The gut microbiome plays an important role in regulation of metabolic processes, including digestion, absorption, and synthesis of bioactive molecules that signal physiological host mechanisms. Changes in the human gut microbiome are associated with type 2 diabetes and insulin resistance. Water-soluble dietary fibres like inulin and beta-glucan are fermented in the colon, and beta-glucan increases viscosity. Blueberries improve insulin sensitivity through an antioxidant effect. A cobiotic, consisting of purified inulin, sugar-free blueberry pomace extract, and an oat preparation of purified beta-glucan was developed for twice a day (bid) consumption as a smoothie drink to repair the gastrointestinal dysbiosis in type 2 diabetes. A 30-year-old man presented with new onset type 2 diabetes and a fasting glucose (FBS) of 375 mg/dl. Metformin 500 mg bid was initiated and increased to 1 g bid after 1 week. During the first 9 days of metformin treatment, he developed diarrhoea, but his FBS only dropped to 325 mg/dl. The cobiotic bid was added on the 9th day of metformin treatment, and after 2 days, his FBS dropped to 175 mg/dl. After 8 weeks on metformin and the cobiotic, his blood sugar was 100 mg/dl and he lost 5.5 kg. His stools became soft and formed on the cobiotic, reverted to diarrhoea when off of it for 2 days, and returned to normal on resuming the cobiotic formulation. Metformin is a safe, effective and inexpensive generic medication favouring weight loss, recommended as initial treatment of type 2 diabetes by the American Diabetes Association. However, a 20% incidence of diarrhoea limits its tolerability. A safe food supplement that can increase the efficacy of metformin and its tolerability, as occurred in this case report, would have significant positive public health consequences. A controlled clinical trial of the cobiotic with metformin is planned.

AIM:

Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents.

MATERIALS AND METHODS:

Post-hoc analysis of 312 diabetic and 1,957 non-diabetic gout patients (baseline serum urate levels [sUA] ≥8.0 mg/dL) enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout, and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA <6.0mg/dL. Safety was monitored throughout the trial.

RESULTS:

Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (BMI >30 kg/m(2) ) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p <0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhea and URIs as the most common AEs.

CONCLUSIONS:

Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dL more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.

The gastrointestinal microbiota is a complex ecosystem with each human individual hosting at least 160 different bacterial strains. Our understanding of its role is rapidly expanding as a result of the molecular microbiological techniques that can accurately characterise its composition and 'omics' technologies that measure its metabolic activity. Since 1995, extensive research has investigated the prebiotic concept, which describes how supplementation of some non-digestible oligosaccharides can stimulate the growth and/or activity of specific genera including bifidobacteria. However, the vast majority of studies are in healthy human subjects, with few undertaken in patients with disorders relevant to clinical nutrition. Marked alterations of the luminal microbiota have been demonstrated in patients with digestive disorders, highlighting mechanisms through which they might be involved in their pathogenesis, including higher clostridia in patients who develop diarrhoea during enteral nutrition and the influence of bifidobacteria on intestinal dendritic cell phenotype in Crohn's disease. The impact of prebiotics on the intestinal microbiota of healthy people has not been consistently replicated in patients with digestive disorders. For example, a number of studies show that inulin/oligofructose do not increase bifidobacteria in enteral nutrition and Crohn's disease. Indeed, in Crohn's disease and irritable bowel syndrome there is evidence that some prebiotics in high doses worsen functional symptoms. Unlike healthy human subjects, patients experience a number of issues that may alter their gastrointestinal microbiota (disease, antibiotics and inflammation) and the use of microbiota modifying therapies, such as prebiotics, do not always elicit the same effects in patients as they do in healthy people.

OBJECTIVE:

The aim of this study was to evaluate the association of serum magnesium levels with proton pump inhibitors (PPIs) use and other factors.

METHODS:

This was a cross-sectional study of 151 patients admitted with acute diseases in the Internal Medicine Division of the Hospital de Clinicas de Porto Alegre, after the exclusion of conditions that are commonly associated with hypomagnesemia: diarrhea; vomiting; chronic alcohol use; severely uncompensated diabetes mellitus; and chronic use of laxatives, diuretics or other drugs causing magnesium deficiency.

RESULTS:

All patients had normal serum magnesium levels. Serum albumin and creatinine levels were positively associated with serum magnesium levels, after adjusting for confounders. There was no difference between mean serum magnesium levels of PPI users and non-users, nor between men and women; there was also no correlation among age, serum phosphorus, and potassium levels with serum magnesium levels. Limitations of this study include the absence of an instrument for measuring adherence to PPI use and the sample size.

CONCLUSION:

The association of PPI use and hypomagnesemia is uncommon. Congenital defects in the metabolism of magnesium may be responsible for hypomagnesemia in some patients using this drug class.

Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths. METHODOLOGYPRINCIPAL FINDINGS: We undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co-morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart.In our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co-morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions.

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an anti-inflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective anti-inflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for COPD patients with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include ?extended indications of roflumilast (i) in patients with COPD and (ii) in other respiratory (e.g., asthma) and non-respiratory chronic inflammatory/metabolic conditions (eg diabetes) ?as well as (iii) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile.

INTRODUCTION:

: Thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia. Previous studies have shown that cyclosporine (CsA) is associated with TMA but the number of reported cases is very limited. We describe a 13-year-old girl with CsA-associated TMA and thrombocytopenia-associated multiple organ failure (TAMOF).

CASE REPORT:

: The patient was diagnosed with polyglandular deficiency syndrome and had a history of celiac disease, autoimmune thyroiditis, and diabetes mellitus type I. CsA was started 7 months before her admission to our pediatric intensive care unit for persistent diarrhea associated with celiac disease. At the time of her admission to our pediatric intensive care unit, she was thrombocytopenic and anemic with multiple organ failure. Laboratory and clinical findings were consistent with TMA and TAMOF. CsA was discontinued and therapeutic plasma exchange was performed daily for 5 days. The patient improved clinically, laboratory findings normalized, and TMA and multiple organ failure dissolved.

CONCLUSION:

: This case report indicates that therapeutic plasma exchange may be effective in the treatment of CsA-associated TMA and TAMOF, especially in the presence of systemic findings.

BACKGROUND:

There are concerns about the extent of impaired endocrine and exocrine pancreatic function and poor quality of life (QoL) after pancreatectomy, but there is little information from large prospective follow-up studies.

METHODS:

Consecutive patients undergoing pancreaticoduodenectomy or distal pancreatectomy between 2007 and 2011 were included. Relative bodyweight (RBW), triceps skinfold thickness (TSFT), serum protein, albumin, transferrin, fasting blood glucose, postprandial 2-h glucose (PP2), glycosylated haemoglobin A1c and stool elastase measurements, and European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires were collected serially for 1 year.

RESULTS:

Some 136 patients undergoing pancreatic resection completed the study. RBW and TSFT recovered to over 90 per cent of the preoperative value by 12 months, whereas transferrin, albumin and protein had returned to preoperative levels by 3 months. Diabetes mellitus, impaired fasting glucose or raised PP2 was present in 42 of 76 patients at 6 months and 36 of 76 at 12 months. Although steatorrhoea and diarrhoea had mainly resolved by 3 months, stool elastase level decreased after operation and showed no recovery. Nutritional status, pancreatic endocrine function and QoL returned to preoperative levels in 63 (46·3 per cent), 72 (52·9 per cent) and 77 (56·6 per cent) of 136 patients within 6 months of pancreatectomy. Multivariable analysis revealed that age 60 years or more, operation type, chronic pancreatitis and malignant disease had a significant impact on nutritional index, pancreatic function and QoL.

CONCLUSION:

About half of all patients can expect recovery from pancreatectomy after 6 months, but those with risk factors need more careful follow-up and supportive management.

Chinese bayberry (Myrica rubra Sieb. et Zucc.) is a subtropical fruit tree native to China and other Asian countries, and culture of this Myricaceae plant has been recorded in Chinese history for more than 2000 years. Bayberry fruit is delicious with attractive color, flavor, and high economic value. Compared with other berries, bayberry fruit is a rich source of cyanidin-3-glucoside (C3G, e.g., 64.8 mg/100 g fresh weight in 'Biqi' cultivar), which accounts for at least 85 % of the anthocyanins in the fruit. Bayberry is also a plant with high medicinal value since different organs have been used historically as folk medicines. Research efforts suggest bayberry extracts contain antioxidants that exhibit bioactivities counteracting inflammation, allergens, diabetes, cancer, bacterial infection, diarrhea and other health issues. Bayberry compounds have been isolated and characterized to provide a better understanding of the chemical mechanisms underlying the biological activities of bayberry extracts and to elaborate the structure-activity relationships. As the identification of compounds progresses, studies investigating the in vivo metabolism and bioavailability as well as potential toxicity of bayberry extracts in animal models are receiving more attention. In addition, breeding and genetic studies of bayberry with high accumulation of health-benefiting compounds may provide new insight for the bayberry research and industry. This review is focused on the main medicinal properties reported and the possible pharmaceutically active compounds identified in different bayberry extracts.

AIMS/

HYPOTHESIS:

The aim of this work was to compare treatment intensification strategies based on orally administered vs injectable incretin-based antihyperglycaemic agents in patients with type 2 diabetes mellitus on metformin monotherapy.

METHODS:

In a 26 week, open-label study, 653 patients (baseline HbA1c = 8.2% [66 mmol/mol]) were randomised at 111 sites in 21 countries in a 1:1 ratio to a strategy using oral agents (starting with sitagliptin 100 mg/day) or a strategy using the injectable drug liraglutide starting at a dose of 0.6 mg/day, up-titrated to 1.2 mg/day after 1 week. The following patients with type 2 diabetes mellitus were recruited for the study: those aged 18-79 years, on a stable dose of metformin monotherapy ≥1,500 mg/day for ≥12 weeks, with an HbA1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) and a fasting fingerstick glucose (FFG) <15 mmol/l (<270 mg/dl) at the randomisation visit, deemed capable by the investigator of using a Victoza pen injection device (containing 6 mg/ml liraglutide; Novo Nordisk, Bagsværd, Denmark). Women taking part in the study agreed to remain abstinent or use an acceptable method of birth control during the study. Randomisation was performed via a computer-generated allocation schedule using an interactive voice response system. After 12 weeks, patients on sitagliptin with HbA1c  ≥ 7.0% (53 mmol/mol) and fasting glucose >6.1 mmol/l had their treatment intensified with glimepiride; patients on liraglutide with HbA1c  ≥ 7.0% (53 mmol/mol) had the dose up-titrated to 1.8 mg/day. The primary analysis assessed whether the strategy using oral drugs was non-inferior to that using an injectable drug regarding HbA1c change from baseline at week 26 using a per-protocol (PP) population and a non-inferiority margin of 0.4%.

RESULTS:

In the PP population (522 patients included: oral strategy, n = 269; injectable strategy, n = 253) antihyperglycaemic therapy was intensified at week 12 in 50.2% and 28.5%, respectively. HbA1c decreased over 26 weeks in both treatment strategy groups, with a larger initial reduction at week 12 in the injectable strategy group. The LS mean change in HbA1c at week 26 was -1.3% (95% CI -1.4, -1.2) in the oral strategy group and -1.4% (95% CI -1.5, -1.3) in the injectable strategy group; the study met the non-inferiority criterion. Both treatment regimens were generally well tolerated; hypoglycaemia was reported more often with the oral strategy, while nausea, vomiting, diarrhoea and abdominal pain were reported more often with the injectable strategy.

CONCLUSIONS

/

INTERPRETATION:

An oral, incretin-based treatment strategy with sitagliptin and, if needed, glimepiride may be a good approach in many patients with type 2 diabetes mellitus for managing inadequate glycaemic control on metformin monotherapy, as compared with an injectable treatment strategy with liraglutide. The oral and injectable strategies had similar effects on HbA1c and had good overall tolerability. Trial registration ClinicalTrials.gov NCT01296412 Funding The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc., Whitehouse Station, NJ, USA.