Effects of intraduodenal infusion of lauric acid and L-tryptophan, alone and combined, on glucoregulatory hormones, gastric emptying and glycaemia in healthy men.

BACKGROUND AND AIM: In healthy men, intraduodenal administration of the fatty acid, lauric acid ('C12') and the amino acid, L-tryptophan ('TRP'), at loads that individually do not affect energy intake, reduce energy intake substantially when combined. C12 and TRP may also stimulate cholecystokinin and glucagon-like peptide-1 (GLP-1), which both slow gastric emptying, a key determinant of postprandial blood glucose. Accordingly, combination of C12 and TRP has the potential to reduce post-meal glycaemia more than either nutrient alone. METHODS: Twelve healthy, lean men (age (mean ± SD): 28 ± 7 years) received, on 4 separate occasions, 45-min intraduodenal infusions of C12 (0.3 kcal/min), TRP (0.1 kcal/min), C12 + TRP (0.4 kcal/min), or 0.9% saline (control), in a randomised, double-blind fashion. 30 min after commencement of the infusion a mixed-nutrient drink was consumed and gastric emptying measured (13C breath-test) for 3 h. Blood samples were obtained at baseline, in response to treatments alone, and for 2 h post-drink for measurements of plasma glucose, cholecystokinin, GLP-1, C-peptide, insulin and glucagon. 'Early' (first 30 min) and 'overall' glycaemic and hormone responses were evaluated. RESULTS: C12 + TRP and C12 delayed the rise in, but did not affect the overall glycaemic response to the drink, compared with control and TRP (all P < 0.05). C12 + TRP slowed gastric emptying compared with control and TRP (both P < 0.005), and C12 non-significantly slowed gastric emptying compared with control (P = 0.090). C12 + TRP and C12 delayed the rise in C-peptide and insulin, and also stimulated CCK and glucagon, compared with control and TRP (all P < 0.05). Only C12 + TRP stimulated early and overall GLP-1 compared with control (P < 0.05). CONCLUSIONS: In healthy men, C12 + TRP and C12, in the loads administered, had comparable effects to delay the rise in glucose following a nutrient drink, probably primarily by slowing of gastric emptying, as a result of CCK and GLP-1 stimulation, while TRP had no effect.

Heat acclimation mediated cardioprotection is controlled by mitochondrial metabolic remodeling involving HIF-1α.

Heat acclimation (HA) induces metabolic plasticity to resist the effects of environmental heat with cross-tolerance to novel stressors such as oxygen supply perturbations, exercise, and alike. Our previous results indicated that hypoxia inducible transcription factor (HIF-1α) contributes to this adaptive process. In the present study, we link functional studies in isolated cardiomyocytes, with molecular and biochemical studies of cardiac mitochondria and demonstrate that HA remodels mitochondrial metabolism and performance. We observed the significant role that HIF-1α plays in the HA heart, as HA reduces oxidative stress during ischemia by shifting mitochondrial substrate preference towards pyruvate, with elevated level and activity of mitochondrial LDH (LDHb), acting a pivotal role. Increased antioxidative capacity to encounter hazards is implicated. These results deepen our understanding of heat acclimation-mediated cross tolerance (HACT), in which adaptive bioenergetic-mechanisms counteract the hazards of oxidative stress.

Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

Touch DNA: The effect of the deposition pressure on the quality of latent fingermarks and STR profiles.

Latent fingermarks (FMs) present unique, and sometimes the only, evidence found at a crime scene. Several factors affect their quality, including deposition pressure (DP). Its effect on FM size and quality, and on STR amplification success rate, is an emerging area of interest in forensic science. This study examined 540 FM samples, each consisting of index, middle and ring fingers, deposited by 30 donors on glass, polythene (PE) and paper under a range of weights from 0.1 to 10 kg. Both length and width of FMs increased with the increasing DP. FMs deposited under lower (≤0.5 kg) DPs varied in size (p < 0.01), while those deposited at higher (≥3 kg) DPs were more consistent. FM quality on glass and PE, as determined by the AFIS minutiae count and by a fingerprint examiner on a scale from 0 to 4, improved with the increasing DP, but it deteriorated on PE at DP of 10 kg. FM quality on paper continued to improve from DP of 1 kg up to the maximum DP of 10 kg. The effect DP has on the efficacy of DNA profiling from latent FMs was significant as shown by an increase in the DNA amount recovered, the number of amplified loci per FM sample, and the number of forensically useful DNA profiles (defined here as those with ≥8 full STR loci detected) as DP increased. This effect was most pronounced with PE (R = 0.98) and paper (R = 0.96). Altogether, the success rate of DNA profiling varied from 16.3% in FMs deposited on paper to 21.2% and 22.5% of those on PE and glass. The highest number of useful DNA profiles was obtained from glass under DP of 10 kg. Forensically useful FMs obtained at low (≤1 kg) DP from all three substrates significantly outnumbered that of STR profiles, while an opposite, though less pronounced trend, was observed at high (≥3 kg) DP on PE and paper. Application of the simple device for collecting of FMs under controlled pressure designed for this study, and the palm-up mode of FM deposition as described, allowed us to eliminate the undesirable effect of the hand self-weight and to objectively assess the actual effect of increasing DP on FM size and quality, as well as on the efficacy of DNA profiling.

Automated electrotransformation of Escherichia coli on a digital microfluidic platform using bioactivated magnetic beads.

This paper reports on the use of a digital microfluidic platform to perform multiplex automated genetic engineering (MAGE) cycles on droplets containing Escherichia coli cells. Bioactivated magnetic beads were employed for cell binding, washing, and media exchange in the preparation of electrocompetent cells in the electrowetting-on-dieletric (EWoD) platform. On-cartridge electroporation was used to deliver oligonucleotides into the cells. In addition to the optimization of a magnetic bead-based benchtop protocol for generating and transforming electrocompetent E. coli cells, we report on the implementation of this protocol in a fully automated digital microfluidic platform. Bead-based media exchange and electroporation pulse conditions were optimized on benchtop for transformation frequency to provide initial parameters for microfluidic device trials. Benchtop experiments comparing electrotransformation of free and bead-bound cells are presented. Our results suggest that dielectric shielding intrinsic to bead-bound cells significantly reduces electroporation field exposure efficiency. However, high transformation frequency can be maintained in the presence of magnetic beads through the application of more intense electroporation pulses. As a proof of concept, MAGE cycles were successfully performed on a commercial EWoD cartridge using variations of the optimal magnetic bead-based preparation procedure and pulse conditions determined by the benchtop results. Transformation frequencies up to 22% were achieved on benchtop; this frequency was matched within 1% (21%) by MAGE cycles on the microfluidic device. However, typical frequencies on the device remain lower, averaging 9% with a standard deviation of 9%. The presented results demonstrate the potential of digital microfluidics to perform complex and automated genetic engineering protocols.

Effects of small intestinal glucose on glycaemia, insulinaemia and incretin hormone release are load-dependent in obese subjects.

BACKGROUND/OBJECTIVES: Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects. SUBJECTS/METHODS: Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m-2) and 12 controls (age 34.7±4.0 years, BMI 23.9±0.7 kg m-2) received intraduodenal infusions of glucose at 1 or 3 kcal min-1, or saline for 60 min (t=0-60 min), followed by intraduodenal saline (t=60-120 min). In obese subjects, an oral glucose tolerance test was performed. Blood glucose, serum insulin, plasma total GLP-1 and total gastric inhibitory polypeptide (GIP) were measured. RESULTS: In both the groups (P<0.001), the incremental areas under the curve (iAUC)0-60 min for glucose was greater with the 3 kcal min-1 than the 1 kcal min-1 infusion; the iAUC0-120 min for glucose during 3 kcal min-1 was greater (P<0.05), in the obese. Insulin responses to 1 kcal min-1 and, particularly, 3 kcal min-1 were greater (P<0.001) in the obese. Stimulation of GLP-1 and GIP were greater (P<0.001) in response to 3 kcal min-1, compared with 1 kcal min-1 and saline, without any difference between the groups. In the obese, glycaemic, insulinaemic and GIP, but not GLP-1, responses to oral and intraduodenal glucose were related (P<0.05). CONCLUSIONS: The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.

Can we agree on patient-reported outcome measures for assessing hematopoietic cell transplantation patients? A study from the CIBMTR and BMT CTN.

Much research into the impact of hematopoietic cell transplantation (HCT) on recipients' symptoms, functioning and health-related quality of life uses diverse patient-reported outcome (PRO) measures. Robust conclusions regarding PROs in HCT patients are constrained by methodological issues, including the use of multiple different and noncomparable assessment measures. We reviewed 114 publications addressing PROs in HCT patients. Although three multi-item measures were most frequently used (FACT-BMT, n=28; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30, n=26; and SF-36, n=26), 25 additional measures were used in more than one study. Another 50 measures were used in single studies. Over 50% of studies used more than one measure. We recommend that the field agrees upon a set of measures to address the core domains important to patients, to reduce heterogeneity and allow comparisons across studies and between different populations. Measures should be available in a free and easily accessible manner internationally. We discuss the relative benefits of the National Institutes of Health-supported Patient-Reported Outcomes Measurement Information System (PROMIS) system to achieve these goals. To further address these issues, the Blood and Marrow Transplant Clinical Trials Network has recently created a task force to implement PROMIS measures alongside traditional PRO measures in future clinical trials. Robust comparisons between measures in this setting may allow for the development of a standard for HCT patients.

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Experimental demonstration of nonlinear pulse propagation in a fiber Bragg grating written in a fiber amplifier.

We study experimentally nonlinear propagation of sub-nanosecond optical pulses in a fiber Bragg grating written in a Ytterbium-doped fiber amplifier (YD-FBG). The magnitude and the sign of group velocity dispersion (GVD) in YD-FBG can be controlled by adjusting the fiber tension. In the case of anomalous GVD, pulse breakup was observed due to modulation instability. However, for the same input pulse power in the normal GVD regime, the output pulse duration was increased, and pulse breakup was not observed. The deterioration of pulse spectrum due to Raman and four-wave mixing effect was also reduced in the normal GVD regime. Since GVD in YD-FBG is six orders of magnitude higher than in standard fibers, the advantages of normal GVD in fiber amplifiers that were demonstrated in previous works for femtosecond and picosecond pulses can be exploited for amplifying sub-nanosecond pulses. The experimental results are in good agreement with numerical simulations. We have also demonstrated a gain coefficient enhancement by a factor of 1.7 due to slow-light propagation in the YD-FBG.

The duodenal glucose load impacts the oral disposition index in healthy subjects.

AIM: In healthy subjects, the oral disposition index (ratio of insulin response to insulin sensitivity) is predictive of the development of Type 2 diabetes. Gastric emptying, which exhibits a substantial interindividual variation, is a major determinant of postprandial glycaemia in health and diabetes. We sought to determine whether the rate of intraduodenal glucose delivery affects the disposition index in people without diabetes. METHODS: Nineteen Caucasian males received glucose infusions via an intraduodenal catheter at either 2 kcal/min (ID2) or 4 kcal/min (ID4) for 120 min, on two separate days with measurements of blood glucose (G) and plasma insulin (I) at frequent intervals. The insulin response was estimated by the ratio of the change in insulin to that of change in glucose at 30 min (∆I(0-30)/∆G(0-30)) and 60 min (∆I(0-60)/∆G(0-60)). Insulin sensitivity was estimated as 1/fasting insulin. The oral disposition index (DI) was calculated as ∆I(0-30)/∆G(0-30) × 1/fasting insulin and ∆I(0-60)/∆G(0-60) × 1/fasting insulin. RESULTS: The overall glycaemic response was comparable on both days, but the insulin response was much greater at ID4 when calculated at either 30 or 60 min (P < 0.05). DI was also greater (P < 0.05) in response to ID4 than ID2. CONCLUSIONS: The rate of duodenal glucose delivery has a major impact on insulin release and, thereby, DI. This suggests that the rate of gastric emptying, which determines duodenal glucose delivery, is a determinant of DI.

Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males.

The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and blood glucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum and duodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min(-1) over 120 min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity, age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was sampled frequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as the insulin:glucose ratio and the insulinogenic index 1 (IGI1) were greater (P<0.05 for each) after intrajejunal (i.j.) than intraduodenal glucose infusion, without a significant difference in blood glucose or plasma glucagon. Pooled analyses revealed direct relationships between IGI1 and the responses of GLP-1 and GIP (r=0.48 and 0.56, respectively, P<0.05 each), and between glucagon and GLP-1 (r=0.70, P<0.001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion than intraduodenal glucose in healthy humans, suggesting regional specificity of the gut-incretin axis.

Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma.

Autologous hematopoietic cell transplantation (Auto-HCT) is commonly an in-patient procedure. However, Auto-HCT is increasingly being offered on an outpatient basis. To better characterize the safety of outpatient Auto-HCT, we compared the outcome of 230 patients who underwent Auto-HCT on an in-patient vs outpatient basis for myeloma or lymphoma within a single transplant program. All outpatient transplants occurred in a cancer center day hospital. Hematopoietic recovery occurred earlier in the outpatient cohort, with median time to neutrophil recovery of 10 vs 11 days (P<0.001) and median time to platelet recovery of 19 vs 20 days (P=0.053). Fifty-one percent of the outpatient cohort never required admission, with this percentage increasing in later years. Grade 3-4 non-hematologic toxicities occurred in 29% of both cohorts. Non-relapse mortality at 1 year was 0% in the outpatient cohort and 1.5% in the in-patient cohort (P=0.327). Two-year PFS was 62% for outpatient vs 54% for in-patient (P=0.155). One- and two-year OS was 97% and 83% for outpatient vs 91% and 80% for in-patient, respectively (P=0.271). We conclude that, with daily outpatient evaluation and aggressive supportive care, outpatient Auto-HCT can result in excellent outcomes for myeloma and lymphoma patients.

Measurement of resonant and nonresonant induced refractive index changes in Yb-doped fiber grating amplifier.

We have measured the refractive index change (RIC) induced in a fiber Bragg grating (FBG) written in a Yb-doped fiber amplifier (YB-FBG) because of the amplifier pumping. The measurement was performed by exploiting the high sensitivity of the YD-FBG transmission to the RIC. We have separated between electronic and thermal contributions to the RIC based on the difference between the time-scales of the two effects. Because of high UV-induced loss in FBGs, the thermal contribution to the RIC is increased, in comparison with previously published work, where no grating was written in the fiber amplifier. The measurement method allows us to find the sign of each contribution to the RIC, and it requires only a few centimeters of fiber. Optimal pumping scheme for reducing the RIC in a YB-FBG is studied.

Islet cell transplantation in Australia: screening, remote transplantation, and incretin hormone secretion in insulin independent patients.

Islet cell transplantation has emerged as a treatment modality for type 1 diabetes in the last 15 years due to the Edmonton protocol leading to consistent and sustained exogenous insulin independence post-transplantation. In recent years, consortia that involve both local and remote islet cell centers have been established, with local centers responsible for processing and shipping of islet cells, and remote centers only transplanting them. There are, however, few data on patient outcomes at remote centers. A tendency for high fasting glucose despite insulin independence was noted by us and others with an unknown mechanism. This review provides a brief history of islet cell transplantation, and focuses on the South Australian remote center experience: the challenges, screening criteria, and the impact on incretin hormone secretion of insulin independent transplant patients.

Effects of sitagliptin on blood pressure and heart rate in response to intraduodenal glucose infusion in patients with Type 2 diabetes: a potential role for glucose-dependent insulinotropic polypeptide?

AIMS: To evaluate the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on blood pressure and heart rate, measured during a previously reported study, in which the effects of sitagliptin during intraduodenal glucose infusion at the rate of 2 kcal/min on glucose homeostasis were examined in patients with Type 2 diabetes. METHODS: A total of 10 people with Type 2 diabetes were studied on two different days, 30 min after oral ingestion of sitagliptin (100 mg) or placebo. Intraduodenal glucose was infused at 2 kcal/min (60 g over 120 min), and blood pressure, heart rate, plasma glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (total and intact), glucose, insulin and glucagon responses were evaluated. RESULTS: In response to intraduodenal glucose infusion, heart rate (treatment effect: P = 0.001) and serum insulin concentration (treatment × time interaction: P = 0.041) were higher after sitagliptin treatment than placebo, without a significant difference in blood pressure, plasma glucagon or glucose. During intraduodenal glucose infusion, there was a substantial increase in plasma total glucose-dependent insulinotropic polypeptide on both days (time effect: P < 0.001), but not in total glucagon-like peptide-1. After sitagliptin, plasma intact glucagon-like peptide-1 concentration increased slightly (treatment × time interaction: P = 0.044) and glucose-dependent insulinotropic polypeptide concentration increased substantially (treatment × time interaction: P = 0.003).The heart rate response to intraduodenal glucose was related directly to plasma intact glucose-dependent insulinotropic polypeptide concentrations (r = 0.75, P = 0.008). CONCLUSIONS: Sitagliptin increased the heart rate response to intraduodenal glucose infusion at 2 kcal/min in people with Type 2 diabetes, which was associated with augmentation of plasma intact glucose-dependent insulinotropic polypeptide concentrations. These observations warrant further clarification of a potential role for glucose-dependent insulinotropic polypeptide in the control of the 'gut-heart' axis.