Book Reviews

Book Reviews: the Water of Life, a Jungian Journey Through Hawaiian Myth by Rita Knipe; Before the Horror: the Population of Hawai'i on the Eve of Western Contact by David E. Stannard; Observations and Interpretation of Hawaiian Volcanism and Seismicity 1779-1955. An Annotated Bibliography and Subject Index by Thomas L. Wright and Taeko Jane Takahashi; An Account of Two Voyages to the South Seas, to Australia, New Zealand, Oceania 1826-1829 in the Corvette Astrolabe; and to the Straits of Magellan, Chile, Oceania, Southeast Asia, Australia, Antarctica, New Zealand, and the Torres Strait 1837-1840 in the Corvettes Astrolabe and Zelee. by Jules S. C. Dumont d'Urville, Translated and edited by Helen Rosenman; Paths of Duty: American Missionary Wives in Nineteenth-Century Hawaii by Patricia Grimshaw; Journal of Stephen Reynolds Edited by Pauline King; Moramona: the Mormons in Hawaii by R. Lanier Britsch; the Peopling of Hawai'i by Eleanor C. Nordyk

Optimising outcomes of exercise and corticosteroid injection in patients with subacromial pain (impingement) syndrome: a factorial randomised trial

Objectives: To compare the clinical effectiveness of (1) physiotherapist-led exercise versus an exercise leaflet, and (2) ultrasound-guided subacromial corticosteroid injection versus unguided injection for pain and function in subacromial pain (formerly impingement) syndrome (SAPS).Methods: This was a single-blind 2×2 factorial randomised trial. Adults with SAPS were randomised equally to one of four treatment groups: (1) ultrasound-guided corticosteroid injection and physiotherapist-led exercise, (2) ultrasound-guided corticosteroid injection and an exercise leaflet, (3) unguided corticosteroid injection and physiotherapist-led exercise and (4) unguided corticosteroid injection and an exercise leaflet. The primary outcome was the Shoulder Pain and Disability Index (SPADI), collected at 6 weeks, 6 and 12 months and compared at 6 weeks for the injection interventions and 6 months for the exercise interventions by intention to treat.Results: We recruited 256 participants (64 treatment per group). Response rates for the primary outcome were 94% at 6 weeks, 88% at 6 months and 80% at 12 months. Greater improvement in total SPADI score was seen with physiotherapist-led exercise than with the exercise leaflet at 6 months (adjusted mean difference -8.23; 95% CI -14.14 to -2.32). There were no significant differences between the injection groups at 6 weeks (-2.04; -7.29 to 3.22), 6 months (-2.36; -8.16 to 3.44) or 12 months (1.59; -5.54 to 8.72).Conclusions: In patients with SAPS, physiotherapist-led exercise leads to greater improvements in pain and function than an exercise leaflet. Ultrasound guidance confers no additional benefit over unguided corticosteroid injection

The fluorescent protein iLOV as a reporter for screening of high-yield production of antimicrobial peptides in Pichia pastoris

The methylotrophic yeast Pichia pastoris is commonly used for the production of recombinant proteins at scale. The identification of an optimally overexpressing strain following transformation can be time and reagent consuming. Fluorescent reporters like GFP have been used to assist identification of superior producers, but their relatively big size, maturation requirements and narrow temperature range restrict their applications. Here, we introduce the use of iLOV, a flavin-based fluorescent protein, as a fluorescent marker to identify P. pastoris high-yielding strains easily and rapidly. The use of this fluorescent protein as a fusion partner is exemplified by the production of the antimicrobial peptide NI01, a difficult target to overexpress in its native form. iLOV fluorescence correlated well with protein expression level and copy number of the chromosomally integrated gene. An easy and simple medium-throughput plate-based screen directly following transformation is demonstrated for low complexity screening, while a high-throughput method using fluorescence-activated cell sorting (FACS) allowed for comprehensive library screening. Both codon optimization of the iLOV_NI01 fusion cassettes and different integration strategies into the P. pastoris genome were tested to produce and isolate a high-yielding strain. Checking the genetic stability, process reproducibility and following the purification of the active native peptide are eased by visualization of and efficient cleavage from the iLOV reporter. We show that this system can be used for expression and screening of several different antimicrobial peptides recombinantly produced in P. pastoris

Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Climate change and water in the UK: past changes and future prospects

Climate change is expected to modify rainfall, temperature and catchment hydrological responses across the world, and adapting to these water-related changes is a pressing challenge. This paper reviews the impact of anthropogenic climate change on water in the UK and looks at projections of future change. The natural variability of the UK climate makes change hard to detect; only historical increases in air temperature can be attributed to anthropogenic climate forcing, but over the last 50 years more winter rainfall has been falling in intense events. Future changes in rainfall and evapotranspiration could lead to changed flow regimes and impacts on water quality, aquatic ecosystems and water availability. Summer flows may decrease on average, but floods may become larger and more frequent. River and lake water quality may decline as a result of higher water temperatures, lower river flows and increased algal blooms in summer, and because of higher flows in the winter. In communicating this important work, researchers should pay particular attention to explaining confidence and uncertainty clearly. Much of the relevant research is either global or highly localized: decision-makers would benefit from more studies that address water and climate change at a spatial and temporal scale appropriate for the decisions they mak