection of its food, bacteria, which are ingested and transported to the intestine by a muscular pharynx. The structure of the pharynx and the circuitry of the pharyngeal nervous system that regulates pharyngeal activity have been described in some detail. This has provided a platform for understanding how this simple organism finely tunes its feeding behavior in response to the changing availability and quality of its food, and in the context of its own nutritional status. This resonates with fundamental principles of energy homeostasis that occur throughout the animal kingdom.

Objective: Hypertension (HTN) impairs the regulation of blood flow leading to cardiovascular morbidity and mortality. A “new player” in blood-flow regulation is the endothelium Epithelial Sodium Channel (vascular ENaC). We hypothesise that dysfunction in HTN is due to changes in vascular ENaC activity. Aldosterone regulates renal ENaC and has a pivotal role in HTN and recently it has been suggested that aldosterone antagonism (spironolactone therapy) is beneficial beyond that predicted by the reduction in blood pressure. We propose that these additional effects are due to re-establishment of normal vascular function through modulation of vascular ENaC activity. Design and method: An experimental model of HTN, compared to normotensive (NTN) controls, with/without spironolactone therapy (n = 3–5) was used. HTN was induced in adult male transgenic rats (TG strain: Cyp1a1-Ren2), via diet-driven (0.167% w/w indol-3-carbinol) activation of renin-angiotensin-aldosterone system. Spironolactone treatment was administered daily (orally, 8.8 mg/kg/day) starting 7 weeks following initiation of HTN. Flow-mediated changes in the internal diameter (% change from no-flow) of isolated 3rd order mesenteric arteries, in the presence/absence of 10 μM amiloride were measured to determine the role of ENaC. Flow was induced through the vessels, whilst mean intraluminal pressure was maintained at 60 mmHg. Results: Isolated NTN arteries demonstrated flow mediated-constriction (−9.9 ± 3.6%) under basal conditions which was reduced (−6.3 ± 3.1%) by amiloride. The basal response was absent in HTN (0.8 ± 1.0%) vessels, and unaffected by amiloride (0 ± 1.5%). Spironolactone treatment of NTN rats resulted in a slight augmentation (−11.8 ± 1.9 %) of flow-mediated constriction which was unaffected by amiloride (−11.6 ± 1.7%). Spironolactone treatment did not improve the lack of flow-mediated response of HTN vessels (0.5 ± 0.7%), and was unaffected by amiloride (−0.4 ± 1.3%). Conclusions: Vascular ENaC activity augments flow-mediated constriction of mesenteric arteries. The attenuation of flow-mediated responsiveness in experimental RAAS-driven HTN is linked, in part, to a reduction in vascular ENaC activity. Spironolactone augments flow-mediated responsiveness of NTN vessels, although this may not be through increased ENaC activity. Initiation of spironolactone treatment at a late stage of HTN doesn’t appear to modulate ENaC function or re-establish normal vascular function.

IntroductionLithium is the first‐choice medication for treatment of bipolar disorder, but causes Nephrogenic Diabetes Insipidus (Li‐NDI), a urinary concentrating defect. Li‐NDI is characterized by polyuria, polydipsia and metabolic acidosis, and is caused by downregulation of principal cell AQP2 and an increased intercalated/principal cell ratio of the collecting duct (remodeling). Recently, others and we showed that lithium induces principal cell proliferation in vitro and in vivo, which can be due to aerobic glycolysis (Warburg effect), a condition in which the cells switch from oxidative phosphorylation to glycolysis to produce cell building blocks and ATP. Collecting duct remodeling has been ascribed to metabolic acidosis due to inhibition of α‐intercalated cells H‐ATPase and H/K‐exchangers, but, as aerobic glycolysis goes with increased lactate excretion, this may also underlie remodeling. This was investigated here.MethodsPolarized mpkCCD cells were cultured in transwells and exposed to LiCl chloride on the apical (10 mM) and basolateral side (1 mM) to mimic clinical conditions in patients. C57BL6/J mice were fed a normal rodent diet or a diet with lithium chloride in a concentration of 40 mmol/kg of chow. Rats were treated similarly with/without amiloride for 4 weeks. 24‐hrs water intake and urine output/osmolality was obtained. Kidneys were analyzed for remodeling.ResultsLithium induced proliferation in mpkCCD cells (increased PCNA levels) coincided with increased excretion of lactate, increased abundance of lactate dehydrogenase, hexokinase‐2, and a decreased ratio of phospho‐pyruvate dehydrogenase pPDH/PDH. These aerobic glycolysis characteristics were also found in the kidney and urine of mice treated for 10 days with lithium. Li‐induced increase in urinary lactate, however, was absent in mice lacking the epithelial sodium channel ENaC, the principal cell entry pathway for lithium. Moreover, 4‐weeks treatment of rats with lithium revealed NDI, lactate excretion and collecting duct remodeling, which where all attenuated in the presence of amiloride. In mpkCCD cells, inhibition of lithium‐induced glycolysis using 2‐deoxyglucose slightly attenuated lithium‐induced downregulation of AQP2 abundance and cell surface expression. 2‐deoxyglucose also significantly reduced the lithium‐induced increase in lactate production in 10‐day treated mice, but did not reduce urine volume or increase urine osmolality.Conclusionwe show that the ENaC‐mediated lithium influx in principal cells induces aerobic glycolysis in mpkCCD cells, mice and rats and that inhibition of principal cell lithium entry attenuates the extent of aerobic glycolysis and collecting duct remodeling. Inhibition of aerobic glycolysis, however, did not attenuate Li‐NDI. Our data indicate that the lithium‐induced aerobic glycolysis of principal cells and the consequent acidification of the micro‐environment underlies collecting duct remodeling.