NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Patient safety incidents involving transdermal opioids: data from the Danish Patient Safety Database.

Background Transdermal opioids are widely used among elderly adults with chronic pain. However, transdermal patches may be involved in a significant proportion of opioid-related patient safety incidents, as the application process includes several subprocesses, each associated with an individual risk of error. Objective The aim was to obtain specific knowledge on patient safety incidents related to transdermal opioid treatment within both the primary care sector and the hospital sector in Denmark. Setting The study is descriptive with data provided by the Danish Patient Safety Database. Methods We manually retrieved all patient safety incidents concerning transdermal opioids reported for 2018 from (1) the hospital sector and (2) the primary care sector. Study data were collected and managed using REDCap electronic data capture tools. Main outcome measure The available information for each incident was sorted into the following categories: location, medication process, type of problem, outcome at time of reporting, and outcome classification. Results A total of 866 patient safety incidents involving transdermal opioids were reported to the Danish Patient Safety Database in 2018. No fatal incidents were present in the database. In 386 cases, the incidents were reported as harmful, and these 386 cases were analysed. Most reports came from the primary care sector (nursing home, home care or social housing). The majority of incidents were related to the administration of the patch in the medication process, and the most prevalent problem was the omission of doses. Conclusion This study has demonstrated that the administration of transdermal opioids is challenging and may cause harm, particularly in the primary care sector. To improve patient safety, optimized systems, including guidelines on drug management and the continuing education of healthcare personnel in transdermal opioid management, are necessary. These guidelines should preferably incorporate reminders and checklists, since the omission of doses was the most reported problem.

Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Immunosuppressive cells in the tumor microenvironment allow cancer cells to escape immune recognition and support cancer progression and dissemination. To improve therapeutic efficacy, we designed a liposomal oxaliplatin formulation (PCL8-U75) that elicits cytotoxic effects toward both cancer and immunosuppressive cells via protease-mediated, intratumoral liposome activation. The PCL8-U75 liposomes displayed superior therapeutic efficacy across all syngeneic cancer models in comparison to free-drug and liposomal controls. The PCL8-U75 depleted myeloid-derived suppressor cells and tumor-associated macrophages in the tumor microenvironment. The combination of improved cancer cell cytotoxicity and depletion of immunosuppressive populations of immune cells is attractive for combination with immune-activating therapy. Combining the PCL8-U75 liposomes with a TLR7 agonist induced immunological rejection of established tumors. This combination therapy increased intratumoral numbers of cancer antigen-specific cytotoxic T cells and Foxp3- T helper cells. These results are encouraging toward advancing liposomal drug delivery systems with anticancer and immune-modulating properties into clinical cancer therapy.

The prevalence of type 2 diabetes in people with psychiatric disorders: an umbrella review protocol.

BACKGROUND: Many epidemiological studies have investigated the prevalence of type 2 diabetes in individuals with a psychiatric disorder. In an umbrella review, we aim to systematically summarize existing systematic reviews examining the prevalence of type 2 diabetes in people with a psychiatric disorder. When information is available in the identified systematic reviews, comparisons with control groups without a psychiatric disorder will be made. Furthermore, we aim to assess the quality of the included systematic reviews. METHODS: The umbrella review will be based on a comprehensive systematic search of systematic reviews of observational (cross-sectional or longitudinal) studies investigating the prevalence of type 2 diabetes in people with a psychiatric disorder. Four electronic databases (Embase, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews) will be searched. Retrieved papers will be screened for eligibility by two independent reviewers. Furthermore, the reference lists of all included publications will be screened. Data will be extracted by using an a priori developed data extraction form and two independent reviewers will assess the risk of bias in the included systematic reviews using with the Risk of Bias in Systematic Reviews (ROBIS) tool. A narrative data-synthesis and a subsequent meta-analysis based on the primary studies will be made. DISCUSSION: For each psychiatric disorder, the data regarding the prevalence of type 2 diabetes will be summarized and discussed. When possible, comparisons with control groups will be reported and discussed. Finally, future implications and recommendations for clinical care will be presented. SYSTEMATIC REVIEW REGISTRATION: This protocol was submitted for registration with the International Prospective Register of Systematic Reviews (PROSPERO) on December 9, 2019 (registration number: pending).

Changes to steps, lying, and eating behavior during lactation in Jersey and Holstein cows and the relationship to feed intake, yield, and weight.

Devices that record behavior automatically have made it possible to accurately measure the lying and eating behavior of large numbers of dairy cows. During lactation, weight, feed intake, and production of cows change; however, longitudinal studies of how the behavior of dairy cows is correlated with production traits during lactation are limited. This study describes changes in duration of lying and eating behavior throughout lactation and how these variables are related to changes in milk yield, live weight, and feed intake in lactating primi- and multiparous Holstein and Jersey cows. Data were from 255 cow lactations (43 primi- and 80 multiparous Jersey cows, and 56 primi- and 76 multiparous Holstein cows) from 5 to 200 d in milk. Leg-mounted tags were used to record lying time and steps; ad libitum feed intake (of a partial mixed ration) variables were recorded from feed bins on weight cells; and milk yield and live weight were recorded during automatic milking, all on a daily basis. The lactation trajectory was split into 4 segments. Data were analyzed using mixed effects linear models. Holstein cows spent more time lying and eating than Jersey cows, whereas Jersey cows had a greater number of steps (25-37%). First-lactation cows spent less time eating and had more steps than older cows. Average daily lying time was approximately 1 h longer during February than the shortest lying time, which was observed in August. Both Holstein and Jersey multiparous cows had longer lying times than cows in first parity after parturition; however, the lying time of multiparous cows decreased, whereas that of primiparous cows increased in the beginning of lactation. Later in lactation, older cows tended to increase duration of lying more than younger cows did. The daily change in behavior (lying, eating, and steps) and milk yield, live weight, and dry matter intake, characterized as slopes in the lactation period for each cow, were not strongly correlated. However, we found a moderate correlation between changes in milk yield and dry matter intake, and between changes in eating time and rate of eating. An increase in eating rate in multiparous Holstein cows was correlated with increasing lying time. In conclusion, the use of automated behavior recording enabled thorough investigations of relationships between a range of behavior traits and frequently recorded production traits, and revealed that patterns of change during lactation are strongly affected by breed and parity.

Effects of an individual cow concentrate strategy on production and behavior.

The aim of this study was to investigate the effects of a concentrate strategy based on the individual cow partial mixed ration (PMR) intake compared with a flat rate. Half of the cows were fed the individual concentrate strategy, whereas the other half were fed the control strategy. The individually fed cows were offered a concentrate proportion equal to 30% of the ad libitum intake of the PMR in the automatic milking system, and the control cows were offered 3 kg of concentrate/d in the automatic milking system. The cows (83 Holstein and 64 Jersey), kept in 2 separate groups, were blocked between the treatments according to expected calving date, breed, and parity and were randomly divided between treatments. Lactation was divided into 3 periods (early, mid, and late lactation), and the MIXED and GLIMMIX procedures in SAS (SAS Institute Inc., Cary, NC) were used to analyze the production and behavioral responses. The response trajectories during lactation were analyzed with a MIXED procedure fitted by Wilmink parameters. The individually fed cows had a higher concentrate intake and a lower PMR intake than control cows. Moreover, the total dry matter intake and energy-corrected milk yield did not differ between concentrate strategies. The actual average concentrate intake reached 19% of the PMR intake during mid lactation and not 30% of the PMR intake, as intended with the strategy. This was due to leftovers and lower allocation than intended. The cow behavior did not differ between concentrate strategies. However, variation in PMR intake and eating rate between cows fed individually was lower during mid lactation and lower for lying bouts during early lactation compared with control cows. This may indicate that an individual cow concentrate strategy results in a more stable PMR intake and time budget, which potentially could improve welfare, but this needs further investigation. The overall conclusion is that the cows were robust to adjustments in the concentrate allowance.

Loneliness, health and mortality.

AIMS: Literature suggests an association between loneliness and mortality for both males and females. Yet, the linkage of loneliness to mortality is not thoroughly examined, and need to be replicated with a long follow-up time. This study assessed the association between loneliness and mortality, including associations to gender, in 1363 adult swedes. METHODS: This community-based prospective cohort study from the Swedish Lundby Study included 1363 individuals of whom 296 individuals (21.7%) were identified as lonely with use of semi-structured interviews in 1997. The cohort was followed until 2011 and survival analyses were used to estimate the relative risk of death. RESULTS: Death occurred with an incidence rate of 2.63 per 100 person-years and 2.09 per 100 person-years for lonely and non-lonely individuals, respectively. In crude analysis, loneliness was associated with a significant increased mortality risk of 27% compared with non-lonely individuals [hazard ratio (HR) 1.27; 95% CI 1.01-1.60]. Unadjusted, lonely females had a significant increased risk (HR 1.76; 95% CI 1.31-2.34) and adjusted insignificant increased mortality risk of 27% (HR 1.27; 95% CI 0.92-1.74), compared with non-lonely females. Lonely males were found to have an adjusted significant decreased risk of mortality (HR 0.50; 95% CI 0.32-0.80), compared with non-lonely males. CONCLUSIONS: Findings suggest an association between loneliness and increased risk of mortality and that gender differences may exist, which have not been previously reported. If replicated, our results indicate that loneliness may have differential physical implications in some subgroups. Future studies are needed to further investigate the influence of gender on the relationship.

Validation of AfiTagII, a device for automatic measuring of lying behaviour in Holstein and Jersey cows on two different bedding materials.

Lying behaviour is important for the welfare of the cow. Therefore, reliable electronic devices may improve the management of the cows, and the devices can be used as a tool in research. However, accelerometer-based devices measure acceleration, and an algorithm is therefore necessary for the calculation of lying behaviour. Thus, validation of such devices is imperative prior to use. The objective of this study was to validate the use of the AfiTagII device for measurements of the lying time and frequency of lying bouts of Danish Holstein (DH) and Danish Jersey (DJ) cows in a loose-house system on two different bedding materials. The validation included correlations and linear regression analyses of data collected by the AfiTagII compared with data collected both by direct observations and recordings from a previously validated device (IceQube). In total, 40 cows were observed directly with primiparous and multiparous DJ and DH cows, equally represented. Furthermore, 21 cows were monitored with both AfiTagII and IceQube devices, and data from both devices were collected simultaneously. The devices were attached to the hind leg of the cow. The estimates of the lying time from the AfiTagII device was highly correlated with the recordings from direct observations (r=0.98), and there was a linear relation between these with an intercept equal to 0 and a slope close to 1. The estimates of the lying time from the AfiTagII device was also highly correlated with the IceQube recordings (r=0.94). However, the intercept deviated from 0. The frequency of lying bouts recorded by the AfiTAgII compared to direct observations showed a positive predictive value of 0.96 for lactating cows on the slatted floor and of 0.85 for the dry cows on the deep bedding. The correlations between frequency of lying bouts recorded with the two devices were high (r=0.94), but the intercept deviated from 0. In conclusion, the AfiTagII has a high accuracy for the measurements of lying behaviour in both DH and DJ cows kept on different bedding materials.

Short-term responses in production and behavior during periods of change in concentrate allowance for dairy cows.

The aim of this study was to investigate the short-term responses of dairy cows during periods of change in the concentrate allowance in an automatic milking system. The experiment had a design with a 2 × 2 factorial arrangement including 2 types of concentrates and 2 amounts of concentrates (type O: mix of pelleted concentrate and steamrolled, acidified barley; type S: pelleted) in amounts of 3 and 6 kg/d. The experiment length was 11 wk. The concentrate type changed between wk 6 and 7 and included both increase and decrease in concentrate allowance for each concentrate type. The concentrate allowance was changed by 0.5 kg/d over 6 d. The 96 cows (48 Danish Jersey, 48 Danish Holstein) included in the experiment were blocked according to breed, parity, and days in milk, and randomly divided into 8 groups of treatment order. The cows visited the automatic milking unit more often when concentrate type O was offered, but not when an increased concentrate allowance was provided. The changes in concentrate intake and partial mixed ration (PMR) eating time showed a symmetrical pattern between the periods of increasing allowance and decreasing allowance. However, PMR intake and milk yield varied in the magnitude of the responses, indicating that these responses may not be driven by the same underlying mechanisms during increase and decrease in concentrate allowance. The daily lying time increased and the PMR eating rate decreased during periods of both increase and decrease in concentrate allowance. We found no significant change in milk yield during increase in concentrate allowance, despite a higher milk yield during periods with constant concentrate allowance at the high concentrate amount; however, the milk yield decreased during periods of decrease in concentrate allowance. Visit frequency, lying time, and steps changed during periods of changes in concentrate allowance without showing any differences at the constant concentrate allowance. In conclusion, these results indicate that it may be difficult to adjust the individual concentrate allowance based on the short-term responses of the cow.

Glucose effectiveness is a critical pathogenic factor leading to glucose intolerance and type 2 diabetes: An ignored hypothesis.

BACKGROUND: Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. METHODS: A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and "at risk" individuals, was undertaken to determine GE's contribution to glucose homeostasis. RESULTS: GE accounts for ~45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic "at risk" relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in "at risk" individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and ß-cell dysfunction. These studies demonstrate that in "at risk" individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. CONCLUSION: In "at risk" individuals, a low GE and genetically determined vulnerable ß-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.

Exercise gaming - a motivational approach for older adults with vestibular dysfunction.

Purpose The purpose of the study was to identify possible reasons for a modest level of exercise compliance during computer-assisted training for vestibular rehabilitation. Method Qualitative design and analysis of 14 semi-structured interviews with seven participants before and after a period with computer-assisted home training. The interviews evolved around themes, such as the elderly participants' self-efficacy, motivation and acceptance of the technology. Results Age was not an excuse for the modest exercise compliance. The participants were basically self-efficient and accepted the technology, but their knowledge and understanding of the training programme were insufficient. The participants asked for a greater variation in the exercises and asked for closer contact with the physiotherapist. When Mitii is used for vestibular rehabilitation, the system has some limitations. Conclusions The modest level of exercise compliance can be explained by (1) missing variety of exercise speed and duration and lack of introducing new exercises, (2) insufficient interaction with the physiotherapist regarding the participants' performance and lack of social contact with other patients and (3) desire for a deeper understanding of the training programme with supplying information on the parts of the vestibular system addressed by the training. Implications for Rehabilitation Computer-assisted technologies should generate feedback on the quality of user performance and inform the patient of the relevance of the exercise. The technology should support social contact among patients with the same diagnosis and establish contact with the physiotherapist at the hospital advice and feedback. Varity and adjustments to exercises are necessary to maintain motivation and exercise compliance.

Abolished ventilation and perfusion of lung caused by blood clot in the left main bronchus: auto-downregulation of pulmonary arterial blood supply.

It is generally assumed that the lungs possess arterial autoregulation associated with bronchial obstruction. A patient with pneumonia and congestive heart failure unexpectedly developed frequent haemoptysis. High-resolution CT and diagnostic CT were performed as well as ventilation/perfusion (V/Q) scintigraphy with single-photon emission CT (SPECT)/CT. V/Q SPECT/CT demonstrated abolished ventilation due to obstruction of the left main bronchus and markedly reduced perfusion of the entire left lung, a condition that was completely reversed after removal of a blood clot. We present the first pictorially documented case of hypoxia-induced pulmonary vasoconstriction and flow shift in a main pulmonary artery due to a complete intrinsic obstruction of the ipsilateral main bronchus. The condition is reversible, contingent on being relieved within a few days.

A hydrogel based nanosensor with an unprecedented broad sensitivity range for pH measurements in cellular compartments.

Optical pH nanosensors have been applied for monitoring intracellular pH in real-time for about two decades. However, the pH sensitivity range of most nanosensors is too narrow, and measurements that are on the borderline of this range may not be correct. Furthermore, ratiometric measurements of acidic intracellular pH (pH < 4) in living cells are still challenging due to the lack of suitable nanosensors. In this paper we successfully developed a multiple sensor, a fluorophore based nanosensor, with an unprecedented broad measurement range from pH 1.4 to 7.0. In this nanosensor, three pH-sensitive fluorophores (difluoro-Oregon Green, Oregon Green 488, and fluorescein) and one pH-insensitive fluorophore (Alexa 568) were covalently incorporated into a nanoparticle hydrogel matrix. With this broad range quadruple-labelled nanosensor all physiological relevant pH levels in living cells can be measured without being too close to the limits of its pH-range. The nanosensor exhibits no susceptibility to interference by other intracellular ions at physiological concentrations. Due to its positive surface charge it is spontaneously internalized by HeLa cells and localizes to the lysosomes where the mean pH was measured at 4.6. This quadruple-labelled nanosensor performs accurate measurements of fluctuations of lysosomal pH in both directions, which was shown by treatment with the V-ATPase inhibitor bafilomycin A1 or its substrate ATP in HeLa cells. These measurements indicate that this novel quadruple-labelled nanosensor is a promising new tool for measuring the pH of acidic compartments in living cells.

Prevalence of tonsillar human papillomavirus infections in Denmark.

The incidence of tonsillar carcinomas associated with Human Papillomavirus (HPV) infection has increased dramatically over the last three decades. In fact, currently in Scandinavia, HPV-associated cases account for over 80 % of tonsillar carcinoma cases. Yet, the epidemiology and natural history of tonsillar HPV infections remains poorly characterized. Our aim was to characterize such infections in the Danish population in tumor-free tonsillar tissue. Unlike previous studies, we considered both palatine tonsils. We examined both tonsils from 80 patients with peritonsillar abscess (n = 25) or chronic tonsillar disease (n = 55). HPV was detected by nested PCR with PGMY 09/11 and GP5+/GP6+L1 consensus primers, and typed by sequencing. Samples were also analyzed using a higher-throughput method, the CLART HPV 2 Clinical Array Assay. The overall prevalence of HPV tonsillar infection was 1.25 % (1/80, 95 % CI 0.03-6.77 %) by nested PCR, and 0 % by CLART HPV2 Clinical Array. The HPV-positive patient was a 16-year-old female with recurrent tonsillitis and tonsillar hypertrophy. The type detected was HPV6. HPV was not detected in the contralateral tonsil of this patient. Compared to cervical HPV infections in Denmark, tonsillar HPV infections are 10- to 15-fold less frequent. In the HPV-positive patient in this study, HPV was detected in only one of the tonsils. This raises the possibility that prior studies may underestimate the prevalence of HPV infections, as they do not consider both palatine tonsils.

Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension.

Diabetic patients with hypertension are at particularly high risk of vascular damage and consequently cardiovascular and renal disease. Fibulin-1, an extracellular matrix glycoprotein, is increased in arterial tissue and plasma from individuals with type 2 diabetes. This study aimed to evaluate whether antihypertensive treatment with spironolactone changes plasma fibulin-1 levels. In a multicenter, double-blind, randomized, placebo-controlled study, 119 patients with type 2 diabetes and resistant hypertension were included. A dose of spironolactone 25 mg or matching placebo was added to previous treatment at randomization. Blood pressure (BP) and plasma fibulin-1 were measured at baseline and at 16 weeks follow-up. Overall, 112 patients completed the study. All measures of BP were reduced in the spironolactone group at follow-up. Plasma fibulin-1 was significantly reduced after spironolactone treatment (P=0.009), but increased after placebo (P=0.017). Baseline plasma fibulin-1 correlated with BP and estimated glomerular filtration rate. Increased levels of plasma fibulin-1 (P=0.004) were observed in diabetic participants reporting erectile dysfunction as compared with participants who did not. Treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. This supports the hypothesis that the antihypertensive effect of the mineralocorticoid receptor blocker in part may be due to regression of vascular remodeling.

Antibody development to Fusobacterium necrophorum in patients with peritonsillar abscess.

A polymicrobial mixture of aerobic and anaerobic bacteria is commonly recovered from peritonsillar abscess (PTA) aspirates. Previous studies have suggested a role for Fusobacterium necrophorum (FN) in the development of PTA. The purpose of the current study was to explore whether anti-FN antibodies were produced in patients with PTA. We developed a novel immunofluorescence-based method to measure anti-FN antibody levels in acute and convalescent sera from 15 patients with PTA and 47 patients with chronic tonsillar conditions (controls) undergoing acute or elective tonsillectomy, respectively. Bacterial cultures were performed on tonsillar cores and surfaces, pus aspirates, and blood. An increase in anti-FN antibody levels (of at least doubling of the previous level) was observed in 8 of 11 (73 %) PTA patients with FN-positive pus aspirate cultures (FN-positive patients). In contrast, the four FN-negative PTA patients did not have an increase in anti-FN antibody levels (p = 0.026). The change in anti-FN antibody levels in FN-positive PTA patients was also significantly greater than that for FN-positive electively tonsillectomized patients (p = 0.0014) and all electively tonsillectomized patients (p < 0.001). Our results validate FN as a significant and prevalent pathogen in PTA. This finding has implications for the diagnostic work-up of PTA and may also have implications for the treatment of acute tonsillitis.

Glucose effectiveness in nondiabetic relatives: dysglycemia and ß-cell function at 10 years.

AIMS: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release. METHODS: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)IVGTT, and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIROGTT were determined. RESULTS: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIROGTT were reduced (P ≤ .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG10y correlated significantly with FG0y and body mass index0y and negatively with √GE and 2-hour OGTT glucose10y with FG0y and negatively with AIRIVGTT0y and AIROGTT0y. Log AIROGTT10y correlated with √GE, log AIRIVGTT0y and log AIROGTT0y. Multiple regression analyses demonstrated the following: REL FG10y was predicted by combined FG0y, √GE and body mass index0y (radj(2) = 56%; P ≤ .001) and 2-hour OGTT glucose10y weakly related by FG0y,and √GE (r(adj)(2) = 25%; P = .06). Log AIROGTT10y was predicted by AIRIVGTT0y and √GE (r(adj)(2) = 46%; P ≤ .004). CONCLUSION: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.

Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats.

BACKGROUND AND PURPOSE: Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH: Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS: Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS: Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.

The role of viruses in the pathogenesis of peritonsillar abscess.

Peritonsillar abscess (PTA) is the most frequent complication of acute tonsillitis and a prevalent cause for acute admission to otorhinolaryngology departments. Our aim was to examine the role of viruses in the pathogenesis of PTA, as this has not previously been considered. We examined both palatine tonsils from 25 patients undergoing acute tonsillectomy for PTA, using PCR-based assays for herpes simplex virus-1 and -2 (HSV-1 and -2), adenovirus, Epstein-Barr virus (EBV), influenza A and B, and respiratory syncytial virus (RSV) A and B. We similarly examined tonsils from 55 patients undergoing elective tonsillectomy due to chronic tonsillar conditions. These patients served as a control group, as they did not have a clinically apparent infection at the time of surgery. Only HSV-1 (5/80, 6.3%), adenovirus (11/80, 13.8%), and EBV (71/80, 88.8%) were detected in our study population. There was no statistically significant difference in the frequency of these viruses across different diagnostic groups. Quantification of EBV load demonstrated no differences between the PTA and the elective tonsillectomy group, nor between the abscessed and non-abscessed tonsil of PTA patients. In summary, our data do not support a significant role for the examined viruses in the pathogenesis of PTA.

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect. METHODS: Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function. RESULTS: After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71 ± 3.2% and 67 ± 4.6% (p = 0.4) before treatment, but decreased significantly in both groups to 58 ± 5.2% and 32 ± 8.8% (p < 0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio. CONCLUSION/INTERPRETATION: Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT. TRIAL REGISTRATION: ClinicalTrials.gov NCT00784745. FUNDING: This study was supported by a grant from the Novo Nordisk Foundation.