Impact of food texture modifications on oral processing behaviour, bolus properties and postprandial glucose responses.

Several studies have demonstrated food texture manipulation on oral processing behaviour (OPB). We explored the effect of texture-differences of equivalent carbohydrate load on OPB, bolus properties and postprandial glycaemic responses (PPG). In a randomised cross-over, within-subjects, non-blinded design, healthy male participants (N = 39) consumed fixed portions of white rice (WR) and rice cake (RC) while being video recorded to measure microstructural eating behaviours. PPG was compared between test foods over a period of 120-min, and the bolus properties and saliva uptake at swallow were measured for both test foods. RC displayed higher instrumental hardness, chewiness and Young's modulus than WR (p = 0.01), and participants perceived RC as more springy and sticky than WR (p < 0.001). The RC meal was chewed more per bite (p < 0.001) and consumed at a faster eating rate (p = 0.033) than WR. WR bolus particles were smaller at swallow (p < 0.001) with a larger total surface area (p < 0.001), compared to RC. The glucose response for RC was significantly higher during the first 30-min postprandial period (p = 0.010), and lower in the later (30-120 min) postprandial period (p = 0.031) compared to WR. Total blood glucose iAUC did not differ significantly between WR and RC meals despite their large differences in texture, OPB and bolus properties. Oro-sensory exposure time was a significant predictor of glucose iAUC30min for both test meals (RC, p = 0.003; WR, p = 0.029). Saliva uptake in the bolus was significantly positively associated with blood glucose during the first 30-min postprandial period for the RC meal (p = 0.008), but not for WR. We conclude that food texture modifications can influence OPB and bolus properties which are key contributors to the dynamic evolution of the glycaemic response. Total blood glucose responses were the same for both test foods, though differences in oral processing and bolus properties influenced temporal changes in PPG.

Mechanical stimuli for left ventricular growth during pressure overload.

BACKGROUND: The mechanical stimulus (i.e. stress or stretch) for growth occurring in the pressure-overloaded left ventricle (LV) is not exactly known. OBJECTIVE: To address this issue, we investigate the correlation between local ventricular growth (indexed by local wall thickness) and the local acute changes in mechanical stimuli after aortic banding. METHODS: LV geometric data were extracted from 3D echo measurements at baseline and 2 weeks in the aortic banding swine model (n = 4). We developed and calibrated animal-specific finite element (FE) model of LV mechanics against pressure and volume waveforms measured at baseline. After the simulation of the acute effects of pressure-overload, the local changes of maximum, mean and minimum myocardial stretches and stresses in three orthogonal material directions (i.e., fiber, sheet and sheet-normal) over a cardiac cycle were quantified. Correlation between mechanical quantities and the corresponding measured local changes in wall thickness was quantified using the Pearson correlation number (PCN) and Spearman rank correlation number (SCN). RESULTS: At 2 weeks after banding, the average septum thickness decreased from 10.6 ± 2.92mm to 9.49 ± 2.02mm, whereas the LV free-wall thickness increased from 8.69 ± 1.64mm to 9.4 ± 1.22mm. The FE results show strong correlation of growth with the changes in maximum fiber stress (PCN = 0.5471, SCN = 0.5111) and changes in the mean sheet-normal stress (PCN= 0.5266, SCN = 0.5256). Myocardial stretches, however, do not have good correlation with growth. CONCLUSION: These results suggest that fiber stress is the mechanical stimuli for LV growth in pressure-overload.

Using machine learning to characterize heart failure across the scales.

Heart failure is a progressive chronic condition in which the heart undergoes detrimental changes in structure and function across multiple scales in time and space. Multiscale models of cardiac growth can provide a patient-specific window into the progression of heart failure and guide personalized treatment planning. Yet, the predictive potential of cardiac growth models remains poorly understood. Here, we quantify predictive power of a stretch-driven growth model using a chronic porcine heart failure model, subject-specific multiscale simulation, and machine learning techniques. We combine hierarchical modeling, Bayesian inference, and Gaussian process regression to quantify the uncertainty of our experimental measurements during an 8-week long study of volume overload in six pigs. We then propagate the experimental uncertainties from the organ scale through our computational growth model and quantify the agreement between experimentally measured and computationally predicted alterations on the cellular scale. Our study suggests that stretch is the major stimulus for myocyte lengthening and demonstrates that a stretch-driven growth model alone can explain [Formula: see text] of the observed changes in myocyte morphology. We anticipate that our approach will allow us to design, calibrate, and validate a new generation of multiscale cardiac growth models to explore the interplay of various subcellular-, cellular-, and organ-level contributors to heart failure. Using machine learning in heart failure research has the potential to combine information from different sources, subjects, and scales to provide a more holistic picture of the failing heart and point toward new treatment strategies.

Multiscale characterization of heart failure.

Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 µm, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure. STATEMENT OF SIGNIFICANCE: Heart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse heart failure.

Effect of intra-myocardial Algisyl-LVR™ injectates on fibre structure in porcine heart failure.

Recent preclinical trials have shown that alginate injections are a promising treatment for ischemic heart disease. Although improvements in heart function and global structure have been reported following alginate implants, the underlying structure is poorly understood. Using high resolution ex vivo MRI and DT-MRI of the hearts of normal control swine (n = 8), swine with induced heart failure (n = 5), and swine with heart failure and alginate injection treatment (n = 6), we visualized and quantified the fibre distribution and implant material geometry. Our findings show that the alginate injectates form solid ellipsoids with a retention rate of 68.7% ±â€¯21.3% (mean ±â€¯SD) and a sphericity index of 0.37 ±â€¯0.03. These ellipsoidal shapes solidified predominantly at the mid-wall position with an inclination of -4.9°â€¯±â€¯31.4° relative to the local circumferential direction. Overall, the change to left ventricular wall thickness and myofiber orientation was minor and was associated with heart failure and not the presence of injectates. These results show that alginate injectates conform to the pre-existing tissue structure, likely expanding along directions of least resistance as mass is added to the injection sites. The alginate displaces the myocardial tissue predominantly in the longitudinal direction, causing minimal disruption to the surrounding myofiber orientations.

DNA barcoding relates Trichuris species from a human and a man's best friend to non-human primate sources.

Trichuris trichiura, the whipworm of humans, is one of the most prevalent soiltransmitted helminths (STH) reported worldwide. According to a recent study, out of 289 STH studies in Southeast Asia, only three studies used molecular methods. Hence, the genetic assemblages of Trichuris in Southeast Asia are poorly understood. In this study, we used partial mitochondrial DNA (cytochrome c oxidase subunit 1 or COI) sequences for analysis. Trichuris grouped in a same clade with different hosts indicate the potential of cross infection between hosts. Based on COI, the adult Trichuris isolated from a Malaysian patient was most closely related to Trichuris isolated from Papio anubis (olive baboons) from the USA. The Trichuris isolated from the dog from Malaysia was genetically similar to a Trichuris species isolated from Macaca silenus (lion-tailed macaque) from Czech Republic. Both the human and dog isolated Trichuris grouped in clades with different hosts indicating the potential of cross infection between hosts. Specific PCR primers based on the partial COI of T. trichiura isolated from African green monkey and T. serrata were designed and successfully amplified using multiplex PCR of the pooled DNA samples. Our results suggest a complex parasite-host relationship, and support the theory of cross infection of Trichuris between humans and non-human primates as suggested in previous publications.

DNA barcoding relates Trichuris species from a human and a man’s best friend to non-human primate sources

@#Trichuris trichiura, the whipworm of humans, is one of the most prevalent soiltransmitted helminths (STH) reported worldwide. According to a recent study, out of 289 STH studies in Southeast Asia, only three studies used molecular methods. Hence, the genetic assemblages of Trichuris in Southeast Asia are poorly understood. In this study, we used partial mitochondrial DNA (cytochrome c oxidase subunit 1 or COI) sequences for analysis. Trichuris grouped in a same clade with different hosts indicate the potential of cross infection between hosts. Based on COI, the adult Trichuris isolated from a Malaysian patient was most closely related to Trichuris isolated from Papio anubis (olive baboons) from the USA. The Trichuris isolated from the dog from Malaysia was genetically similar to a Trichuris species isolated from Macaca silenus (lion-tailed macaque) from Czech Republic. Both the human and dog isolated Trichuris grouped in clades with different hosts indicating the potential of cross infection between hosts. Specific PCR primers based on the partial COI of T. trichiura isolated from African green monkey and T. serrata were designed and successfully amplified using multiplex PCR of the pooled DNA samples. Our results suggest a complex parasite-host relationship, and support the theory of cross infection of Trichuris between humans and non-human primates as suggested in previous publications.

The melioidosis agent Burkholderia pseudomallei and related opportunistic pathogens detected in faecal matter of wildlife and livestock in northern Australia.

The Darwin region in northern Australia has experienced rapid population growth in recent years, and with it, an increased incidence of melioidosis. Previous studies in Darwin have associated the environmental presence of Burkholderia pseudomallei, the causative agent of melioidosis, with anthropogenic land usage and proximity to animals. In our study, we estimated the occurrence of B. pseudomallei and Burkholderia spp. relatives in faecal matter of wildlife, livestock and domestic animals in the Darwin region. A total of 357 faecal samples were collected and bacteria isolated through culture and direct DNA extraction after enrichment in selective media. Identification of B. pseudomallei, B. ubonensis, and other Burkholderia spp. was carried out using TTS1, Bu550, and recA BUR3-BUR4 quantitative PCR assays, respectively. B. pseudomallei was detected in seven faecal samples from wallabies and a chicken. B. cepacia complex spp. and Pandoraea spp. were cultured from wallaby faecal samples, and B. cenocepacia and B. cepacia were also isolated from livestock animals. Various bacteria isolated in this study represent opportunistic human pathogens, raising the possibility that faecal shedding contributes to the expanding geographical distribution of not just B. pseudomallei but other Burkholderiaceae that can cause human disease.

Ipilimumab for metastatic melanoma.

Malignant melanoma is currently the fifth most common cancer in American men and the seventh most common in American women. Despite the advances made for early disease, the prognosis for metastatic melanoma is dismal, with an overall 5-year mortality rate of 90%. It is estimated that 8,000 Americans will die of melanoma in 2012. Recent advances in the understanding of the complex cellular interactions regulating cancer immunity have led to new strategies in the development of cancer immunotherapy. The discovery of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of immune activity, has led to the development of a monoclonal antibody, ipilimumab, that can abrogate immune suppression. Ipilimumab is the first immunotherapy approved by the FDA for patients with advanced melanoma based on the overall survival benefit in a phase III setting. It represents a paradigm shift in melanoma management with its success promoting the evaluation of monoclonal antibodies targeted against a number of other regulatory checkpoints in patients with advanced melanoma.

Role of distension on duodenal and colonic contractility in mice: a novel myograph for intestines.

BACKGROUND: The role of mechanical distension (stretch and tension) on intestinal contractility is poorly understood. METHODS: We introduce a novel isovolumic myograph to quantify the intestinal contractility in response to mechanical stimulation. To evaluate the role of distension on contractility, an external restraint was used to restrict intestinal distension or stretch induced by inflation pressure. The amplitude of intraluminal pressure at isovolumic condition was defined as an index of intestinal contractility. KEY RESULTS: The in situ maximal contraction (1.42 ± 0.39 mmHg) of duodenum in response to inflation pressure was similar to the in vitro maximal contraction (1.39 ± 0.37 mmHg). As the pressure was increased, the in situ duodenal contraction attenuated faster than the in vitro one. The in situ maximal contraction (4.86 ± 1.32 mmHg) of distal colon in response to inflation pressure was significantly larger than the in vitro maximal contraction (2.31 ± 0.67 mmHg). With increase of pressure, the in situ colonic contractility (1.82 ± 0.87 mmHg) became similar to the in vitro counterpart (1.61 ± 0.98 mmHg). With restraint, the maximal contraction of duodenum and distal colon decreased from 4.86 ± 1.32 and 1.42 ± 0.39 mmHg to 2.91 ± 0.87 and 0.97 ± 0.29 mmHg, respectively. Finally, a significant linear relation was found between strain and amplitude of contraction for both duodenum and colon which became non-significant with restraint. CONCLUSIONS & INFERENCES: Our results suggest that distension is an important stimulus for intestinal contractility and nervous regulation is implicated in the intestinal contractility response to mechanical stimulus.

New method to measure coronary velocity and coronary flow reserve.

Coronary flow reserve (CFR) is an important index of coronary microcirculatory function. The objective of this study was to validate the reproducibility and accuracy of intravascular conductance catheter-based method for measurements of baseline and hyperemic coronary flow velocity (and hence CFR). The absolute coronary blood velocity was determined by measuring the time of transit of a saline injection between two pairs of electrodes (known distance) on a conductance catheter during a routine saline injection without the need for reference flow. In vitro validation was made in the velocity range of 5 to 70 cm/s in reference to the volume collection method. In 10 swine, velocity measurements were compared with those from a flow probe in coronary arteries at different CFR attained by microsphere embolization. In vitro, the mean difference between the proposed method and volume collection was 0.7 ± 1.34 cm/s for steady flow and -0.77 ± 2.22 cm/s for pulsatile flow. The mean difference between duplicate measurements was 0 ± 1.4 cm/s. In in vivo experiments, the flow (product of velocity and lumen cross-sectional area that is also measured by the conductance catheter) was determined in both normal and stenotic vessels and the mean difference between the proposed method and flow probe was -1 ± 12 ml/min (flow ranged from 10 to 130 ml/min). For CFR, the mean difference between the two methods was 0.06 ± 0.28 (range of 1 to 3). Our results demonstrate the reproducibility and accuracy of velocity and CFR measurements with a conductance catheter by use of a standard saline injection. The ability of the combined measurement of coronary lumen area (as previously validated) and current velocity and CFR measurements provides an integrative diagnostic tool for interventional cardiology.

A transatrial pericardial access: lead placement as proof of concept.

A safe, easy, and quick access into the pericardial space may provide a window for diagnostics and therapeutics to the heart. The objective of this study was to provide proof of concept for an engagement and access catheter that allows access to the pericardial space percutaneously. A multilumen catheter was developed to allow navigation and suction fixation to the right atrial appendage/wall in a normal swine model. Advancement through the multilumen catheter using a second catheter with a distal needle tip allows access to the pericardial space without pericardial puncture and advancement of a standard guide wire into the space. Navigation into the pericardial space was undertaken by fluoroscopy alone and was accomplished in 10 swine (5 acute and 5 chronic). As a specific application of this pericardial access method, a pacing lead was implanted on the epicardial surface. Five chronic swine experiments were conducted with successful pacing engagement verified by lead impedance and pacing threshold and sensing. Lead impedance exceeded 1,000 Omega preengagement and dropped by an average of 200 Omega upon implant (769 +/- 498 Omega). Pacing thresholds at 0.4 ms ranged from approximately 0.5 to 2.1 V acutely (1.03 +/- 0.92 V). No cardiac effusion or tamponade was observed in any of the acute or chronic studies. The ability to engage, maintain, and retract the right atrial appendage/wall and to engage an epicardial lead was successfully demonstrated. These findings support the feasibility of safe access into the pericardial space in a normal swine model and warrant further investigations for clinical translation.

Granzymes and perforin in solid organ transplant rejection.

Rejection of solid organ allografts by the recipient immune system is mediated, to a major extent, by T cell effector mechanisms. Granzymes and perforin are protein regulators of cytotoxic T lymphocyte-mediated target cell death. In this review, I discuss clinical data implicating granzymes and perforin in acute and chronic solid organ transplant rejection, as well as data from cell and animal experiments that support a main role for these effector molecules in allograft rejection.

Generation of NO by bystander human CD8 T cells augments allogeneic responses by inhibiting cytokine deprivation-induced cell death.

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in bystander human CD8 T cells, augments the accumulation of allogeneically activated human CD8 T cells in vitro and in vivo. Here, we report that iNOS-derived NO does not affect T-cell proliferation but rather inhibits cell death of activated human CD8 T cells after activation by allogeneic endothelial cells in culture. Exogenous NO did not affect activation-induced cell death of human CD8 T cells but specifically reduced death of activated T cells due to cytokine deprivation. NO-mediated inhibition of T-cell death did not involve cGMP signaling, and NO did not affect the expression of Bcl-2-related proteins known to regulate cytokine deprivation-induced cell death. However, NO inhibited the activity of caspases activated as a consequence of cytokine deprivation in activated T cells. This protective effect correlated with S-nitrosylation of caspases and was phenocopied by z-VAD.fmk and z-LEHD.fmk, pharmacological inhibitors of caspases. In summary, our findings indicate that NO augments the accumulation of activated human T cells principally by inhibiting cytokine deprivation-induced cell death through S-nitrosylation of caspases.

New reports of Australian cutaneous leishmaniasis in Northern Australian macropods.

Cutaneous leishmaniasis caused by various species of Leishmania is a significant zoonotic disease in many parts of the world. We describe the first cases of Australian cutaneous leishmaniasis in eight northern wallaroos, one black wallaroo and two agile wallabies from the Northern Territory of Australia. Diagnosis was made through a combination of gross appearance of lesions, cytology, histology, direct culture, serology and a species-specific real-time PCR. The causative organism was found to be the same unique species of Leishmania previously identified in red kangaroos. These clinical findings provide further evidence for the continuous transmission of the Australian Leishmania species and its presence highlights the importance of continued monitoring and research into the life-cycle of this parasite.

Stability analysis of zinc oxide-nanoencapsulated conjugated linoleic acid and gamma-linolenic acid.

Conjugated linoleic acid (CLA) and gamma-linolenic acid (GLA) were encapsulated with hydrated zinc oxide nanoparticles in an effort to improve their time and thermal stability. Encapsulated and nonencapsulated CLA and GLA were stored at 20, 30, 40, and 50 degrees C for 49 d. At various time points, encapsulated CLA and GLA were extracted, methylated, and analyzed using GC-FID. Both encapsulated CLA and control CLA were stable when stored at 20, 30, and 40 degrees C for up to 49 d. However, control CLA was 100% degraded after 28 d at 50 degrees C, whereas encapsulated CLA was stable at 50 degrees C for 49 d. Similarly, both encapsulated GLA and control GLA were stable when stored at 20 degrees C for 49 d, but nonencapsulated GLA was 92% degraded after 49 d at 30 degrees C; encapsulated GLA was stable at 30 degrees C. Therefore, nanoencapsulation improves the time and temperature stability of CLA and GLA.

Left atrial appendage thrombus in a patient in sinus rhythm with endocarditis and a severe aortic valve insufficiency.

A left atrial thrombus is most often associated with atrial fibrillation and/or rheumatic mitral stenosis. It is very infrequently detected in the presence of sinus rhythm. The present report describes the case of a 66-year-old woman who presented with a stroke and was subsequently found to have two potential sources of embolization, including a vegetation on the native aortic valve, with associated severe aortic insufficiency, and a left atrial appendage thrombus despite being in sinus rhythm. To the authors' knowledge, the present report is the first to describe a left atrial thrombus in sinus rhythm associated with aortic valve endocarditis.

Cutaneous leishmaniasis in red kangaroos: isolation and characterisation of the causative organisms.

This is the first report of cutaneous leishmaniasis in kangaroos where infection was acquired within Australia. The diagnosis is based on the clinical criteria used for humans, the lesion histopathology, the detection and isolation of parasites from the lesions, and the analysis of the small subunit ribosomal RNA genes using the polymerase chain reaction. Despite a clear indication that the parasites belong to the genus Leishmania, no assignation to a known Leishmania species could be made using these or other less conserved genetic loci such as the non-transcribed spacer of the mini-exon repeat. As is the case in humans, some but not all animals harbouring lesions had antibodies to the isolated parasites or to several other Leishmania species. The isolated parasites displayed two well characterised Leishmania glycoconjugates, the lipophosphoglycan and proteophosphoglycan. They were infectious for mouse macrophages in vitro and established long-term infection at 33 degrees C but not at 37 degrees C. Our findings raise the possibility of transmission to humans, which may be unrecognised and suggest the possibility that imported species of Leishmania could become endemic in Australia.