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Efficient readout of individual electronic spins associated with atomlike impurities in the solid state is essential for applications in quantum information processing and quantum metrology. We demonstrate a new method for efficient spin readout of nitrogen-vacancy (NV) centers in diamond. The method is based on conversion of the electronic spin state of the NV to a charge-state distribution, followed by single-shot readout of the charge state. Conversion is achieved through a spin-dependent photoionization process in diamond at room temperature. Using NVs in nanofabricated diamond beams, we demonstrate that the resulting spin readout noise is within a factor of 3 of the spin projection noise level. Applications of this technique for nanoscale magnetic sensing are discussed. [ABSTRACT FROM AUTHOR]

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute leukemias, in particular poor prognosis early T-cell precursor-like (ETP-) acute lymphoblastic leukemia (ALL). The primary effect of Lmo2 is to cause self-renewal of developing CD4−CD8− (double negative, DN) T cells in the thymus, leading to serially transplantable thymocytes that eventually give rise to leukemia. These self-renewing thymocytes are intrinsically radioresistant implying that they may be a source of leukemia relapse after therapy. The homeobox transcription factor, Hhex, is highly upregulated in Lmo2-transgenic thymocytes and can phenocopy Lmo2 in inducing thymocyte self-renewal, implying that Hhex may be a key component of the Lmo2-induced self-renewal program. To test this, we conditionally deleted Hhex in the thymi of Lmo2-transgenic mice. Surprisingly, this did not prevent accumulation of DN thymocytes, nor alter the rate of overt leukemia development. However, deletion of Hhex abolished the transplantation capacity of Lmo2-transgenic thymocytes and overcame their radioresistance. We found that Hhex regulates Kit expression in Lmo2-transgenic thymocytes and that abrogation of Kit signaling phenocopied loss of Hhex in abolishing the transplantation capacity and radioresistance of these cells. Thus, targeting the Kit signaling pathway may facilitate the eradication of leukemia-initiating cells in immature T-cell leukemias in which it is expressed. [ABSTRACT FROM AUTHOR]

Diabet. Med. 27, 157–161 (2010) Aims To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1α gene ( HNF1A). Methods We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. Results Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects ( P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. Conclusions We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile. [ABSTRACT FROM AUTHOR]

Background and aims Hepatocyte nuclear factor-1 alpha ( HNF1A) gene mutations are the commonest cause of monogenic diabetes, but patients are often misdiagnosed as having Type 1 diabetes and started on insulin treatment. Patients with HNF1A diabetes are particularly sensitive to the glucose-lowering effect of sulphonylureas, which are the pharmacological treatment of choice. We aimed to assess if patients do change from insulin to sulphonylurea treatment when HNF1A diabetes is confirmed and the impact of this treatment change on long-term glycaemic control. Methods We investigated the clinical course of 43 patients who were insulin treated from diagnosis for a median 4 years (range 1–14) before an HNF1A gene mutation was identified. Results Thirty-four patients (79%) stopped insulin following genetic testing and transferred to sulphonylureas. Twenty-four of them (71%) remained off insulin at a median 39 months (range 17–90) post-transfer. The 10 patients who recommenced insulin had a trend towards a longer duration of diabetes (18 vs. 7 years, P = 0.066) compared with those remaining on tablets. The median glycated haemoglobin (HbA1c) was good (6.9%; interquartile range 6.3–8.0%) in the patients who remained off insulin and 19/24 patients (79%) achieved HbA1c < 7.5% or improved their pre-genetic diagnosis HbA1c by > 1.0%. Transfer off insulin was not attempted in eight patients: one of these was planning pregnancy and two chose to remain on insulin. Conclusion In this observational study we found that a molecular genetic diagnosis of HNF1A diabetes does alter treatment in clinical practice, with 79% attempting transfer to sulphonylureas. Transfer to sulphonylureas was successful in the majority of patients without deterioration in glycaemic control. [ABSTRACT FROM AUTHOR]

The article focuses on challenge of diagnosing type 1 diabetes in older adults. Topics include the clinical feature that being strongly predictive of type 1 diabetes in older adults at diagnosis is rapid insulin requirement, the develop absolute insulin deficiency will be initially treated as having type 2 diabetes by their clinician, and the ineligible for the education and technology needed to effectively manage their glycaemia.

Aims A subset of patients who present as if they have Type 2 diabetes have positive pancreatic autoantibodies, and have been referred to as having latent autoimmune diabetes in adults (LADA). We assessed the prevalence and clinical characteristics of patients with glutamic acid decarboxylase antibodies (GADA) in a cohort clinically selected for Type 2 diabetes and determined the presence of diabetes and GADA in their first-degree relatives. Methods GADA were measured in 2059 subjects, not known to be related, and clinically selected as having Type 2 diabetes for genetic studies. Clinical characteristics were compared in GADA positive and GADA negative subjects. Diabetes and GAD antibody status were compared in 208 first-degree relatives of GADA positive and GADA negative probands. Results Of the subjects, 136 (7%) were GADA positive. Compared with the GADA negative subjects, they were slimmer ( P < 0.001), diagnosed at a younger age ( P = 0.011) and progressed to insulin faster ( P < 0.001). Thirty-three per cent of GADA positive subjects had a first-degree relative with diabetes compared with 42% of GADA negative subjects ( P = 0.034). The overall prevalence of GADA was similar in the first-degree relatives of GADA positive and GADA negative probands (4 v 5%), and 19 of 22 (86%) diabetic relatives of GADA positive probands were GADA negative. Conclusion Despite clinically selecting a Type 2 diabetes cohort, 7% were GADA positive with an altered phenotype. These GADA positive patients had a strong family history of non-autoimmune diabetes. This suggests that, in this subgroup of patients, autoimmune pancreatic β-cell destruction occurs on a background of Type 2 diabetes genetic susceptibility. [ABSTRACT FROM AUTHOR]

Seven years ago, Pediatric Cardiology published the first version of a review article outlining the various medications used in the field of heart diseases in children. This article is an update and expansion to what we have previously presented. Therapeutic intervention, both surgical and through cardiac catheterization. has enabled cure and palliation of an increasingly expanding spectrum of diseases at earlier ages and with more complex lesions. Refinement of these procedures includes more advanced tools as well as the support of an expanding armament of pharmacopoeia used to stabilize and support patients before, during, and after such procedures. In addition to updating previously published data regarding inotropes, antiarrhythmics. vasodilators, diuretics, sedatives, and analgesics as well as a variety of miscellaneous medications, this article describes the use of pulmonary medications frequently needed in patients with congestive heart failure, pulmonary edema, and chronic lung disease. We also describe the difficult management of withdrawal as a result of use of sedatives and analgesics. The most recent recommendation for subacute bacterial endocarditis prophylactic antibiotic regimens is also described. [ABSTRACT FROM AUTHOR]

Summary Respiratory syncytial virus (RSV) G glycoprotein mediates cell attachment through surface glycosaminoglycans (GAGs). Feldman et al. [10] suggested that specific basic amino acids in residues 184–198 of G defined a critical heparin binding domain (HBD). To further define the G HBD we made a series of truncated G proteins expressed in Escherichia coli. G88 (G residues 143–231), bound to HEp-2 cells in a dose dependent manner and binding was inhibited >99% with heparin. Cell binding of G88 was unaltered by alanine substitution mutagenesis of all basic amino acids in Feldman’s region 184–198. A G88 variant truncated beyond residue 198, G58, and G58 fully alanine substituted in the region 184–198, G58A6, bound to HEp-2 cells about half as well and 100-fold less well than G88, respectively. G88 and all alanine substitution mutants of G88 inhibited RSV plaque formation by 50% (ID50) at concentrations of ∼50 nM; the ID50 of G58 was ∼425 nM while G58A6 had an ID50 >1600 nM. These data show that the G HBD includes as much as residues 187–231, that there is redundancy beyond the previously described HBD, and that the cell-binding and virus infectivity-blocking functions of these recombinant G proteins were closely linked and required at least one HBD. [ABSTRACT FROM AUTHOR]

Background Visual analogue scales (VAS) are used to assess the strength of perceptions of both children and adults in many clinical and research settings. Although the VAS has been shown by some authors to be reliable for use by children aged 5 years and older, others have proposed that young children, generally ≤7 years of age, may not have the conceptual ability to use a VAS. Objective To identify demographic and cognitive variables that would maximize the accuracy of predicting children's abilities to use a VAS. Methods Forty kindergarten children performed a seriation task, used a VAS to perform a calibration task and completed the Block Design and Vocabulary subtests of the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSi-R). An estimated IQ was calculated from the WPPSIR subtest scores. Socioeconomic status was assessed using the Hollingshead Four Factor Index of Social Status. Logistic regression was used to determine the best predictive models. Sensitivity, specificity, negative predictive value, positive predictive value and accuracy were calculated for statistically significant predictive models. Main outcome measure Successful completion of the calibration study by the child. Results Only 42% of the subjects could use a VAS. The subject's age (≥5.6 years), combined with estimated IQ (≥ 100), was the best predictor of a child's ability to use a VAS (88% accuracy). Conclusion The majority of kindergarten children in our study could not complete a VAS accurately. Cognitive ability, combined with chronological age, was the best predictor of a child's accurate use of a VAS, as determined by logistic regression. Paediatric researchers may need to consider alternative rating scales to measure perceptions in children under 7 years of age. [ABSTRACT FROM AUTHOR]

Investigations of a fish kill at an irrigation reservoir in the Deschutes River basin, Oregon, documented at least 153 dead largescale suckers Catostomus macrocheilus, all heavily infected with large Ligula intestinalis (Cestoda). Moribund fish nearshore were similarly infected, with no evidence of secondary disease or infection. Morbidity and mortality in all cases was probably due to severe mechanical damage to internal host organs resulting from infection with multiple, large L. intestinalis. The pathology of L. intestinalis documented in largescale sucker in this study contrasts sharply with previous accounts and may represent a new and emerging disease for largescale suckers. Copyright 2002 The Fisheries Society of the British Isles. Published by Elsevier Science Ltd. All rights reserved. [Copyright &y& Elsevier]

The article focuses on temporal and spatial segregation of spawning by wild and farm-reared brown trout, in the River Avon, Wiltshire, England. In the British Isles, peak spawning activity of wild brown trout, Salmo trutta L., generally occurs from late October to mid-November. However, in the chalk-streams of southern England native wild trout spawn from late December to mid-February, although limited spawning as late as mid-March has been observed. Farm-reared trout appear to mature earlier than wild chalk-stream trout in the Upper River Avon, a finding that is supported by evidence from other Southern England chalk-streams.

Background Measuring endogenous insulin secretion using C-peptide can assist diabetes management, but standard stimulation tests are impractical for clinical use. Random non-fasting C-peptide assessment would allow testing when a patient is seen in clinic. Methods We compared C-peptide at 90 min in the mixed meal tolerance test ( sCP) with random non-fasting blood C-peptide ( rCP) and random non-fasting urine C-peptide creatinine ratio ( rUCPCR) in 41 participants with insulin-treated diabetes [median age 72 (interquartile range 68-78); diabetes duration 21 (14-31) years]. We assessed sensitivity and specificity for previously reported optimal mixed meal test thresholds for severe insulin deficiency (sCP < 200 pmol//l) and Type 1 diabetes/inability to withdraw insulin (< 600 pmol//l), and assessed the impact of concurrent glucose. Results rCP and sCP levels were similar (median 546 and 487 pmol//l, P = 0.92). rCP was highly correlated with sCP, r = 0.91, P < 0.0001, improving to r = 0.96 when excluding samples with concurrent glucose < 8 mmol//l. An rCP cut-off of 200 pmol//l gave 100% sensitivity and 93% specificity for detecting severe insulin deficiency, with area under the receiver operating characteristic curve of 0.99. rCP < 600 pmol//l gave 87% sensitivity and 83% specificity to detect sCP < 600 pmol//l. Specificity improved to 100% when excluding samples with concurrent glucose < 8 mmol//l. rUCPCR (0.52 nmol/mmol) was also well-correlated with sCP, r = 0.82, P < 0.0001. A rUCPCR cut-off of < 0.2 nmol/ mmol gave sensitivity and specificity of 83% and 93% to detect severe insulin deficiency, with area under the receiver operating characteristic curve of 0.98. Conclusions Random non-fasting C-peptide measures are strongly correlated with mixed meal C-peptide, and have high sensitivity and specificity for identifying clinically relevant thresholds. These tests allow assessment of C-peptide at the point patients are seen for clinical care. [ABSTRACT FROM AUTHOR]

The nitrogen-vacancy center (NV) in diamond, with its exceptional spin coherence and convenience in optical spin initialization and readout, is increasingly used both as a quantum sensor and as a building block for quantum networks. Employing photonic structures for maximizing the photon collection efficiency in these applications typically leads to broadened optical linewidths for the emitters, which are commonly created via nitrogen ion implantation. With studies showing that only native nitrogen atoms contribute to optically coherent NVs, a natural conclusion is to either avoid implantation completely or substitute nitrogen implantation by an alternative approach to vacancy creation. Here, we demonstrate that implantation of carbon ions yields a comparable density of NVs as implantation of nitrogen ions and that it results in NV populations with narrow optical linewidths and low charge-noise levels even in thin diamond microstructures. We measure a median NV linewidth of 150 MHz for structures thinner than 5 μm, with no trend of increasing linewidths down to the thinnest measured structure of 1.9 μm. We propose a modified NV creation procedure in which the implantation is carried out after instead of before the diamond fabrication processes and confirm our results in multiple samples implanted with different ion energies and fluences. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 90-93 (2012) Abstract Aims Serum C-peptide can be used in Type 2 diabetes as a measure of endogenous insulin secretion, but practicalities of collection limit its routine clinical use. Urine C-peptide creatinine ratio is a non-invasive alternative that is stable for at least 3 days at room temperature in boric acid preservative. We aimed to assess the utility of urine C-peptide creatinine ratio in individuals with Type 2 diabetes as an alternative to serum C-peptide. Methods We assessed, in 77 individuals with Type 2 diabetes, the reproducibility of, and correlations between, fasting and postprandial urine C-peptide creatinine ratio and serum C-peptide, and the impact of renal impairment (estimated glomerular filtration rate < 60 ml min−1 1.73 m−2) on these correlations. Results Urine C-peptide creatinine ratio was at least as reproducible as serum C-peptide [fasting coefficient of variation mean (95% CI): 28 (21-35)% vs. 38 (26-59)% and 2-h post-meal 26 (18-33)% vs. 27 (20-34)%. Urine C-peptide creatinine ratio 2 h post-meal was correlated with stimulated serum C-peptide, both the 2-h value ( r = 0.64, P < 0.001) and the 2-h area under the C-peptide curve ( r = 0.63, P < 0.001). The association seen was similar in patients with and without moderate renal impairment ( P = 0.6). Conclusions In patients with Type 2 diabetes, a single urine C-peptide creatinine ratio is a stable, reproducible measure that is well correlated with serum C-peptide following meal stimulation, even if there is moderate renal impairment. Urine C-peptide creatinine ratio therefore has potential for use in clinical practice in the assessment of Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Inland fisheries in England and Wales have high economic and social values. Managing participation to maximise fishery performance is key to maintaining this status. The capital value of fishing rights for migratory salmonid fisheries is €165 million. Coarse fisheries contribute €1030 million to the economy. The central tenet to increasing participation in recreational salmonid fisheries is that an increase in stock size will result in more anglers accessing the fishery. This was examined for salmon on the rivers Usk and Lune where exploitation restrictions increased the number of salmon available to anglers. On the River Lune, the number of salmon available post-intervention increased by 66%. There was no significant increase in catch while the number of anglers decreased by 16.3%. On the River Usk, the closure of the net fishery potentially resulted in an additional ∼1200 salmon being available. Following closure, there was no significant change in rod catch or in the number of anglers. Increased participation is dependent less upon stock manipulation for coarse fisheries and more upon facilitating the activity. In recent years, urban fishery development programmes have provided improved access to local fishing opportunity. Also, new anglers have been targeted through campaigns such as Get Hooked on Fishing and the Scout Angler Badge. [ABSTRACT FROM AUTHOR]

AIMS: Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. METHODS: We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects). RESULTS: When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]. CONCLUSION: Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects. [ABSTRACT FROM AUTHOR]

Aims Common polymorphisms in the transcription factor 7-like 2 ( TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. Methods We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged ≥ 45 years (community control subjects). Results When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13–1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38–1.80), P = 1.4 × 10−11] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41–1.54), P < 10−20]. Conclusion Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects. [ABSTRACT FROM AUTHOR]

The development and use of biological reference points (BRPs) for salmon, Salmo salar L., conservation on the River Lune, England were examined. The Lune supports recreational and net fisheries with annual catches averaging 1332 and 2146 salmon, respectively. Using models transported from other river systems, BRPs were developed that were exclusive to the Lune; specifically the number of eggs deposited and carrying capacity estimates for age 0+ and 1+ parr. The conservation limit was estimated at 11.9 million eggs, and to ensure that the conservation limit was exceeded 80% of the time, the management target was set at 14.4 million eggs (equivalent to ∼5000 adults). Between 1989 and 1998 the management target was exceeded in only 2 years. Comparison of juvenile salmon densities in 1991 and 1997 with estimates of carrying capacity indicated that 0+ and 1+ parr densities were at around 60% of carrying capacity and may relate to the number of eggs deposited in 1990 and 1996 being approximately 70% of the target value. From, and including, the 2000 fishing season, regulations to ensure that the conservation limit is met 4 years out of 5 were introduced. These consisted of a reduction from 26 to 12 haaf nets, from 10 to seven drift nets and a four-fish bag limit for the rod fishery. In the period between 2000 and 2004 there was a marked increase in the estimated number of salmon spawning and the management target value of ∼5000 spawning adults was exceeded in all years. There was also an increase in the juvenile salmon population. The estimated level of exploitation in the net and rod fisheries reduced from 29.9% to 13.8% and from 26.4% to 14.8% respectively, after the introduction of the regulations. [ABSTRACT FROM AUTHOR]

HNF1alpha (TCF1) is a key transcription factor that is essential for pancreatic beta-cell development and function. Rare mutations of HNF1alpha cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1alpha gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (approximately 3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (<5%) alleles in type 2 diabetes risk. [ABSTRACT FROM AUTHOR]

Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position -30 of the GCK beta-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(-30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(-30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25-102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(-30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight. [ABSTRACT FROM AUTHOR]

Aims: Misclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes. Methods: We classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non‐type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin‐containing islets along with multiple insulin‐deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data [autoantibodies, type 1 diabetes genetic risk score (T1D‐GRS)], and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC‐ROC). Results: Diagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D‐GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC‐ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C‐peptide [median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non‐type 1 diabetes; P < 0.0001]. Conclusions: Our study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C‐peptide‐based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible. Parts of this study were presented in abstract form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19–22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6–8 March 2019. What's new?: Misclassification of diabetes at diagnosis is common due to an overlap in the clinical features of type 1 and type 2 diabetes.Combining clinical features and biomarkers in a diagnostic model improved discrimination of diabetes type, defined by insulin deficiency (measured by C‐peptide assays), over use of any single characteristic.No diabetes classification studies have used pancreatic histology to define type 1 diabetes.A diagnostic model, developed using diabetes type defined by C‐peptide level as an outcome, validates against histologically defined insulin deficiency.C‐peptide provides a robust surrogate definition of type 1 diabetes that can be used in diagnostic model development.Our study provides the first histological evidence for a clinical diagnostic model having utility to identify type 1 diabetes in clinical practice. [ABSTRACT FROM AUTHOR]

We present an implementation of all-diamond scanning probes for scanning nitrogen-vacancy (NV) magnetometry fabricated from (111)-oriented diamond material. The realized scanning probe tips on average contain single NV spins, a quarter of which have their spin quantization axis aligned parallel to the tip direction. Such tips enable single-axis vector magnetic field imaging with a nanoscale resolution, where the measurement axis is oriented normal to the scan plane. We discuss how these tips bring multiple practical advantages for NV magnetometry, in particular, regarding quantitative analysis of the resulting data. We further demonstrate the beneficial optical properties of NVs oriented along the tip direction, such as polarization-insensitive excitation, which simplifies optical setups needed for NV magnetometry. Our results will be impactful for scanning NV magnetometry in general and for applications in spintronics and the investigation of thin film magnets in particular. [ABSTRACT FROM AUTHOR]

Aims: Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c, hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C‐peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. Methods: We conducted a cross‐sectional case–control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C‐peptide after a mixed‐meal tolerance test. We compared self‐reported hypoglycaemia (n = 160), HbA1c, insulin dose and microvascular complications (n = 140) in those with preserved and low C‐peptide. Results: Stimulated median (IQR) C‐peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C‐peptide respectively. Participants with preserved C‐peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C‐peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06). Conclusions: Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self‐reported hypoglycaemic episodes, but no difference in HbA1c. This is consistent with non‐intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin. What's new?: Little is known about the clinical impact of persistent C‐peptide in long‐duration Type 1 diabetes.We found that in adults with long‐duration Type 1 diabetes, persistent C‐peptide was associated with reduced self‐reported hypoglycaemia and insulin dose but was not associated with reduced HbA1c.This suggests that individuals with persistent C‐peptide receiving routine care are potentially undertreated.Routinely testing C‐peptide and subsequently setting personalized targets for treatment intensification in adults with persistent C‐peptide may improve glycaemic control and complication rates in this group. [ABSTRACT FROM AUTHOR]

Aims To determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. Methods We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age ≥45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was ≤0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio ≤ 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. Results A total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios ≤ 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C-peptide <0.2 nmol/l and 9/9 subjects with urinary C-peptide creatinine ratio >0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m2, P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. Conclusions Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion. [ABSTRACT FROM AUTHOR]

Abstract: Drosophila RNP-4F is a highly conserved protein from yeast to human and functions as a spliceosome assembly factor during pre-mRNA splicing. Two major developmentally regulated rnp-4f mRNA isoforms have been described during fly development, designated “long” and “short,” differing by a 177-nt tract in the 5′-UTR. This region potentially folds into a single long stable stem–loop by pairing of intron 0 and part of exon 2. Since the coding potential for the two isoforms is identical, the interesting question arises as to the functional significance of this evolutionarily-conserved 5′-UTR feature. Here we describe the effects of wild-type and mutated stem–loop on modulation of rnp-4f gene expression in embryos using a GFP reporter assay. In this work, a new GFP expression vector designated pUAS-Neostinger was constructed. The UAS-GAL4 system was utilized to trigger GFP expression using tissue-specific promoter driver fly lines. Fluorescence microscopy visualization, Western blotting and real-time qRT-PÇR were used to study and quantify GFP reporter protein and mRNA levels. A significant increase in GFP reporter protein expression due to presence of the wild-type stem–loop sequence/structure was unexpectedly observed with no concomitant increase in GFP reporter mRNA levels, showing that the 177-nt region enhancement acts posttranscriptionally. The effects of potential cis-acting elements within the stem–loop were evaluated using the reporter assay in two mutant constructs. Results of GFP reporter over-expression show that RNP-4F translational regulation is highly sensitive in the developing fly central nervous system. The potential molecular mechanism behind the observed translational enhancement is discussed. [Copyright &y& Elsevier]

Diabet. Med. 29, 1279-1284 (2012) Abstract Aims The mixed meal tolerance test is the gold standard measure of endogenous insulin secretion. Practical issues limit the routine clinical use of this test, including omitting insulin prior to the ingestion of a high-carbohydrate liquid mixed meal, which can result in marked hyperglycaemia. We aimed to assess whether insulin omission is necessary during the mixed meal tolerance test and whether fasting C-peptide was a practical alternative to the test. Methods Ninety-one adults with insulin-treated diabetes (Type 1 n = 56, Type 2 n = 35) underwent two mixed meal tolerance tests; one standard without insulin and one with the patient's usual morning insulin. Results The 90-min serum C-peptide was highly correlated in the standard mixed meal tolerance test and the test with insulin ( r = 0.98, P < 0.0001). There was a 20% reduction in the peak C-peptide value when insulin was given {test with insulin [0.39 (0.01-1.16) vs. test without insulin 0.48 (0.01-1.36) nmol/l, P = 0.001]}, but the original serum C-peptide cut-off for significant endogenous insulin secretion (≥ 0.2 nmol/l) still correctly classified 90/91 patients (98% sensitivity/100% specificity). Fasting serum C-peptide was highly correlated to 90-min serum C-peptide during the test ( r = 0.97, P < 0.0001). A fasting serum C-peptide ≥ 0.07 nmol/l was the optimal cut-off (100% sensitivity and 97% specificity) for significant endogenous insulin secretion (defined as 90-min stimulated serum C-peptide ≥ 0.2 nmol/l). Conclusions Insulin omission may not always be necessary during a mixed meal tolerance test and fasting serum C-peptide may offer a practical alternative in insulin-treated patients. [ABSTRACT FROM AUTHOR]

Diamond nanophotonics have evolved tremendously from the study of color centers in bulk single crystals and nanocrystals to their characterization in nanostructured environments. This development was facilitated by the ability to generate monolithic, sophisticated nanodevices in high quality single crystal diamond. Here, we present some recent contributions to the field of diamond nanophotonics: increase in single photon collection from nitrogen vacancy (NV) centers embedded in diamond nanowires, broadband spontaneous emission enhancement of single NV centers in plasmonic resonators, and coupling of single NV centers to planar resonators on-chip. [ABSTRACT FROM AUTHOR]

Diabet. Med. 28, 1034-1038 (2011) Abstract Aims Serum C-peptide measurement can assist clinical management of diabetes, but practicalities of collection limit widespread use. Urine C-peptide creatinine ratio may be a non-invasive practical alternative. The stability of C-peptide in urine allows outpatient or community testing. We aimed to assess how urine C-peptide creatinine ratio compared with serum C-peptide measurement during a mixed-meal tolerance test in individuals with late-onset, insulin-treated diabetes. Methods We correlated the gold standard of a stimulated serum C-peptide in a mixed-meal tolerance test with fasting and stimulated (mixed-meal tolerance test, standard home meal and largest home meal) urine C-peptide creatinine ratio in 51 subjects with insulin-treated diabetes (diagnosis after age 30 years, median age 66 years, median age at diagnosis 54, 42 with Type 2 diabetes, estimated glomerular filtration rate > 60 ml min−1 1.73 m−2). Results Ninety-minute mixed-meal tolerance test serum C-peptide is correlated with mixed-meal tolerance test-stimulated urine C-peptide creatinine ratio ( r = 0.82), urine C-peptide creatinine ratio after a standard breakfast at home ( r = 0.73) and urine C-peptide creatinine ratio after largest home meal ( r = 0.71). A stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.3 nmol/mmol had a 100% sensitivity and 96% specificity (area under receiver operating characteristic curve = 0.99) in identifying subjects without clinically significant endogenous insulin secretion (mixed-meal tolerance test-stimulated C-peptide < 0.2 nmol/l). In detecting a proposed serum C-peptide threshold for insulin requirement (stimulated serum C-peptide < 0.6 nmol/l), a stimulated (largest home meal) urine C-peptide creatinine ratio cut-off of 0.6 nmol/mmol had a sensitivity and specificity of 92%. Conclusion In patients with insulin-treated diabetes diagnosed after age 30 years, urine C-peptide creatinine ratio is well correlated with serum C-peptide and may provide a practical alternative measure to detect insulin deficiency for use in routine clinical practice. [ABSTRACT FROM AUTHOR]

Diabet. Med. 28, 1028-1033 (2011) Abstract Aim Maturity-onset diabetes of the young is a monogenic form of familial, young-onset diabetes. It is rare (∼1% diabetes) and may be misdiagnosed as Type 1 diabetes and inappropriately treated with insulin. Type 1 diabetes is characterized by the presence of islet autoantibodies, including glutamate decarboxylase (GAD) and islet antigen-2 (IA-2) antibodies. The prevalence of islet autoantibodies is unknown in maturity-onset diabetes of the young and may have the potential to differentiate this form of diabetes from Type 1 diabetes. The aim of this study was to determine the prevalence of GAD and IA-2 antibodies in patients with maturity-onset diabetes of the young and Type 1 diabetes. Methods We measured plasma GAD and IA-2 antibodies in 508 patients with the most common forms of maturity-onset diabetes of the young ( GCK: n = 227; HNF1A: n = 229; HNF4A: n = 52) and 98 patients with newly diagnosed Type 1 diabetes (diagnosed < 6 months). Autoantibodies were considered positive if ≥ 99th centile of 500 adult control subjects. Results GAD and/or IA-2 antibodies were present in 80/98 (82%) patients with Type 1 diabetes and 5/508 (< 1%) patients with maturity-onset diabetes of the young. In the cohort with Type 1 diabetes, both GAD and IA-2 antibodies were detected in 37.8% of patients, GAD only in 24.5% and IA-2 only in 19.4%. All five patients with maturity-onset diabetes of the young with detectable antibodies had GAD antibodies and none had detectable IA-2 antibodies. Conclusion The prevalence of GAD and IA-2 antibodies in maturity-onset diabetes of the young is the same as in control subjects (< 1%). The finding of islet autoantibodies, especially IA-2 antibodies, makes the diagnosis of maturity-onset diabetes of the young very unlikely and genetic testing should only be performed if other clinical characteristics strongly suggest this form of diabetes rather than Type 1 diabetes. This supports routine islet autoantibody testing before proceeding to more expensive molecular genetic testing. [ABSTRACT FROM AUTHOR]

Aims Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes where correct diagnosis alters treatment, prognosis and genetic counselling. The first UK survey of childhood MODY identified 20 White, but no Asian children with MODY. We hypothesized that MODY causes diabetes in UK Asians, but is underdiagnosed. Methods Children with dominant family histories of diabetes were recruited. Direct sequencing for mutations in the two most common MODY genes; HNF1A (TCF1) and GCK was performed in autoantibody-negative probands. We also compared MODY testing data for Asian and White cases from the Exeter MODY database, to 2001 UK census data. Results We recruited 30 families and identified three Asian families with MODY gene mutations (two HNF1A, one GCK) and three White UK families (two HNF1A, one GCK). Heterozygous MODY phenotypes were similar in Asians and Whites. Only eight (0.5%) of 1369 UK referrals for MODY testing were known to be Asian, but in 2001 Asians represented 4% of the English/Welsh population and have a higher prevalence of diabetes. Conclusions We identified three cases of childhood MODY in UK Asians and demonstrated reduced rates of MODY testing in Asians, which has negative implications for treatment. It is unclear why this is. MODY should be considered in autoantibody-negative Asian diabetes patients lacking evidence of insulin resistance. [ABSTRACT FROM AUTHOR]