High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction

Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.

Investigational agents that protect pancreatic islet β-cells from failure

Type 2 diabetes is associated with insulin resistance and reduced insulin secretion, which results in hyperglycaemia. This can then lead to diabetic complications such as retinopathy, neuropathy, nephropathy and cardiovascular disease. Although insulin resistance may be present earlier in the progression of the disease, it is now generally accepted that it is the deterioration in insulin-secretory function that leads to hyperglycaemia. This reduction in insulin secretion in Type 2 diabetes is due to both islet β-cell dysfunction and death. Therefore, interventions that maintain the normal function and protect the pancreatic islet β-cells from death are crucial in the treatment of Type 2 diabetes so that plasma glucose levels may be maintained within the normal range. Recently, a number of compounds have been shown to protect β-cells from failure. This review examines the evidence that the existing therapies for Type 2 diabetes that were developed to lower plasma glucose (metformin) or improve insulin sensitivity (thiazolidinediones) may also have islet-protective function. Newer emerging therapeutic agents that are designed to increase the levels of glucagon-like peptide-1 not only stimulate insulin secretion but also appear to increase islet β-cell mass. Evidence will also be presented that the future of drug therapy designed to prevent β-cell failure should target the formation of advanced glycation end products and alleviate oxidative and endoplasmic reticulum stress.

Nutritional psychiatry research: an emerging discipline and its intersection with global urbanization, environmental challenges and the evolutionary mismatch

In 21st-century public health, rapid urbanization and mental health disorders are a growing global concern. The relationship between diet, brain function and the risk of mental disorders has been the subject of intense research in recent years. In this review, we examine some of the potential socioeconomic and environmental challenges detracting from the traditional dietary patterns that might otherwise support positive mental health. In the context of urban expansion, climate change, cultural and technological changes and the global industrialization and ultraprocessing of food, findings related to nutrition and mental health are connected to some of the most pressing issues of our time. The research is also of relevance to matters of biophysiological anthropology. We explore some aspects of a potential evolutionary mismatch between our ancestral past (Paleolithic, Neolithic) and the contemporary nutritional environment. Changes related to dietary acid load, advanced glycation end products and microbiota (via dietary choices and cooking practices) may be of relevance to depression, anxiety and other mental disorders. In particular, the results of emerging studies demonstrate the importance of prenatal and early childhood dietary practices within the developmental origins of health and disease concept. There is still much work to be done before these population studies and their mirrored advances in bench research can provide translation to clinical medicine and public health policy. However, the clear message is that in the midst of a looming global epidemic, we ignore nutrition at our peril.

Brain targeted PLGA nanocarriers alleviating amyloid-Β expression and preserving basal survivin in degenerating mice model

The chronic systemic administration of d-Galactose in C57BL/6J mice showed a relatively high oxidative stress, amyloid-β expression and neuronal cell death. Enhanced expression of pyknotic nuclei, caspase-3 and reduced expression of neuronal integrity markers further confirmed the aforesaid insults. However, concomitant treatment with the recombinant protein (SurR9-C84A) and the anti-transferrin receptor antibody conjugated SurR9-C84A (SurR9+TFN) nanocarriers showed a significant improvement in the disease status and neuronal health. The beauty of this study is that the biodegradable Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA) nanocarriers enhanced the biological half-life and the efficacy of the treatments. The nanocarriers were effective in lowering the amyloid-β expression, enhancing the neuronal integrity markers and maintaining the basal levels of endogenous survivin that is essential for evading the caspase activation and apoptosis. The current study herein reports for the first time that the brain targeted SurR9-C84A nanocarriers alleviated the d-Galactose induced neuronal insults and has potential for future brain targeted nanomedicine application.

Over-winter lipid depletion and mortality of age-0 rainbow trout (Oncorhynchus mykiss)

In this study we identify the size-dependent risk of winter starvation mortality as a strong selective pressure on age-0 rainbow trout (Oncorhynchus mykiss) that could promote the risk-taking behaviour and allocation of energy to lipids previously observed in young trout cohorts. Age-0 trout subjected to simulated winter starvation conditions gradually depleted lipid reserves to a critical minimum lipid content below which death occurred. Small fish with lower lipid content exhausted lipid reserves earlier, and experienced high mortality rates sooner, than larger fish with greater lipid content. Consequently, winter starvation endurance was dependent upon size-dependent lipid reserves and winter duration. To validate the laboratory findings in the field, we stocked several size classes of hatchery-raised trout with known lipid content at the start of winter into two experimental lakes, and estimated survival and lipid depletion at winter's end. Larger age-0 trout had greater initial lipid reserves than smaller trout. Individuals depleted most of their lipid reserves over the winter, and experienced mortality that ranged from just under 60% for the largest individuals to just over 90% of the smallest individuals. Many survivors had lipid contents near, but none were below, the minimum lipid content determined in the laboratory.

Eri silk fibre attributes and sliver preparation

Eri silk produced by Philosamia cynthia ricini silkworm is a fibre not well-known to the silk industry, in spite of the fact that Eri silk is finer, softer, and has better mechanical and thermal properties than most animal fibres. Eri silk has a high commercial potential, as the host plants of Eri silk worms are widespread in diverse geographical locations, and the worms also have a higher degree of disease resistance than most other silk worms. Mills are often not aware of the properties of Eri for designing appropriate end products. Thus, Eri silk yarn is traditionally produced by hand spinning, and Eri silk usually ends up as material for handwoven shawls. The potential for bulk fibre processing and the development of soft luxurious novel Eri silk products is yet to be discovered. To better understand the material and its processing behaviour, Eri silk was characterised and cocoons were processed into tops through degumming, opening, and cutting filaments into different lengths, followed by a worsted spun silk processing route. Fibre properties such as fineness, crimp, strength and length at different processing stages up to combed tops were measured. The results indicate that staple Eri silk can be processed via the worsted topmaking route, using a cut length of 200 mm or 150 mm for filament sheets prepared from degummed cocoons.

Transmission electron microscopy investigation of substitution reactions from carbon nanotube template to silicon carbide nanowires

Substitution reactions between multiwalled carbon nanotubes and silicon monoxide vapour have been investigated using transmission electron microscopy. Different reactions occurred inside the multiwalled nanotubes and on the nanotube external surfaces, resulting in the formation of silicon carbide nanowires with a core–shell structure. The substitution reaction process and end products are strongly affected by nanotube structures and a ball milling treatment of the starting materials.

A quantitative approach to analysing reliability of engagement responses to dance

Perhaps one of the most important end products of a dance work is how it  effects its observers (typically its audience, but also the dancers and choreographers). Of the many ways of discussing and analysing dance, one
approach in its infancy is quantification. Our research involves combining continuous response techniques and human response methods to see if we can tease out relationships between continuous, quantitative evaluative responses and the more qualitative choreographer intentions. The aim of this paper is to describe how evaluative responses can be quantified at all, then how they can be related to an unfolding dance work, and finally, how we can isolate ‘meaningful’ or ‘significant’ or ‘reliable’ evaluations of a dance work from those which are no more than a spurious set of not-very-useful numbers presented under the guise of a valid assessment.

Steroidogenesis in cultured mammalian glial cells

A protocol for culturing mammalian type 1 astrocytic cells, using female post-natal rat cerebral cortical tissue, was established and refined for use in steroidogenic metabolic studies incorporating progestin radioisotopes. Cultures were characterised for homogeneity using standard morphological and immunostaining techniques. Qualitative and quantitative studies were conducted to characterise the progesterone (P) metabolic pathways present in astrocytes in vitro. Of particular interest was the formation of the P metabolite, 5á-pregnan-3á-ol-20-one (THP). THP is a GABA(A) receptor agonist, believed to play a vital role in neural functioning and CNS homeostasis. One aim of this study was to observe any modulatory effects selected neuroactive ligands have on the conversion of P into THP, in an attempt to link astrocytic steroidogenesis with neuronal control. In qualitative studies, chromatographic procedures were used to establish the progestin profile of cerebral cortical astrocytes. Tritiated P, DHP (5á-pregnan-3,20-dione) and THP incurbates were preliminary fractionated by either normal phase (NP) or reverse phase (RP) high performance liquid chromatography (HPLC). The radiometabolites associated with each fraction were further chromatographed, before and/or after chemical derivatistation, by the aforemention HPLC procedures and thin layer chromatography (TLC). Steroid radiometabolites were tentatively identified by comparing their chromatographic mobility with authentic steroids. The identity of the main putative 5á-reduced P metabolities, DHP, THP and 5á-pregnan-3á,20á-diol (20áOH-THP) were further confirmed by isotopic dilution analysis. Their conclusive identification, along with the tentative identification of 20á-hydroxypreg-4-en-3-one (20áOH-P) and 20á-hydroxy-5á-pregnan-3-one (20áOH-DHP), verify the localisation of 5á-reductase, 3á-hydroxy steroif oxidoreductase (HSOR), and 20á-HSOR activity in the cultured astrocytes utilised in this study programme. Other minor metabolites detected were tentatively identified, including 5á-pregnan-3á,21-diol-20-one (THDoc), indicating the presence of 21-hydroxylase enzymatic activity. THDoc, like THP, is a GABA(A) receptor agonist. The chemical and physical characterisation of several yet unidentified progestin metabolites, associated with a highly polar RP HPLC fraction (designated RP peak 1*), indicate the presence of one or more extra hydroxylase enzymes. Quantitative analysis included a preliminary study. In this study, the percentage yields of radiometabolites formed in cultures incubated with increasing substrate concentrations of (3)H-P for 24 hours were determined. At the lower concentrations examined (ie 0.5 to 50nM), the metabolites associated with the polar RP HPLC fraction (RP peak 1*) collectively have the highest percentage yield. They are subsequently considered metabolic end products of degradative catabolic P pathways. The percentage yield of THP peaks in the medium concentration ranges (ie 5 to 500nM), whereas DHP remains fairly static at a low level with increasing concentration. Both DHP and THP are considered metabolic pathway intermediates. The percentage yield of 20áOH-THP continues to increase with increasing concentration over 5nM, superseding THP approaching the highest concentration examined (5000nM). This indicated the formation of 20áOH-THP does not occur entirely via THP. 20áOH-THP also possibly serves as the direct intermediate in the formation of the main radiometabolites associated with RP peak 1*. A time/yield study incorporating incubation times from one to 24 hours was also conducted. The full array of radiometabolites (individually or in groups) formed in astrocyte cultures incubated with 50nM tritiated P, DHP of THP, were assayed. Cultures were observed to rapidly convert any DHP into THP, showing astrocytic 3á-HSOR activity is very high. The study also showed 5á-reduction (ie the conversation of P into DHP) is the rate limiting reaction in the two step conversion of P into THP. 5á-Reduction also appears to be a rate limiting step in the formation of 20á-hydroxylated metabolites in astrocytes. Cultures incubated with the tritiated 5á-reduced pregnanes from one to four hours form greater quantities to 20á-hydroxylated radiometabolites compared to cultures incubated with (3)H-P. The time yield/studies also provided further evidence the unidentified polar radiometabolites associated with RP peak 1* are metabolic end products. For the P and DHP incubates, the collective formation of the aforementioned polar radiometabolites initially lags behind the formation of THP. As the formation of the latter begins to plateau with increasing time between four to 24 hours, the net yield of radiometabolites associated with RP peak 1* continues to rise. The time/yield studies also indicate 5á-reduction and perhaps 3á-hydroxylation are pre-requisite steps in the formation of the polar metabolites. Cultures incubated with the 5á-reduced progestins from one to four hours form higher yields of the radiometabolites associated with RP peak 1* compared to cultures incubated with P as substrate. The net yields of the radiometabolites associated with RP peak 1* for cultures incubated with THP were substantially higher compared to cultures incubated with DHP after equivalent times. The effect selected neuroligands have on the yield of radiometabolites formed by cultured astrocytes incubated with 50nM (3)H-P was also examined. Dibutyryl cyclic adenosine monophosphate (DBcAMP), not actually a neuroligand per se, but an analog of the intracellular secondary messenger cAMP, was also utilised in these studies. The inhibitory neurotransmitter ă-amino-nbutyric acid (GABA), DBcAMP and isoproterenol (a â-adrenergic receptor agonist) all quickly induce a transient but substantial increase in 20á-HSOR activity in cultured astrocytes. Cultures pretreated with these three compounds (10, 20 and 1µM respectively) form substantially higher yields of 20á-hydroxylated metabolites, including 20áOH-THP (between 200 to 580% greater), when incubated with 50nM (3)H-P for one to four hours. These increases also coincide with increases in the net yield of metabolites formed (by 16 to 48%). The same pre-treated cultures form significantly lower yields of THP, by 25 to 41%, after one hour. This is most likely due to the increased metabolism of any formed THP into 20áOH-THP. Octopamine (an á-adrenergic agonist) only induces a slight increase in 20á-HSOR activity, having relatively little effect on the yield of 20áOH-THP formed. Pretreatment with octopamine induces a significant increase in the yield of THP for cultures incubated with (3)H-P for four hours (by 24%). The increase in THP formation appears to be due to an increase in 3á-HSOR activity, as judged by the concomitant drop in the yield of the 5á-reduced, 3-keto substrates. An increase in 5á-reductase activity cannot be excluded however. Isoproterenol appears to induce an increase in 5á-reductase activity as isoproterenol appears to induce an increase in 5á-reductase activity as isoproterenol one and four hour incubates have higher yields of DHP. This is in contrast to the other three incubates. After 12 hours, all incubates have higher yields of THP (15-30%).

Randomized controlled study of the urinary excretion of biophenols following acute and chronic intake of olive leaf supplements

Olive leaf supplement was characterised by HPLC and administered to healthy young adults over 28 d (three tablets or equivalent liquid dose per day), or in a single bolus dose of three tablets (or liquid equivalent). Oleuropein was the major biophenol in the extracts. There are no data on the excretion of urinary end-products of the metabolism of the olive leaf biophenols. Following both chronic and acute ingestion neither oleuropein, nor its hydrolysis product, hydroxytyrosol, were detected in urine samples. However, glucuronic acid conjugates, derived from oleuropein aglycone were detected in all urine samples up to 6 h following acute ingestion. The data suggest that oleuropein is bioavailable, which is a necessary pre-condition for bioactivity.

Life and living in advanced age: a cohort study in New Zealand - Te Puāwaitanga o Nga Tapuwae Kia Ora Tonu, LiLACS NZ: Study protocol

The number of people of advanced age (85 years and older) is increasing and health systems may be challenged by increasing health-related needs. Recent overseas evidence suggests relatively high levels of wellbeing in this group, however little is known about people of advanced age, particularly the indigenous Māori, in Aotearoa, New Zealand. This paper outlines the methods of the study Life and Living in Advanced Age: A Cohort Study in New Zealand. The study aimed to establish predictors of successful advanced ageing and understand the relative importance of health, frailty, cultural, social & economic factors to successful ageing for Māori and non-Māori in New Zealand.

The development of ultrafine-grained hot rolling products using advanced thermomechanical processing

The aim of the work is development of industry guidance concerning production of ultrafine-grained (UFG) High Strength Low Alloy (HSLA) steels using strain-induced dynamic phase transformations during advanced thermomechanical processing. In the first part of the work, the effect of processing parameters on the grain refinement was studied. Based on the obtained results, a multiscale computer model was developed in the second part of the work that was subsequently used to predict the mechanical response of studied structures. As an overall outcome, a process window was established for the production of UFG steels that can be adopted in existing hot rolling mills. © 2014 Elsevier B.V.

Symptoms and distress in children with advanced cancer: prospective patient-reported outcomes from the PediQUEST Study

PURPOSE: Thousands of children are living with advanced cancer; yet patient-reported outcomes (PROs) have rarely been used to describe their experiences. We aimed to describe symptom distress in 104 children age 2 years or older with advanced cancer enrolled onto the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) Study (multisite clinical trial evaluating an electronic PRO system).

METHODS: Symptom data were collected using age- and respondent-adapted versions of the PediQUEST Memorial Symptom Assessment Scale (PQ-MSAS) at most once per week. Clinical and treatment data were obtained from medical records. Individual symptom scores were dichotomized into high/low distress. Determinants of PQ-MSAS scores were explored using linear mixed-effects models.

RESULTS: During 9 months of follow-up, PQ-MSAS was administered 920 times: 459 times in teens (99% self-report), 249 times in children ages 7 to 12 years (96% child/parent report), and 212 times in those ages 2 to 6 years (parent reports). Common symptoms included pain (48%), fatigue (46%), drowsiness (39%), and irritability (37%); most scores indicated high distress. Among the 73 PQ-MSAS surveys administered in the last 12 weeks of life, pain was highly prevalent (62%; 58% with high distress). Being female, having a brain tumor, experiencing recent disease progression, and receiving moderate- or high-intensity cancer-directed therapy in the prior 10 days were associated with worse PQ-MSAS scores. In the final 12 weeks of life, receiving mild cancer-directed therapy was associated with improved psychological PQ-MSAS scores.

CONCLUSION: Children with advanced cancer experience high symptom distress. Strategies to promote intensive symptom management are indicated, especially with disease progression or administration of intensive treatments.