The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation.

Intercellular communication via gap junctions has a fundamental role in regulating cell growth and tissue homeostasis, and its dysregulation may be involved in cancer development and radio- and chemotherapy resistance. Connexin43 (Cx43) is the most ubiquitously expressed gap junction channel protein in human tissues. Emerging evidence indicates that dysregulation of the sorting of Cx43 to lysosomes is important in mediating the loss of Cx43-based gap junctions in cancer cells. However, the molecular basis underlying this process is currently poorly understood. Here, we identified the E3 ubiquitin ligase ITCH as a novel regulator of intercellular communication via gap junctions. We demonstrate that ITCH promotes loss of gap junctions in cervical cancer cells, which is associated with increased degradation of Cx43 in lysosomes. The data further indicate that ITCH interacts with and regulates Cx43 ubiquitination and that the ITCH-induced loss of Cx43-based gap junctions requires its catalytic HECT (homologous to E6-AP C-terminus) domain. The data also suggest that the ability of ITCH to efficiently promote loss of Cx43-based gap junctions and degradation of Cx43 depends on a functional PY (PPXY) motif in the C-terminal tail of Cx43. Together, these data provide new insights into the molecular basis underlying the degradation of Cx43 and have implications for the understanding of how intercellular communication via gap junctions is lost during cancer development.

The Impact of Social Determinants of Health on Medication Adherence: a Systematic Review and Meta-analysis.

BACKGROUND: Medication adherence (MA) is critical to successful chronic disease management. It is not clear how social determinants of health (SDH) impact MA. We conducted a systematic review and meta-analysis to summarize the evidence on the relationship between SDH and MA. METHODS: We conducted a systematic review of the literature using a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) format. A literature search was performed using three databases: PubMed, Scopus, and Cochrane Clinical Trials Register in December of 2018. Included studies were completed in the USA, included adults aged 18 years and older, measured at least one social determinant of health, and medication adherence was the primary outcome measure. Data from included full texts were independently extracted using a standardized data extraction form. We then conducted a meta-analysis and pooled the odds ratios from the included studies for each social determinant as well as for all SDH factors collectively. RESULTS: A total of 3137 unduplicated abstracts were identified from our database searches. A total of 173 were selected for full text review after evaluating the abstract. A total of 29 articles were included for this systematic review. Economic-related SDH factors and MA were mostly commonly examined. The meta-analysis revealed a significant relationship between food insecurity (aOR = 0.56; 95% CI 0.42-0.7), housing instability (aOR = 0.64; 95% CI 0.44-0.93), and social determinants overall (aOR = 0.75; 95% CI 0.65-0.88) and medication adherence. DISCUSSION: Food insecurity and housing instability most consistently impacted medication adherence. Although included studies were heterogenous and varied widely in SDH and MA measurements, adverse social determinants overall were significantly associated with lower MA. The relationship between SDH and MA warrants more attention and research by health care providers and policymakers.

Sustained Chemosensory Dysfunction during the COVID-19 Pandemic.

INTRODUCTION: Chemosensory dysfunction (CD) has proven valuable in prediction of COVID-19, as it is a frequent and specific symptom of the disease. The aim of this study was to investigate the duration of CD in patients with sudden subjective olfactory and/or gustatory loss during the SARS-CoV-2 pandemic. The secondary aim was to identify possible prognostic factors for the duration of CD. METHODS: An online baseline questionnaire was designed to assess subjective CD. Three rounds of follow-up questionnaires were sent out to any participants with persistent CD in 6-week intervals, prospectively assessing subjective chemosensory function and extending the follow-up time of this cohort significantly. RESULTS: In total, 467 participants completed the baseline questionnaire. The most significant improvement and recovery of chemosensory function was observed within the first month after the initial loss. Rates became stagnant after about 2 months, and only little improvement and recovery was seen after 2-4 months. After a mean follow-up of 95.9 days (olfactory dysfunction) and 94.0 days (gustatory dysfunction), 86.7% of participants reported gustatory improvement and 82.6% reported olfactory improvement, while 55.0% reported full gustatory recovery and 43.8% reported full olfactory recovery. Female gender was associated with better improvement of gustatory function. High subjective severity of chemosensory loss was associated with lower rates of olfactory and gustatory recovery as well as improvement of olfactory function. Young age was not associated with a better prognosis. DISCUSSION/CONCLUSION: Rates of improvement and recovery of chemosensory function decreased after 2-4 months after initial chemosensory loss, possibly indicating that prolonged and perhaps permanent chemosensory loss may be a complication of SARS-CoV-2 infections. High subjective severity of CD may worsen the prognosis for improvement and recovery of chemosensory function.

Long-term cardiac computed tomography follow-up after left atrial appendage occlusion.

BACKGROUND: Left atrial appendage occlusion (LAAO) is performed increasingly, but long-term follow-up imaging data are lacking. AIMS: The aim of this study was to evaluate the safety and durability of the Amplatzer Amulet device >4 years after LAAO. METHODS: This was a prospective observational cohort study including 52 patients implanted with the Amplatzer Amulet device at Aarhus University Hospital, Denmark. A >4-year follow-up cardiac computed tomography (CT) scan after LAAO was performed and compared with the results from the 2-month and 12-month scans. The primary outcome was left atrial appendage (LAA) sealing based on distal LAA contrast patency and peridevice leakage (PDL), stratified into complete occlusion (grade 0 [G0]) and grade 1-3 leakage (G1-3), respectively. Secondary outcomes were low- and high-grade hypoattenuated thickening (HAT), device-related thrombosis (DRT) and device durability. RESULTS: The median (interquartile range [IQR]) follow-up time from LAAO to the latest CT scan was 5.8 years (4.5; 6.3). At 2-month (n=52), 12-month (n=27) and >4-year CT follow-ups (n=52), rates of both complete occlusion (33%, 37%, 35%) and G2 leaks (52%, 52%, 48%) remained stable. Rates of G1 leaks varied (14%, 4%, 6%) and G3 leaks rose (2%, 7%, 12%) from earliest to latest follow-up. The median left atrial (LA) volume increased from 127 mL (96; 176) to 144 mL (108; 182) and 147 mL (107; 193). No DRT was found. The structural device integrity was preserved. CONCLUSIONS: This study indicates a stable LAA sealing status throughout the follow-up period, emphasising the importance of the procedural result in avoiding PDL. Few patients displayed PDL progression, which might partly be related to LA remodelling with increasing volume. The long-term device durability appears excellent. Larger studies are warranted to confirm these findings.

High-fat diet impact on intestinal cholesterol conversion by the microbiota and serum cholesterol levels.

Cholesterol-to-coprostanol conversion by the intestinal microbiota has been suggested to reduce intestinal and serum cholesterol availability, but the relationship between intestinal cholesterol conversion and the gut microbiota, dietary habits, and serum lipids has not been characterized in detail. We measured conserved proportions of cholesterol high and low-converter types in individuals with and without obesity from two distinct, independent low-carbohydrate high-fat (LCHF) dietary intervention studies. Across both cohorts, cholesterol conversion increased in previous low-converters after LCHF diet and was positively correlated with the fecal relative abundance of Eubacterium coprostanoligenes. Lean cholesterol high-converters had increased serum triacylglycerides and decreased HDL-C levels before LCHF diet and responded to the intervention with increased LDL-C, independently of fat, cholesterol, and saturated fatty acid intake. Our findings identify the cholesterol high-converter type as a microbiome marker, which in metabolically healthy lean individuals is associated with increased LDL-C in response to LCHF.

Gut Microbiota and Fecal Microbiota Transplantation in Patients with Food Allergies: A Systematic Review.

The prevalence of food allergies (FAs) has increased considerably in recent decades, with the only available treatment being the avoidance of the specific food items causing the allergy. FAs may have a major impact on quality of life, and it is of great interest to explore new strategies to prevent and treat FAs. Some studies show an altered gut microbiota profile in individuals with FAs, and the modulation of gut microbiota is therefore proposed as a potential strategy for prevention and treatment. This systematic review aimed to investigate: (1) the gut microbiota profile in individuals with FAs compared to healthy individuals and (2) the effect of fecal microbiota transplantation (FMT) on gut microbiota profiles and/or allergy symptoms. A literature search was conducted in PubMed (Medline) on 5 April 2022. Of the 236 publications identified, 12 studies were included based on inclusion and exclusion criteria. Eleven of these studies reported results on the gut microbiota in children with FAs compared to healthy controls (HCs). The majority of studies (six studies) observed no difference in alpha diversity when comparing children with FAs to HCs; however, a difference in beta diversity was observed in five studies. At the phylum level, we observed a high abundance of Firmicutes (six studies) and Proteobacteria (five studies), whereas a low abundance of Bacteroidetes (5 studies) was observed in children with FAs compared to HCs. Of the 12 included studies, four explored the effect of FMT on gut microbiota and/or allergy symptoms. Three studies reported that transferring gut microbiota from children without FAs to germ-free mice, protected the mice against allergic reactions, whereas one study did not report findings on the allergic symptoms. The results on gut microbiota after FMT varied and were too divergent to draw any conclusions. Overall, our results suggest that there are differences in the gut microbiota profile in individuals with FAs compared to individuals without FAs. FMT seems to be a promising strategy to prevent allergic symptoms but needs to be further explored in animal and human models. As the findings in this review are based on a small number of studies (12 studies), further studies are warranted before any clear conclusions can be drawn regarding gut microbiota profiles and the effect of FMT on individuals with FAs.

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster.

Rapamycin is a powerful inhibitor of the TOR (Target of Rapamycin) pathway, which is an evolutionarily conserved protein kinase, that plays a central role in plants and animals. Rapamycin is used globally as an immunosuppressant and as an anti-aging medicine. Despite widespread use, treatment efficiency varies considerably across patients, and little is known about potential side effects. Here we seek to investigate the effects of rapamycin by using Drosophila melanogaster as model system. Six isogenic D. melanogaster lines were assessed for their fecundity, male longevity and male heat stress tolerance with or without rapamycin treatment. The results showed increased longevity and heat stress tolerance for male flies treated with rapamycin. Conversely, the fecundity of rapamycin-exposed individuals was lower than for flies from the non-treated group, suggesting unwanted side effects of the drug in D. melanogaster. We found strong evidence for genotype-by-treatment interactions suggesting that a 'one size fits all' approach when it comes to treatment with rapamycin is not recommendable. The beneficial responses to rapamycin exposure for stress tolerance and longevity are in agreement with previous findings, however, the unexpected effects on reproduction are worrying and need further investigation and question common believes that rapamycin constitutes a harmless drug.

Effects of Plant-Based Diets on Weight Status: A Systematic Review.

There is an increasing number of people who convert to a plant-based diet. The desire for health benefits, including weight management, is often a contributing factor behind this dietary choice. The purpose of this review was to evaluate intervention studies assessing the effects of different plant-based diets on body mass index and weight. A literature search was conducted in PubMed until December 2019. Twenty-two publications from 19 studies were included. The majority of them were randomized controlled trials comparing a low-fat vegan diet to an omnivore diet in participants with overweight, type 2 diabetes mellitus and/or cardiovascular disease. All studies reported weight reductions, of which seven revealed significant differences, and four revealed non-significant differences between the intervention and the control groups. The results suggest that plant-based diets may improve weight status in some patient groups. Due to restrictions in fat intake in many studies, followed by reduced energy intake, the effects of the different interventions differ depending on the specific plant-based diets investigated. Future research should aim to include a representative study population and apply study diets without dietary restrictions.

Effects of Plant-Based Diets on Outcomes Related to Glucose Metabolism: A Systematic Review.

According to the rising prevalence of obesity and metabolic disorders leading to impaired glucose metabolism, effective strategies to prevent and/or delay the onset of disease are of great need. A plant-based diet has been suggested as an effective lifestyle change that may reduce the degree of obesity and improve outcomes related to glucose metabolism. This systematic review aimed to evaluate the effect of a plant-based diet on outcomes related to glucose metabolism. A literature search was conducted in the database PubMed until January 30, 2020. Randomized controlled trials investigating the effect of a plant-based dietary intervention on outcomes related to glucose metabolism in human subjects compared to an omnivorous diet were eligible for inclusion. Of 65 publications identified, nine trials on subjects with overweight/obesity, type 2 diabetes mellitus, or cardiovascular disease were included. Five studies reported that the plant-based intervention significantly improved markers of glycemic control from baseline to end point, of which four revealed a significant improvement in the intervention group compared to the control intervention. The remaining four studies did not observe a significant effect of a plant-based intervention on outcomes related to glucose metabolism. Our findings suggest that a shift to a plant-based diet may lead to favorable effects on glycemic control in individuals diagnosed with type 2 diabetes mellitus and/or obesity. The data were however somewhat conflicting, and the included trials reported results based on different intervention diets and study populations. Overall, no clear conclusions regarding effects of different plant-based diets can be drawn based on the current findings alone.

Supplementation with Low Doses of a Cod Protein Hydrolysate on Glucose Regulation and Lipid Metabolism in Adults with Metabolic Syndrome: A Randomized, Double-Blind Study.

The risk of cardiovascular diseases and type 2 diabetes mellitus are increased in subjects with metabolic syndrome (MetS), and hydrolyzed fish protein may have favorable effects on metabolic health. Here, we investigated the effect of 8 weeks supplementation with 4 g of cod protein hydrolysate (CPH) on glucose metabolism, lipid profile and body composition in individuals with MetS in a double-blind, randomized intervention study with a parallel-group design. Subjects received a daily supplement of CPH (n = 15) or placebo (n = 15). Primary outcomes were serum fasting and postprandial glucose levels. Secondary outcomes were fasting and postprandial insulin and glucagon-like peptide 1 (GLP-1), fasting lipid concentrations and body composition. No difference was observed between CPH and placebo for insulin, glucose or GLP-1 after 8 weeks intervention. Fasting triacylglycerol decreased in both the CPH group and placebo group, with no change between groups. Fasting total cholesterol and low-density lipoprotein cholesterol decreased significantly within both groups from baseline to study end, but no difference was observed between the two groups. In conclusion, supplementing with a low dose of CPH in subjects with MetS for 8 weeks had no effect on fasting or postprandial levels of insulin, glucose or GLP-1, lipid profile or body composition.

The Effect of Supplementation with Low Doses of a Cod Protein Hydrolysate on Satiety Hormones and Inflammatory Biomarkers in Adults with Metabolic Syndrome: A Randomized, Double-Blind Study.

Metabolic syndrome (MetS) is characterised by metabolic abnormalities that increase the risk of developing type 2 diabetes mellitus and cardiovascular disease. Altered levels of circulating ghrelin, several adipokines and inflammatory markers secreted from adipose tissue, such as leptin, adiponectin, tumor necrosis factor alpha, are observed in overweight and obese individuals. We assessed the effect of supplementation with low doses of a cod protein hydrolysate (CPH) on fasting and postprandial levels of acylated ghrelin, as well as fasting levels of adiponectin, leptin and inflammatory markers in subjects with MetS. A multicentre, double-blinded, randomized controlled trial with a parallel group design was conducted. Subjects received a daily supplement of CPH (4 g protein, n = 15) or placebo (0 g protein, n = 15). We observed no effect on fasting or postprandial levels of acylated ghrelin, fasting levels of adiponectin (p = 0.089) or leptin (p = 0.967) after supplementation with CPH, compared to placebo. Overall, our study showed that 8 weeks supplementation with a low dose of CPH in subjects with MetS had no effect on satiety hormones or most of the inflammatory markers, but the levels of high-sensitivity C-reactive protein were statistically significantly different in the CPH-group compared to placebo group. The robustness and clinical relevance of these findings should be explored in future studies with a larger sample size.

Acute effects of whey protein on energy intake, appetite and gastric emptying in younger and older, obese men.

BACKGROUND: Obesity is becoming more prevalent in older people. A management strategy in obese, young adults is to increase dietary protein relative to other macronutrients. It is not clear if this is effective in obese, older individuals. Obesity may be associated with diminished sensitivity to nutrients. We have reported that a 30-g whey protein drink slows gastric emptying more, and suppresses energy intake less, in older, than younger, non-obese men. The aim of this study was to determine the effect of a 30 g whey protein drink on energy intake, GE and glycaemia in obese, older and younger men. METHODS: In randomized, double-blind order, 10 younger (age: 27 ± 2 years; BMI: 36 ± 2 kg/m²), and 10 older (72 ± 1 years; 33 ± 1 kg/m²), obese men were studied twice. After an overnight fast, subjects ingested a test drink containing 30 g whey protein (120 kcal) or control (2 kcal). Postprandial gastric emptying (antral area, 2D Ultrasound) and blood glucose concentrations were measured for 180 min. At t = 180 min subjects were given a buffet meal and ad libitum energy intake was assessed. RESULTS: Older subjects ate non-significantly less (~20%) that the younger subjects (effect of age, P = 0.16). Whey protein had no effect on subsequent energy intake (kcal) compared to control in either the younger (decrease 3 ± 8%) or older (decrease 2 ± 8%) obese men (age effect P > 0.05, protein effect P = 0.46, age × protein interaction effect P = 0.84). Whey protein slowed gastric emptying, to a similar degree in both age groups (50% emptying time: control vs. protein young men: 255 ± 5 min vs. 40 ± 7 min; older men: 16 ± 5 min vs. 50 ± 8 min; protein effect P = 0.001, age effect P = 0.93, age × protein interaction effect P = 0.13). CONCLUSIONS: Our data suggest that obesity may blunt/abolish the age-related effect of whey protein on suppression of energy intake.

Effects of a Cod Protein Hydrolysate Supplement on Symptoms, Gut Integrity Markers and Fecal Fermentation in Patients with Irritable Bowel Syndrome.

Peptides from fish may beneficially affect several metabolic outcomes, including gut health and inflammation. The effect of fish peptides in subjects with irritable bowel syndrome (IBS) has not previously been investigated, hence this study aimed to evaluate the effect of a cod protein hydrolysate (CPH) supplement on symptom severity, gut integrity markers and fecal fermentation in IBS-patients. A double-blind, randomized parallel-intervention with six weeks of supplementation with 2.5 g CPH (n = 13) or placebo (n = 15) was conducted. The outcomes were evaluated at baseline and the end of the study. The primary outcomes were symptom severity evaluated by the IBS severity scoring system (IBS-SSS) and quality of life. The secondary outcomes included gut integrity markers and pro-inflammatory cytokines in serum, fecal fermentation measured by concentration of short-chain fatty acids (SCFAs) and fecal calprotectin. The groups were comparable at baseline. The total IBS-SSS-scores were reduced in both the CPH-group (298 ± 69 to 236 ± 106, p = 0.081) and the placebo-group (295 ± 107 to 202 ± 103, p = 0.005), but the end of study-scores did not differ (p = 0.395). The concentrations of serum markers and SCFAs did not change for any of the groups. The baseline measures for the whole group showed that the total SCFA concentrations were inversely correlated with the total IBS-SSS-score (r = -0.527, p = 0.004). Our study showed that a low dose of CPH taken daily by IBS-patients for six weeks did not affect symptom severity, gut integrity markers or fecal fermentation when compared to the placebo group.

Erratum: Effect of a cod protein hydrolysate on postprandial glucose metabolism in healthy subjects: a double-blind cross-over trial - CORRIGENDUM.

[This corrects the article DOI: 10.1017/jns.2018.23.].

Acute effect of a cod protein hydrolysate on postprandial acylated ghrelin concentration and sensations associated with appetite in healthy subjects: a double-blind crossover trial.

BACKGROUND: Fish protein hydrolysates are suggested to contain bioactive sequences capable of affecting metabolic pathways involved in the regulation of glucose metabolism and body weight when consumed in low doses. Modulation of the appetite-regulating hormone ghrelin may explain suppression of insulin secretion and weight loss observed in previous studies with fish protein hydrolysates. OBJECTIVE: This study aimed to assess the effect of a single, low dose of cod protein hydrolysate (CPH) before a breakfast meal on postprandial acylated ghrelin concentration and sensations associated with appetite in healthy subjects. DESIGN: In this explorative trial with a crossover design, 41 healthy individuals (15 males and 26 females, age 51 ± 6 years) completed 2 study days separated by 4-7 days of washout. On both study days, a test drink containing 20 mg CPH or casein (control) per kg body weight was given immediately before a standardized breakfast meal. Acylated ghrelin concentrations were measured before test drink/breakfast (baseline) and at time 0, 20, 40, 80, and 180 min postprandially. Sensations associated with appetite were measured by a Visual Analog Scale (100 mm) at baseline and 0, 20, 40, and 180 min postprandially. RESULTS: Statistically, no difference was observed between CPH and control for postprandial acylated ghrelin concentrations (mean difference geometric mean: 1.05 pg/mL, 95% confidence interval [CI]: 0.97-1.13, P = 0.266), or between the total area under the curve (tAUC) for acylated ghrelin after CPH (tAUC = 17518 pg/mL × min, 95% CI: 0-47941) and control (tAUC = 17272 pg/mL × min, 95% CI: 0-48048, P = 0.991). No differences were found between CPH and control for sensation of appetite, according to tAUC of postprandial scores for satiety (P = 0.794) and the feeling of fullness (P = 0.996). CONCLUSION: We did not find an effect of a single dose of CPH on postprandial concentrations of acylated ghrelin or sensations related to feeling of hunger, compared to control. Further studies should aim to evaluate the effect of a supplement with CPH given daily over a period of time.

Supplementation with cod protein hydrolysate in older adults: a dose range cross-over study.

A large proportion of older adults are affected by impaired glucose metabolism. Previous studies with fish protein have reported improved glucose regulation in healthy adults, but the evidence in older adults is limited. Therefore, we wanted to assess the effect of increasing doses of a cod protein hydrolysate (CPH) on postprandial glucose metabolism in older adults. The study was a double-blind cross-over trial. Participants received four different doses (10, 20, 30 or 40 mg/kg body weight (BW)) of CPH daily for 1 week with 1-week washout periods in between. The primary outcome was postprandial response in glucose metabolism, measured by samples of serum glucose and insulin in 20 min intervals for 120 min. The secondary outcome was postprandial response in plasma glucagon-like peptide 1 (GLP-1). Thirty-one subjects aged 60-78 years were included in the study. In a mixed-model statistical analysis, no differences in estimated maximum value of glucose, insulin or GLP-1 were observed when comparing the lowest dose of CPH (10 mg/kg BW) with the higher doses (20, 30 or 40 mg/kg BW). The estimated maximum value of glucose was on average 0·28 mmol/l lower when the participants were given 40 mg/kg BW CPH compared with 10 mg/kg BW (P = 0·13). The estimated maximum value of insulin was on average 5·14 mIU/l lower with 40 mg/kg BW of CPH compared with 10 mg/kg BW (P = 0·20). Our findings suggest that serum glucose and insulin levels tend to decrease with increasing amounts of CPH. Due to preliminary findings, the results require further investigation.

Changes in microbiome diversity following beta-lactam antibiotic treatment are associated with therapeutic versus subtherapeutic antibiotic exposure in cystic fibrosis.

In persons with cystic fibrosis (CF), decreased airway microbial diversity is associated with lower lung function. Conflicting data exist on the impact of short-term antibiotics for treatment of acute pulmonary exacerbations. However, whether differences in antibiotic exposure impacts airway microbiome changes has not been studied. We hypothesized that subtherapeutic beta-lactam antibiotic exposure, determined by the pharmacokinetics and pharmacodynamics (PK/PD) after intravenous (IV) antibiotic administration, would be associated with different patterns of changes in CF airway microbial diversity. Eligible children were enrolled when well; study assessments were performed around the time of pulmonary exacerbation. Plasma drug concentrations and bacterial minimum inhibitory concentrations (MICs) were used to determine therapeutic versus subtherapeutic beta-lactam antibiotic exposure. Respiratory samples were collected from children, and extracted bacterial DNA was amplified for the V4 region of the 16S rRNA gene. Twenty children experienced 31 APEs during the study; 45% (n = 14) of antibiotic courses were deemed therapeutic. Those in the therapeutic group had more significant decreases in alpha diversity at end of treatment and post-recovery compared to baseline than those in the subtherapeutic group. Therapeutic and subtherapeutic beta-lactam use is associated with different patterns of changes in CF airway microbial diversity following antibiotic administration.

Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers.

A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping azathioprine, before returning to normal levels. His oral ulcers improved and he was able to tolerate solid food. This case illustrates that decreased TPMT activity is not the only risk factor for pancytopenia as an adverse reaction to azathioprine. Furthermore, HSV stomatitis may be the presenting symptom of pancytopenia. The timeline of improvement in cell counts illustrated in this patient has implications for the management of suspected azathioprine-induced pancytopenia.

Effect of a cod protein hydrolysate on postprandial glucose metabolism in healthy subjects: a double-blind cross-over trial.

The increased prevalence of lifestyle diseases, such as the metabolic syndrome and type 2 diabetes mellitus (T2DM), calls for more knowledge on dietary treatments targeting the specific metabolic pathways involved in these conditions. Several studies have shown a protein preload before a meal to be effective in lowering the postprandial glycaemic response in healthy individuals and patients with T2DM. The aim of the present study was to assess the effect of a marine protein hydrolysate (MPH) from Atlantic cod (Gadus morhua) on postprandial glucose metabolism in healthy, middle-aged to elderly subjects. This double-blind cross-over trial (n 41) included two study days with 4-7 d wash-out in between. The intervention consisted of 20 mg of MPH (or casein as control) per kg body weight given before a breakfast meal. The primary outcome was postprandial response in glucose metabolism, measured by samples of serum glucose, insulin and plasma glucagon-like peptide 1 (GLP-1) in 20 min intervals for 180 min. In a mixed-model regression analysis, no differences were observed between MPH and control for postprandial glucose concentration (mean difference: -0·04 (95 % CI -0·17, 0·09) mmol/l; P = 0·573) or GLP-1 concentration (mean difference between geometric means: 1·02 (95 % CI 0·99, 1·06) pmol/l; P = 0·250). The postprandial insulin concentration was significantly lower after MPH compared with control (mean difference between geometric means: 1·067 (95 % CI 1·01, 1·13) mIU/l; P = 0·032). Our findings demonstrate that a single dose of MPH before a breakfast meal reduces postprandial insulin secretion, without affecting blood glucose response or GLP-1 levels, in healthy individuals. Further studies with repeated dosing and in target groups with abnormal glucose control are warranted.