Search

The cisterna chyli is a lymphatic structure found at the caudal end of the thoracic duct that receives lymph draining from the abdominal and pelvic viscera and lower limbs. In addition to being an important landmark in retroperitoneal surgery, it is the key gateway for interventional radiology procedures targeting the thoracic duct. A detailed understanding of its anatomy is required to facilitate more accurate intervention, but an exhaustive summary is lacking. A systematic review was conducted, and 49 published human studies met the inclusion criteria. Studies included both healthy volunteers and patients and were not restricted by language or date. The detectability of the cisterna chyli is highly variable, ranging from 1.7 to 98%, depending on the study method and criteria used. Its anatomy is variable in terms of location (vertebral level of T10 to L3), size (ranging 2–32 mm in maximum diameter and 13–80 mm in maximum length), morphology, and tributaries. The size of the cisterna chyli increases in some disease states, though its utility as a marker of disease is uncertain. The anatomy of the cisterna chyli is highly variable, and it appears to increase in size in some disease states. The lack of well-defined criteria for the structure and the wide variation in reported detection rates prevent accurate estimation of its natural prevalence in humans.

Introduction: Gut-lymph in animal models of acute disease is altered by intestinal ischemia and contributes to the development of systemic inflammation and organ dysfunction. Investigating gut-lymp...

The thoracic duct (TD) drains most of the body's lymph back to the venous system via its lymphovenous junction (LVJ), playing a pivotal role in fluid homeostasis, fat absorption and the systemic immune response. The respiratory cycle is thought to assist with lymph flow, but the precise mechanism underpinning terminal TD lymph flow into the central veins is not well understood. The aim of this study was to use ultrasonography (US) to explore the relationship between terminal TD lymph flow, the respiratory cycle, and gravity. The left supraclavicular fossa was scanned in healthy non-fasted volunteers using high-resolution (13-5 MHz) US to identify the terminal TD and the presence of a lymphovenous valve (LVV). The TD's internal diameter was measured in relation to respiration (inspiration vs. expiration) and body positioning (supine vs. Trendelenburg). The terminal TD was visualized in 20/33 (61%) healthy volunteers. An LVV was visualized in only 4/20 (20%) cases. The mean terminal TD diameter in the supine position was 1.7 mm (range 0.8-3.1 mm); this increased in full inspiration (mean 1.8 mm, range 0.9-3.2 mm, p < 0.05), and in the Trendelenburg position (mean 1.8 mm, range 1.2-3.1 mm, p < 0.05). The smallest mean terminal TD diameter occurred in full expiration (1.6 mm, range 0.7-3.1 mm, p < 0.05). Respiration and gravity impact the terminal TD diameter. Due to the challenges of visualizing the TD and LVJ, other techniques such as dynamic magnetic resonance imaging will be required to fully understand the factors governing TD lymph flow.

Background: The lymphovenous junction (LVJ) of the thoracic duct (TD) is the principle outlet of the lymphatic system. Interest in this junction is growing as its role in lymphatic outflow obstruction is being realized, and as minimally invasive procedures for accessing the terminal TD become more common. Despite the growing clinical significance of the LVJ, its precise form and function remain unclear. The aim of this article was to systematically review the literature surrounding the structure and function of the LVJ and its associated lymphovenous valve (LVV). Methods and Results: A systematic review of the structure and function of the LVJ and LVV was undertaken using the MEDLINE, Scopus, and Google Scholar databases. Human and animal studies up to November 2019, with no language or past date restriction, were included. Forty-six relevant articles were reviewed. The LVJ shows marked anatomical variation. A valve is frequently absent at the LVJ, but when present it displays numerous distinct morphologies. These include bicuspid semilunar, ostial, and flap-like structure. Other factors, such as functional platelet plugs, or the tangential/intramural course of the terminal TD across the vein wall, may work to prevent blood from entering the lymphatic system. Conclusions: The form and function of the LVJ remain unclear. Dedicated studies of this area in vivo are required to elucidate how this part of the body functions in both health and disease.

BACKGROUND/AIMS: Stress hyperglycemia is common in critical illness but it has not been clearly studied in patients with acute pancreatitis (AP). This study aimed to investigate the specific blood glucose (BG) level that defines stress hyperglycemia and to determine the impact of stress hyperglycemia on clinical outcomes in AP patients. METHODS: AP patients admitted ≤ 48 h after abdominal pain onset were retrospectively analyzed. Patients were stratified by pre-existing diabetes and stress hyperglycemia was defined using stratified BG levels for non-diabetes and diabetes with clinical outcomes compared. RESULTS: There were 967 non-diabetic and 114 diabetic (10.5%) patients met the inclusion criteria and the clinical outcomes between these two groups were not significantly different. In non-diabetes, the cut-off BG level of ≥ 180 mg/dl was selected to define stress hyperglycemia with an 8.8-fold higher odds ratio for persistent organ failure (POF) (95% CI 5.4-14.3; P < 0.001). For diabetes, ≥ 300 mg/dl was selected with a 7.5-fold higher odds ratio for POF (95% CI 1.7-34.3; P = 0.009). In multivariable logistic regression, stress hyperglycemia was independently associated with POF, acute necrotic collection, major infection and mortality. The combination of BG and systemic inflammatory response syndrome (SIRS) score in predicting POF was better than SIRS or Glasgow score alone. CONCLUSIONS: This study identifies a cut-off BG level of ≥ 180 mg/dl and ≥ 300 mg/dl was optimal to define stress hyperglycemia for non-diabetic and diabetic AP patients, respectively. There was a significant relationship between stress hyperglycemia and adverse clinical outcomes.

The majority of lymph generated in the body is returned to the blood circulation via the lymphovenous junction (LVJ) of the thoracic duct (TD). A lymphovenous valve (LVV) is thought to guard this junction by regulating the flow of lymph to the veins and preventing blood from entering the lymphatic system. Despite these important functions, the morphology and mechanism of this valve remains unclear. The aim of this study was to investigate the anatomy of the LVV of the TD. To do this, the TD and the great veins of the left side of the neck were harvested from 16 human cadavers. The LVJs from 12 cadavers were successfully identified and examined macroscopically, microscopically, and using microcomputed tomography. In many specimens, the TD branched before entering the veins. Thus, from 12 cadavers, 21 LVJs were examined. Valves were present at 71% of LVJs (15/21) and were absent in the remainder. The LVV, when present, was typically a bicuspid semilunar valve, although the relative size and position of its cusps were variable. Microscopically, the valve cusps comprised luminal extensions of endothelium with a thin core of collagenous extracellular matrix. This study clearly demonstrated the morphology of the human LVV. This valve may prevent blood from entering the lymphatic system, but its variability and frequent absence calls into question its utility. Further structural and functional studies are required to better define the role of the LVV in health and disease.

Cells from all domains of life release extracellular vesicles (EVs), packages that carry a cargo of molecules that participate in communication, co-ordination of population behaviours, virulence and immune response mechanisms. Mammalian EVs play an increasingly recognised role to fight infection, yet may also be commandeered to disseminate pathogens and enhance infection. EVs released by bacterial pathogens may deliver toxins to host cells, signalling molecules and new DNA to other bacteria, and act as decoys, protecting infecting bacteria from immune killing. In this review, we explore the role of EVs in infection from the perspective of both the pathogen and host, and highlight their importance in the host/pathogen relationship. We highlight proposed strategies for EVs in therapeutics, and call attention to areas where existing knowledge and evidence is lacking.

High prevalence of non-healing chronic wounds contributes to a huge healthcare burden across the world. Early treatment interventions for non-healing wounds are vital. It was previously shown that accumulation of 15% or more of senescent cells in a chronic wound edge is an indicator that the wound is unlikely to heal. However, determining the presence of senescent cells would require invasive procedures such as tissue biopsies to be taken. In this study, we found a strong correlation between decreased collagen area and presence of senescent cells in human chronic wounds i.e. venous leg ulcer (VLU), diabetic foot ulcer (DFU) and pressure ulcer (PRU). We also report that the lowest collagen levels were found in VLU patients less than 60 years of age, with a persistent wound of > 24 months. Elevated levels of senescent cells were also found in VLU of males. Second harmonic imaging of collagen at the edge of chronic wounds with a handheld multiphoton device could be used to predict the number of senescent cells, indicating if the wound is on a healing trajectory or not. Our data support the use of collagen imaging in cutaneous wound assessment for a faster and non-invasive method to predict cellular senescence and determining wound trajectory of healing. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Published version This research is supported by the Agency for Science, Technology and Research (A*STAR) under its Industry alignment fund—Pre-Positioning Programme (IAF-PP) with grant numbers H17/01/a0/0C9 as part of the Wound Care Innovation for the Tropics (WCIT) programme, sub awards H18/01/a0/019 and H1701a0004. The Skin Research Institute of Singapore, Phase 2: SRIS@Novena. AMP is funded by Singapore’s Agency for Science, Technology & Research (A*STAR) through core funds and under the HBMS IAF-PP Project (H1701a0004) and through the National Research Foundation Singapore under its Shared Infrastructure Support grant for SingaScope—a Singapore-wide microscopy infrastructure network (NRF2017_SISFP10)”.

Trichomonas vaginalis is a protozoan parasite that causes trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. Trichomonas vaginalis releases extracellular vesicles that play a role in parasite:parasite and parasite:host interactions. The aim of this study was to characterise the RNA cargo of these vesicles. Trichomonas vaginalis extracellular vesicles were found to encapsulate a cargo of RNAs of small size. RNA-seq analysis showed that tRNA-derived small RNAs, mostly 5' tRNA halves, are the main type of small RNA in these vesicles. The tRNA-derived small RNAs in T. vaginalis extracellular vesicles were shown to be derived from the specific processing of tRNAs within cells. The specificity of this RNA cargo in T. vaginalis extracellular vesicles suggests a preference for packaging. The RNA cargo of T. vaginalis was shown to be rapidly internalised by human cells via lipid raft-dependent endocytosis. The potential role of these tsRNAs - an emerging class of small RNAs with regulatory functions - on altering host cellular responses requires further examination, suggesting a new mode of parasite:host communication.

Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that 'leak' HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.

Carbon nanomaterials possess superb properties and have contributed considerably to the advancement of integrated point-of-care chemical and biological sensing devices. Graphene has been widely researched as a signal transducing and sensing material. Here, a grass-like laser-scribed graphene (LSG) was synthesized by direct laser induction on common polyimide plastics. The resulting LSG grass was employed as a disposable electrochemical sensor for the detection of three neurotransmitters, dopamine (DA), epinephrine (EP), and norepinephrine (NE), and in the presence of uric acid and ascorbic acid as potential interferants, using differential pulse voltammetry and cyclic voltammetry. The LSG grass sensor achieved sensitivities of 0.243, 0.067, and 0.110 μA μM-1 for DA, EP, and NE, respectively, whereas the limits of detection were 0.43, 1.1, and 1.3 μM, respectively. The selectivity of LSG grass was excellent for competing biomarkers with high structural similarity (EP vs NE and EP vs DA). The exceptional performance of LSG grass for DA, EP, and NE detection holds a promising future for carbon nanomaterial sensors with unique surface morphologies.

Intravenous (IV) fluid resuscitation remains the cornerstone for early management of acute pancreatitis (AP), but many questions remain unanswered, including how to determine whether patients will benefit from additional fluids. The aim was to investigate the utility of serum biomarkers of responsiveness IV fluid resuscitation in patients with AP and systemic inflammatory response syndrome (SIRS).Eligible adult patients had abdominal pain for36 h and ≥2 SIRS criteria. Mean arterial pressure (65 mmHg) and urine output (0.5 ml/kg/h) were used to assess responsiveness at 2 and 6-8 h after initiation of IV fluids. Comparison was made between responsive and refractory patients at time points for fluid volume, biomarkers and outcomes.At 2 h 19 patients responded to fluids (Group 1) while 4 were refractory (Group 2); at 6-8 h 14 responded (Group 3) and 9 were refractory (Group 4). No demographic differences between patient groups, but Group 4 had worse prognostic features than Group 3. Refractory patients received significantly more fluid (Group 4 mean 7082 ml vs. Group 3 5022 mL, P 0.001) in first 24 h and had worse outcome. No significant differences in biomarkers between the groups.The serum biomarkers did not discriminate between fluid responsive and refractory patients. Refractory patients at 6-8 h had more severe disease on admission, did not benefit from additional fluids and had a worse outcome. New approaches to guide fluid resuscitation in patients with AP are required.

The thoracic duct (TD) transports lymph drained from the body to the venous system in the neck via the lymphovenous junction. There has been increased interest in the TD lymph (including gut lymph) because of its putative role in the promotion of systemic inflammation and organ dysfunction during acute and critical illness. Minimally invasive TD cannulation has recently been described as a potential method to access TD lymph for investigation. However, marked anatomical variability exists in the terminal segment and the physiology regarding the ostial valve and terminal TD is poorly understood. A systematic review was conducted using three databases from 1909 until May 2017. Human and animal studies were included and data from surgical, radiological and cadaveric studies were retrieved. Sixty‐three articles from the last 108 years were included in the analysis. The terminal TD exists as a single duct in its terminal course in 72% of cases and 13% have multiple terminations: double (8.5%), triple (1.8%) and quadruple (2.2%). The ostial valve functions to regulate flow in relation to the respiratory cycle. The patency of this valve found at the lymphovenous junction opening, is determined by venous wall tension. During inspiration, central venous pressure (CVP) falls and the valve cusps collapse to allow antegrade flow of lymph into the vein. During early expiration when CVP and venous wall tension rises, the ostial valve leaflets cover the opening of the lymphovenous junction preventing antegrade lymph flow. During chronic disease states associated with an elevated mean CVP (e.g. in heart failure or cirrhosis), there is a limitation of flow across the lymphovenous junction. Although lymph production is increased in both heart failure and cirrhosis, TD lymph outflow across the lymphovenous junction is unable to compensate for this increase. In conclusion the terminal TD shows marked anatomical variability and TD lymph flow is controlled at the ostial valve, which responds to changes in CVP. This information is relevant to techniques for cannulating the TD, with the aid of minimally invasive methods and high resolution ultrasonography, to enable longitudinal physiology and lymph composition studies in awake patients with both acute and chronic disease.

Ethnopharmacological relevance Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied. Aim of the study To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model. Material and methods For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 μg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 μl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 μM), or selected active compounds of CQCQD (12.5, 25, and 50 μM) for 30 min, followed by SP incubation for another 30 min. Results The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells. Conclusions CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.

Background Nonocclusive mesenteric ischemia can cause intestinal infarction but the diagnosis is challenging. This prospective study evaluated three plasma biomarkers of intestinal infarction after cardiac surgery. Materials and methods Patients were recruited after cardiac surgery if they required laparotomy (with or without intestinal resection) for suspected nonocclusive mesenteric ischemia. Plasma levels of D-lactate, intestinal fatty acid–binding protein (i-FABP), and smooth muscle actin (SMA) before laparotomy were measured. Results Twenty patients were recruited (68 ± 9 y, EuroSCORE: 8.7 ± 2.8, mortality 70%). A positive laparotomy ( n = 13) was associated with no change in D-lactate ( P = 0.95), decreased i-FABP ( P = 0.007), and increased SMA ( P = 0.01). All patients with high SMA had a positive laparotomy. A subgroup analysis was undertaken in the eight patients who required multiple laparotomies. D-lactate increased between the two laparotomies in nonsurvivors ( n = 4). Plasma i-FABP ( P = 0.008) and SMA ( P = 0.036) significantly decreased after the bowel resection, regardless of survival outcome. Conclusions None of the biomarkers were accurate enough to reliably diagnose intestinal infarction. However, all patients with high values of SMA developed intestinal infarction, thus warranting further investigation. An increasing D-lactate after intestinal resection suggests impending death.

Pancreatic islet β-cells secrete the hormones insulin and amylin, and defective β-cell function plays a central role in the pathogenesis of type-2 diabetes (T2D). Human amylin (hA, also termed hIAPP) misfolds and forms amyloid aggregates whereas orthologous mouse amylin does neither. Furthermore, hA elicits apoptosis in cultured β-cells and β-cell death in ex-vivo islets. In addition, hA-transgenic mice that selectively express hA in their β-cells, manifest β-cell apoptosis and progressive islet damage that leads to diabetes closely resembling that in patients with T2D. Aggregation of hA is thus linked to the causation of diabetes. We employed time-dependent thioflavin-T spectroscopy and ion-mobility mass spectrometry to screen potential suppressors of hA misfolding for anti-diabetic activity. We identified the dietary flavonol rutin as an inhibitor of hA-misfolding and measured its anti-diabetic efficacy in hA-transgenic mice. In vitro, rutin bound hA, suppressed misfolding, disaggregated oligomers and reverted hA-conformation towards the physiological. In hA-transgenic mice, measurements of glucose, fluid-intake, and body-weight showed that rutin-treatment slowed diabetes-progression by lowering of rates of elevation in blood glucose (P = 0.030), retarding deterioration from symptomatic diabetes to death (P = 0.014) and stabilizing body-weight (P < 0.0001). In conclusion, rutin treatment suppressed hA-aggregation in vitro and doubled the lifespan of diabetic mice (P = 0.011) by a median of 69 days compared with vehicle-treated control-diabetic hA-transgenic mice.

The interest in approaches to deliver therapeutics to the lymphatic system has increased in recent years as the lymphatics have been discovered to play an important role in a range of disease states such as cancer metastases, inflammatory and metabolic disease, and acute and critical illness. Therapeutic delivery to lymph has the potential to enhance treatment of these conditions. Currently much of the existing data explores therapeutic delivery to the lymphatic vessels and nodes that drain peripheral tissues and the intestine. Relatively little focus has been given to understanding the anatomy, function and therapeutic delivery to the peritoneal lymphatics. Gaining a better understanding of peritoneal lymphatic structure and function would contribute to the understanding of disease processes involving these lymphatics and facilitate the development of delivery systems to target therapeutics to the peritoneal lymphatics. This review explores the basic anatomy and ultrastructure of the peritoneal lymphatics system, the lymphatic drainage pathways from the peritoneum, and therapeutic and delivery system characteristics (size, lipophilicity and surface properties) that favour lymph uptake and retention after intraperitoneal delivery. Finally, techniques that can be used to quantify uptake into peritoneal lymph are outlined, providing a platform for future studies.

The pulmonary lymphatics are critical for proper lung function, yet seldom considered in lung pathology. Newer and more convenient methods for studying lung lymphatics are now available and might create new diagnosis and treatment opportunities.https://bit.ly/3ldJGeo

Background/objectives Mitochondrial dysfunction occurs in vital organs in experimental acute pancreatitis (AP) and may play an important role in determining severity of AP. However, obtaining vital organ biopsies to measure mitochondrial function (MtF) in patients with AP poses considerable risk of harm. Being able to measure MtF from peripheral blood will bypass this problem. Furthermore, whether mitochondrial dysfunction is detectable in peripheral blood in mild AP is unknown. Therefore, the objective was to evaluate peripheral blood MtF in experimental and clinical AP. Method Mitochondrial respiration was measured using high resolution oxygraphy in an experimental study in caerulein induced AP and in a separate study, in patients with mild AP. Superoxide, cytochrome c , mitochondrial membrane potential (ΔΨ) and adenine triphosphate (ATP) were also measured as other markers of MtF. Results Even though some states of mitochondrial respiration were increased in both experimental and clinical AP, this did not lead to an increase in net ATP in patients with AP. The increased leak respiration in both studies was further proof of dyscoupled mitochondria. In the clinical study there were also features of mitochondrial dysfunction with increased leak flux control ratio, superoxide, ΔΨ and decreased cytochrome c . Conclusion There is evidence of mitochondrial dysfunction with dyscoupled mitochondria, increased superoxide and decreased cytochrome c in patients with mild acute pancreatitis. Further studies should now determine whether mitochondrial function alters with severity in AP and whether mitochondrial dysfunction responds to treatments.

Background The evolution of the “gut-lymph concept” has promoted thoracic duct (TD) lymph drainage as a possible treatment to reduce systemic inflammation and end-organ dysfunction in acute illness. The aim was to review the published experience of thoracic duct interventions (TDIs) aimed at improving clinical outcomes. Methods A search of three databases (MEDLINE, EMBASE, and EMBASE CLASSIC) over the last 60 y. The indications for intervention, the technique, and clinical outcomes were reviewed. Results There were a wide range of indications for TDI. These included reducing rejection after transplantation, treating inflammatory diseases, and reducing chronic failure of the liver, kidney, and heart. The techniques included TD cannulation and lymphovenuous fistula. The outcomes were variable and often equivocal, and this appears to reflect poor design quality. There is clinical equipoise regarding a therapeutic role of (TD lymph drainage in acute pancreatitis, and probably other acute diseases. Conclusions Until well-designed clinical trials are undertaken, the clinical benefits of TDIs will remain promising, but uncertain.

Nonocclusive mesenteric ischemia (NOMI) is a condition that can encompass ischemia, inflammation, and infarction of the intestinal wall. In contrast to most patients with acute mesenteric ischemia, NOMI is distinguished by patent arteries and veins. The clinical presentation of NOMI is often insidious and nonspecific, resulting in a delayed diagnosis. Patients most at risk are those with severe acute and critical disease, including major surgery and trauma. Nonocclusive mesenteric ischemia is part of a spectrum, from mild, asymptomatic, and an unexpected finding on CT scanning, through to those exhibiting abdominal distension and peritonitis. Severe NOMI is associated with a significant mortality rate. This review of NOMI pathophysiology was conducted to document current concepts and evidence, to examine the implications for diagnosis and treatment, and to identify gaps in knowledge that might direct future research. The key pathologic mechanisms involved in the genesis of NOMI represent an exaggerated normal physiological response to maintain perfusion of vital organs at the expense of mesenteric perfusion. A supply–demand mismatch develops in the intestine due to the development of persistent mesenteric vasoconstriction resulting in reduced blood flow and oxygen delivery to the intestine, particularly to the vulnerable superficial mucosa. This mismatch can be exacerbated by raised intra-abdominal pressure, enteral nutrition, and the use of certain vasoactive drugs, ultimately resulting in the development of intestinal ischemia. Strategies for prevention, early detection, and treatment are urgently needed.

Chronic wounds are a growing problem worldwide with no effective therapeutic treatments available. Our objective was to understand the composition of the dermal tissue surrounding venous leg ulcers and diabetic foot ulcers (DFU). We used novel 2‐photon imaging techniques alongside classical histology to examine biopsies from the edges of two common types of chronic wound, venous leg ulcers and DFU. Compared to normal intact skin, we found that collagen levels are significantly reduced throughout the dermis of venous leg ulcer biopsies and DFU, with a reduction in both fibril thickness and abundance. Both wound types showed a significant reduction in elastin in the upper dermis, but in DFU, the loss was throughout the dermis. Loss of extracellular matrix correlated with high levels of CD68‐ and CD18‐positive leukocytes. 2‐photon imaging of the extracellular matrix in the intact tissue surrounding a chronic wound with a hand‐held device may provide a useful clinical indicator on the healing progression or deterioration of these wounds.

As well as systemic vascular endothelial cells, the liver has specialised sinusoidal endothelial cells (LSEC). LSEC dysfunction has been documented in many diseased states yet their phenotype in normal human liver has not been comprehensively assessed. Our aim was to improve characterisation of subsets of endothelial cells and associated pericytes in the human liver. Immunofluorescence microscopy was performed on normal human liver tissue samples to assess endothelial and structural proteins in a minimum of three donors. LSEC are distributed in an acinar pattern and universally express CD36, but two distinctive subsets of LSEC can be identified in different acinar zones. Type 1 LSEC are CD36hiCD32−CD14−LYVE-1− and are located in acinar zone 1 of the lobule, while Type 2 LSEC are LYVE-1+CD32hiCD14+CD54+CD36mid-lo and are located in acinar zones 2 and 3 of the lobule. Portal tracts and central veins can be identified using markers for systemic vascular endothelia and pericytes, none of which are expressed by LSEC. In areas of low hydrostatic pressure LSEC are lined by stellate cells that express the pericyte marker CD146. Our findings identify distinctive populations of LSEC and distinguish these cells from adjacent stellate cells, systemic vasculature and pericytes in different zones of the liver acinus.

Background and aim Extra-pancreatic infectious complications in acute pancreatitis increase morbidity, but their incidence and association with infected pancreatic necrosis is unknown. Half of bacterial cultures of pancreatic necrosis are of non-enteric origin, raising the possibility of other sources of infection. The aim of this systematic review was to assess the incidence of extra-pancreatic infectious complications in acute pancreatitis, their timing, and relation to severity of pancreatitis and mortality. Methods A systematic review was performed using Ovid MEDLINE, Embase and Cochrane Libraries, following PRISMA guidelines. Search terms were “Pancreatitis” AND “Infection” AND (“Complication” OR “Outcome”). Results 19 studies with 1741 patients were included. Extra-pancreatic infectious complication incidence was 32% (95% CI 23–41%), with the commonest being respiratory infection (9.2%) and bacteraemia (8.4%). Extra-pancreatic infectious complications were not associated with the predicted severity or the mortality of acute pancreatitis. Only 3 studies reported a relation of timing between extra-pancreatic and pancreatic infectious complications. Conclusions This is the first systematic review to evaluate the incidence of extra-pancreatic infectious complications in acute pancreatitis, which a third of patients with acute pancreatitis will develop. Implications are vigilance and prompt treatment of extra-pancreatic infection, to reduce possibility of progression to infected pancreatic necrosis.

OBJECTIVE To isolate microRNAs (miRNAs) from mesenteric lymph (ML) and peripheral blood and identify those that change with experimental acute pancreatitis (AP). To assess identified AP-associated miRNAs in patient plasma to evaluate them as clinical biomarkers of AP. BACKGROUND miRNAs, small non-protein-coding molecules that regulate gene expression, are present in many biological fluids. They are increasingly interesting as biomarkers of disease and as novel signaling molecules in pathogenesis. METHODS Affymetrix miRNA profiling was performed on ML collected from 3 groups of rats with either mild or moderate taurocholate-induced AP and sham controls. Quantitative reverse transcription-polymerase chain reaction was used to validate selected miRNAs in matched rat lymph and plasma and then measured in patients with mild or moderate AP and in healthy volunteers. RESULTS Eighty-five miRNAs were detectable in rat ML, and many were abundant in all animals irrespective of the presence of AP. Seven miRNAs, comprising miR-375, -217, -148a, -216a, -122, -214, and -138, were increased in ML from rats with AP (P < 0.01). Their abundance also altered with disease severity. miRNAs miR-217, -375, -122, and -148a were also increased in matched rat plasma samples by quantitative reverse transcription-polymerase chain reaction. In the clinical studies, plasma miR-216a was significantly increased in both mild and moderate AP. CONCLUSIONS This study is the first to demonstrate both the presence of circulating miRNAs in lymph and the alteration of specific miRNAs in AP. Furthermore, these miRNAs alter in rat and human AP plasma and have potential to be explored as novel biomarkers of pancreatitis.

Background Persistent organ failure and infected pancreatic necrosis are major determinants of mortality in acute pancreatitis, but there is a gap in the literature assessing the best available predictors of these two determinants. The purpose of this review was to investigate the utility of predictors of persistent organ failure and infected pancreatic necrosis in patients with acute pancreatitis, both alone and in combination. Methods We performed a systematic search of the literature in 3 databases for prospective studies evaluating predictors of persistent organ failure, infected pancreatic necrosis, or both, with strict eligibility criteria. Results The best predictors of persistent organ failure were the Japanese Severity Score and Bedside Index of Severity in Acute Pancreatitis when the evaluation was performed within 48 h of admission, and blood urea nitrogen and Japanese Severity Score after 48 h of admission. Systemic Inflammation Response Syndrome was a poor predictor of persistent organ failure. The best predictor of infected pancreatic necrosis was procalcitonin. Conclusions Based on the best available data, it is justifiable to use blood urea nitrogen for prediction of persistent organ failure after 48 h of admission and procalcitonin for prediction of infected pancreatic necrosis in patients with confirmed pancreatic necrosis. There is no predictor of persistent organ failure that can be justifiably used in clinical practice within 48 h of admission.

Summary Background & aims Nasojejunal tube feeding is a standard of care in patients with predicted severe acute pancreatitis (AP) and several recent trials suggested that nasogastric tube feeding (NGT) is as safe and efficient as nasojejunal tube feeding in these patients. The aim was to investigate whether NGT presents any benefit to patients with mild to moderate AP. Methods The study design was a randomized controlled trial. The patients in the intervention group received NGT within 24 h of hospital admission. The patients in the control group were on nil per os (NPO). The severity of acute pancreatitis was determined according to the new international multidisciplinary classification. Results There were 17 patients randomly allocated to the NGT group and 18 to the NPO group. The visual analogue pain score decreased to a significantly greater extent in the NGT group (from median 9 (range 7–9) at baseline to 1 (0–3) at 72 h after randomization) compared with the NPO group (from 7 (5–9) to 3 (1–4) ( p = 0.036). The number of patients not requiring opiates at 48 h after randomization was significantly different ( p = 0.024) between NGT (9/17) and NPO (3/18). Oral food intolerance was observed in 1/17 patient in the NGT group and 9/18 patients in the NPO group ( p = 0.004). The overall hospital stay in the NGT group was 9 (5–12) days as compared with 8.5 (6–13) days in the NPO group ( p = 0.91). Conclusions NGT commenced within 24 h of hospital admission is well tolerated in patients with mild to moderate acute pancreatitis. Further, when compared with NPO, it significantly reduces the intensity and duration of abdominal pain, need for opiates, and risk of oral food intolerance, but not overall hospital stay (ClinicalTrials.gov number, NCT01128478).

Background Bacterium-to-host signalling during infection is a complex process involving proteins, lipids and other diffusible signals that manipulate host cell biology for pathogen survival. Bacteria also release membrane vesicles (MV) that can carry a cargo of effector molecules directly into host cells. Supported by recent publications, we hypothesised that these MVs also associate with RNA, which may be directly involved in the modulation of the host response to infection. Methods and Results Using the uropathogenic Escherichia coli (UPEC) strain 536, we have isolated MVs and found they carry a range of RNA species. Density gradient centrifugation further fractionated and characterised the MV preparation and confirmed that the isolated RNA was associated with the highest particle and protein containing fractions. Using a new approach, RNA-sequencing of libraries derived from three different ‘size’ RNA populations (

Skin lesions are common events and we have evolved to rapidly heal them in order to maintain homeostasis and prevent infection and sepsis. Most acute wounds heal without issue, but as we get older our bodies become compromised by poor blood circulation and conditions such as diabetes, leading to slower healing. This can result in stalled or hard-to-heal chronic wounds. Currently about 2% of the Western population develop a chronic wound and this figure will rise as the population ages and diabetes becomes more prevalent [1]. Patient morbidity and quality of life are profoundly altered by chronic wounds [2]. Unfortunately a significant proportion of these chronic wounds fail to respond to conventional treatment and can result in amputation of the lower limb. Life quality and expectancy following amputation is severely reduced. These hard to heal wounds also represent a growing economic burden on Western society with published estimates of costs to healthcare services in the region of $25B annually [3]. There exists a growing need for specific and effective therapeutic agents to improve healing in these wounds. In recent years the gap junction protein Cx43 has been shown to play a pivotal role early on in the acute wound healing process at a number of different levels [4–7]. Conversely, abnormal expression of Cx43 in wound edge keratinocytes was shown to underlie the poor rate of healing in diabetic rats, and targeting its expression with an antisense gel restored normal healing rates [8]. The presence of Cx43 in the wound edge keratinocytes of human chronic wounds has also been reported [9]. Abnormal Cx43 biology may underlie the poor healing of human chronic wounds and be amenable therapeutic intervention [7]. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Poor healing of DFUs (diabetic foot ulcers) is a major clinical problem that can be extremely debilitating and lead to lower limb amputation. In the normal acute wound, the Cx43 (connexin 43) gap junction protein is down-regulated at the wound edge as a precursor to cell migration and healing. In fibroblasts from the human chronic DFU wound edge there was a striking and significant 10-fold elevation of Cx43 protein, as well as a 6-fold increase in N-cadherin and a 2-fold increase in ZO-1 (zonular occludin-1), compared with unwounded skin. In streptozotocin diabetic rats, Cx43 was found to be up-regulated in intact dermal fibroblasts in direct proportion to blood glucose levels and increased 2-fold further in response to wounding of the skin. To mimic diabetes, NIH 3T3 fibroblasts were cultured under different concentrations of glucose or mannitol and Cx43 protein intercellular communication and migration rates were determined. Cultures of fibroblasts in very high (40 mM) glucose conditions showed significantly elevated Cx43 protein levels, as shown by immunostaining and Western blotting, and significantly increasing gap junctional communication, as shown by dye transfer. In scratch wound-healing assays, increased levels of Cx43 from high glucose resulted in repressed filopodial extensions and significantly slower migration rates than in either standard conditions (5.5 mM glucose) or the osmotic control of mannitol. Conversely, when glucose-induced Cx43 up-regulation was prevented with Cx43shRNA (Cx43 short-hairpin RNA) transduction, the fibroblasts extended long filopodia and migrated significantly faster. Cx43 protein was up-regulated in fibroblasts in DFUs as well as after high glucose exposure in culture which correlated with inhibition of fibroblast migration and is likely to contribute to impaired wound healing.

It is 45 years since gap junctions were first described. Universities face increasing commercial pressures and declining federal funding, with governments and funding foundations showing greater interest in gaining return on their investments. This review outlines approaches taken to translate gap junction research to clinical application and the challenges faced. The need for commercialisation is discussed and key concepts behind research patenting briefly described. Connexin channel roles in disease and injury are also discussed, as is identification of the connexin hemichannel as a therapeutic target which appears to play a role in both the start and perpetuation of the inflammasome pathway. Furthermore connexin hemichannel opening results in vascular dieback in acute injury and chronic disease. Translation to human indications is illustrated from the perspective of one connexin biotechnology company, CoDa Therapeutics, Inc.

Background & Aims There is no consistency between the individual studies in the literature on whether organ failure (OF) or infected pancreatic necrosis (IPN) is the main determinant of severity in acute pancreatitis. We aimed to statistically aggregate the available data and determine the pooled influence of OF and IPN on mortality in patients with acute pancreatitis. Methods The search for relevant observational studies was undertaken in the MEDLINE, EMBASE, and Scopus electronic databases, as well as in the proceedings of major gastroenterology meetings. The summary estimates are presented as relative risk (RR) and 95% confidence interval (CI). Results Fourteen studies comprising 1478 patients with acute pancreatitis were meta-analyzed. A total of 600 patients developed OF and 179 of them died (mortality, 30%); 314 patients developed IPN and 102 of them died (mortality, 32%). In a stratified analysis, patients with OF and IPN had a significantly higher risk of death in comparison with patients with OF and no IPN (RR = 1.94; 95% CI: 1.32−2.85; P = .0007) and in comparison with patients with IPN and no OF (RR = 2.65; 95% CI: 1.30−5.40; P = .0007). Conclusions In patients with acute pancreatitis, the absolute influence of OF and IPN on mortality is comparable and thus the presence of either indicates severe disease. The relative risk of mortality doubles when OF and IPN are both present and indicates extremely severe disease or critical acute pancreatitis.

Several clinical guidelines exist for acute pancreatitis, with varying recommendations. The aim of this study was to determine the quality of guidelines for acute pancreatitis.A literature search identified relevant guidelines, which were then reviewed to determine their document format and scope and the presence of endorsement by a professional body. The quality of guidelines was determined using the validated Grilli, Shaneyfelt, and AGREE instruments.Twenty-one of the 30 guidelines analyzed were endorsed by professional bodies. Median quality scores were as follows: Grilli, 2; Shaneyfelt, 13; and AGREE, 50. Guideline quality did not improve over time. Guidelines endorsed by a professional body had higher scores than those without official endorsement. Guidelines with tables, a recommendations summary, evidence grading, and audit goals had significantly higher scores than guidelines lacking those features.The many clinical guidelines for acute pancreatitis range widely in quality. Guidelines developed by professional bodies, and those with tables, a recommendations summary, evidence grading, and audit goals, are of higher quality. Further research is required to determine whether guideline quality alters clinical outcomes.

OBJECTIVE Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble β-sheet–containing oligomers is linked to islet β-cell degeneration and the pathogenesis of type 2 diabetes. Here, we used tetracycline, which modifies hA/hIAPP oligomerization, to probe mechanisms whereby hA/hIAPP causes diabetes in hemizygous hA/hIAPP-transgenic mice. RESEARCH DESIGN AND METHODS We chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival. RESULTS Homozygous mice developed severe spontaneous diabetes due to islet β-cell loss. Hemizygous transgenic animals also developed spontaneous diabetes, although severity was less and progression rates slower. Pathogenesis was characterized by initial islet β-cell dysfunction followed by progressive β-cell loss. Islet amyloid was absent from hemizygous animals with early-onset diabetes and correlated positively with longevity. Some long-lived nondiabetic hemizygous animals also had large islet-amyloid areas, showing that amyloid itself was not intrinsically cytotoxic. Administration of tetracycline dose-dependently ameliorated hyperglycemia and polydipsia, delayed rates of diabetes initiation and progression, and increased longevity compared with water-treated controls. CONCLUSIONS This is the first report to show that treating hA/hIAPP transgenic mice with a modifier of hA/hIAPP misfolding can ameliorate their diabetic phenotype. Fibrillar amyloid was neither necessary nor sufficient to cause diabetes and indeed was positively correlated with longevity therein, whereas early- to mid-stage diabetes was associated with islet β-cell dysfunction followed by β-cell loss. Interventions capable of suppressing misfolding in soluble hA/hIAPP oligomers rather than mature fibrils may have potential for treating or preventing type 2 diabetes.

Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients.We performed a 12 month randomised placebo-controlled study of the effects of treatment with the Cu(II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n = 15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVM(bsa)) was the primary endpoint variable.Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM(bsa) by 5.0 +/- 7.2 g/m(2) (mean +/- SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p = 0.0056 compared with placebo) and by 10.6 +/- 7.6 g/m(2) at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p = 0.0088), whereas LVM(bsa) was unchanged by placebo treatment. In a multiple-regression model that explained ~75% of variation (R (2) = 0.748, p = 0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVM(bsa).Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease.Australian New Zealand Clinical Trials Registry ACTRN 12609000053224 FUNDING: The Endocore Research Trust; Lottery Health New Zealand; the Maurice and Phyllis Paykel Trust; the Foundation of Research, Science and Technology (New Zealand); the Health Research Council of New Zealand; the Ministry of Education (New Zealand) through the Maurice Wilkins Centre for Molecular Biodiscovery; and the Protemix Corporation.

Summary Background Regulated alteration of connexin expression has been shown to be integral to acute wound repair. Downregulation of the gap-junction protein connexin 43 at the wound edge has been correlated with keratinocyte and fibroblast migration, while abnormal overexpression of connexin 43 significantly perturbs healing, as shown in the streptozotocin diabetic rodent impaired healing model. Objectives To examine the protein expression levels of connexin 43, in addition to connexins 26 and 30, in a variety of human chronic wounds. Methods Wound-edge punch biopsies and a matched control from the arm were taken from a cohort of patients with venous leg, diabetic foot or pressure ulcers. Wound connexin expression in each patient was compared with that in a matched, nonwounded arm punch. Tissue was sectioned, stained and imaged by confocal microscopy using identical parameters per patient to permit quantification. Results Epidermal connexin 43, connexin 26 and connexin 30, and dermal connexin 43 were discovered to be strikingly upregulated in every ulcer from all three wound types, pointing to connexin upregulation as a common feature between chronic wounds. Conclusions This result supports efforts to target connexin 43 to promote cell migration and wound healing in chronic ulcers.

Background Impaired motor and hormonal gastrointestinal functions have been implicated in the pathogenesis of acute pancreatitis. The aim of the present study was to investigate the predictive value of the Gastroparesis Cardinal Symptom Index and serum ghrelin in the development of clinically meaningful outcomes in patients with acute pancreatitis. Methods This was a prospective clinical study. The Gastroparesis Cardinal Symptom Index and serum ghrelin were measured for 48 h after hospitalization. Univariate and multivariate logistic regression analyses were conducted. Results The Gastroparesis Cardinal Symptom Index total score alone on day 2 was a significant predictor of oral feeding intolerance in both unadjusted (odds ratio 1.21 (1.01–1.46), P = 0.04) and adjusted (odds ratio 1.30 (1.01–1.69), P = 0.05) analyses. Adding ghrelin to Gastroparesis Cardinal Symptom Index further improved prediction in both unadjusted (odds ratio 1.26 (1.02–1.56), P = 0.03) and adjusted (odds ratio 1.53 (1.00–2.35), P = 0.05) analyses. Conclusion This pilot study demonstrates that the Gastroparesis Cardinal Symptom Index has a potential to be used as a predictor of oral feeding intolerance. Ghrelin, when combined with the Gastroparesis Cardinal Symptom Index, may further improve the predictive accuracy. These findings need to be confirmed in larger studies.

There is increasing need to expand availability of donor liver grafts, including steatotic livers. Steatotic liver is associated with poor outcome post-transplantation but with conflicting results in the literature. The aim of this systematic review was to evaluate the impact of steatotic livers on liver transplantation outcomes. An electronic search of OVID Medline and Embase databases was performed to identify clinical studies that reported outcomes of steatotic livers in liver transplantation. Data were extracted, and basic descriptive statistics were used to summarise data pooled from individual clinical studies. Ninety-two articles were identified, of which 34 met the inclusion criteria, and stratified analysis were performed. There was a lack of standardised definition of primary non-function or impaired primary function amongst the studies and description of type of steatosis. Severely (>60 %) steatotic grafts are associated with increased risk of poor graft function, whilst moderate–severe (>30 %) steatotic grafts are associated with decreased graft survival. Available evidence showed increased risk of poor graft outcome in moderate–severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required.

Background. Ischemia-reperfusion injury is a major cause of post-liver-surgery complications. Ischemic preconditioning (IPC) has been demonstrated to protect against ischemia-reperfusion injury. Clinical studies have examined IPC in liver surgery but with conflicting results. This systematic review aimed to evaluate the effects of IPC on outcome in clinical liver surgery.Methods. An electronic search of OVID Medline and Embase databases was performed to identify studies that reported outcomes in patients undergoing liver surgery subjected to IPC. Basic descriptive statistics were used to summarise data from individual clinical studies.Results. 1093 articles were identified, of which 24 met the inclusion criteria. Seven topics were selected and analysed by subgroup. There were 10 studies in cadaveric liver transplantation, 2 in living-related liver transplantation, and 12 in liver resection. IPC decreases hepatocellular damage in liver surgery as determined by transaminases but does not translate to any significant clinical benefit in orthotopic liver transplant or liver resection.Conclusions. Available clinical evidence does not support routine use of IPC in liver surgery as it does not offer any apparent benefit in perioperative outcome. Further clinical studies will need to be carried out to determine the subset of patients that will benefit from IPC.

Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu(2+) ions are strongly pro-oxidant, and chelatable-Cu(II) is increased in the diabetic heart. We reported previously that treatment by Cu(II)-selective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu(II) in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu(2+)-mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-beta1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose](plasma) in diabetic animals. LV and aortic mRNAs corresponding to TGF-beta1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS](tissue) were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-beta/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.

Background Diabetes mellitus (DM) is common in the general population and it poses a heavy burden to society in the form of long-term disability, healthcare use and costs. The pancreas is a key player in glucose homeostasis, but the occurrence of newly diagnosed DM after acute pancreatitis (AP), the most frequent disease of the pancreas, has never been assessed systematically. The aim of this study was to conduct a systematic literature review to determine the prevalence and time course of DM and related conditions after the first attack of AP as well as the impact of covariates. Methods Relevant literature cited in three electronic databases (Scopus, EMBASE and MEDLINE) was reviewed independently by two authors. The main outcome measures studied were newly diagnosed prediabetes, DM, or DM treated with insulin. Pooled prevalence and 95% CIs were calculated for all outcomes. Results A total of 24 prospective clinical studies, involving 1102 patients with first episode of AP, met all the eligibility criteria. Prediabetes and/or DM was observed in 37% (95% CI 30% to 45%) individuals after AP. The pooled prevalence of prediabetes, DM and treatment with insulin after AP was 16% (95% CI 9% to 24%), 23% (95% CI 16% to 31%), and 15% (95% CI 9% to 21%), respectively. Newly diagnosed DM developed in 15% of individuals within 12 months after first episode of AP and the risk increased significantly at 5 years (relative risk 2.7 (95% CI 1.9 to 3.8)). A similar trend was observed with regard to treatment with insulin. The severity of AP, its aetiology, individuals’ age and gender had minimal effect on the studied outcomes. Conclusions Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced.

The effects of pretransplant obesity, diabetes mellitus (DM), coronary artery disease (CAD), and hypertension (HTN) on outcomes after liver transplantation (LT) are controversial. Questions have also been raised about the appropriateness of the body mass index (BMI) for assessing obesity in patients with end-stage liver disease. Both issues have implications for organ allocation in LT. To address these questions, we undertook a cohort study of 202 consecutive patients (2000-2010) undergoing LT at a national center in New Zealand. BMI and body fat percentage (%BF) values (dual-energy X-ray absorptiometry) were measured before transplantation, and the methods were compared. The influence of pretransplant risk variables (including obesity, DM, CAD, and HTN) on the 30-day postoperative event rate, length of hospital stay, and survival were analyzed. There was agreement between the calculated BMI and the measured %BF for 86.0% of the study population (κ coefficient = 0.73, 95% confidence interval = 0.61-0.85), and this was maintained across increasing Model for End-Stage Liver Disease scores. Obesity was an independent risk factor for the postoperative event rate [count ratio (CR) = 1.03, P0.001], as was DM (CR = 1.4, P0.001). Obesity with concomitant DM was the strongest predictor of the postoperative event rate (CR = 1.75, P0.001) and a longer hospital stay (5.81 days, P0.01). Independent metabolic risk factors had no effect on 30-day, 1-year, or 5-year patient survival. In conclusion, BMI is an adequate tool for assessing obesity-associated risk in LT. Early post-LT morbidity is highest for patients with concomitant obesity and DM, although these factors do not appear to influence recipient survival.

We describe a new, simple, robust and efficient method based on direct-tissue matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry that enables consistent semi-quantitation of peptide hormones in isolated pancreatic islets from normal and diabetic rodents. Prominent signals were measured that corresponded to all the main peptide hormones present in islet-endocrine cells: (α-cells) glucagon, glicentin-related polypeptide/GRPP; (β-cells) insulin I, insulin II, C-peptide I, C-peptide II, amylin; (δ-cells) somatostatin-14; and (PP-cells), and pancreatic polypeptide. The signal ratios coincided with known relative hormone abundances. The method demonstrated that severe insulin deficiency is accompanied by elevated levels of all non-β-cell-hormones in diabetic rat islets, consistent with alleviation of paracrine suppression of hormone production by non-β-cells. It was also effective in characterizing hormonal phenotype in hemizygous human-amylin transgenic mice that express human and mouse amylin in approx. equimolar quantities. Finally, the method demonstrated utility in basic peptide-hormone discovery by identifying a prominent new Gcg-gene-derived peptide (theoretical monoisotopic molecular weight 3263.5 Da), closely related to but distinct from GRPP, in diabetic islets. This peptide, whose sequence is HAPQDTEENARSFPASQTEPLEDPNQINE in Rattus norvegicus, could be a peptide hormone whose roles in physiology and metabolic disease warrant further investigation. This method provides a powerful new approach that could provide important new insights into the physiology and regulation of peptide hormones in islets and other endocrine tissues. It has potentially wide-ranging applications that encompass endocrinology, pharmacology, phenotypic analysis in genetic models of metabolic disease, and hormone discovery, and could also effectively limit the numbers of animals required for such studies.

The lack of a system to classify invasive procedures to treat local complications of acute pancreatitis is an obstacle to comparing interventions. This study aimed to develop and validate a comprehensive multidisciplinary classification.Standardized terminology was used to develop a classification of procedures based on three key components: how the lesion is visualized, the route used during the procedure, and the procedure's purpose. Gastroenterologists, radiologists, and surgeons (n = 22) from three New Zealand centers independently classified 15 published technique descriptions. Inter-rater reliability was calculated for each component. The classification's clarity, ease of use, and potential to achieve its objectives were rated on a Likert scale.The classification's clarity, ease of use, and potential to achieve its objectives had median scores of 4/5. Inter-rater reliability for visualization, route, and purpose components was substantial at 0.73 (95% CI 0.63-0.82), 0.79 (95% CI 0.70-0.87), and 0.64 (95% CI 0.53-0.74), respectively.This article describes the development and validation of a comprehensive classification for the wide range of procedures used to treat the local complications of acute pancreatitis. It has substantial inter-rater reliability and high acceptability, which should enhance communication between clinicians and facilitate comparison between procedures.

Objective Insulin-like growth factor II (IGF-II) is a potent mitogen that regulates prenatal growth and development in both humans and rodents. Its role in post-natal life is less clear although immunohistochemical studies have observed IGF-II-like immunoreactivity (IGF-II-LI) associated with insulin-producing pancreatic β-cells. Here we isolated secretory granules from a β-cell line, βTC6-F7, and characterized the nature of the IGF-II-LI located therein. Design Secretory granules were isolated from cultured mouse βTC6-F7 cells by ultracentrifugation. Granule protein content was separated by reversed-phase HPLC, and assayed for IGF-II (radioimmunoassay) prior to identification by gas-phase NH 2 -terminal sequencing and MALDI-TOF MS. Effects of glucose incorporation into muscle glycogen were determined by incubating with isolated rat soleus muscle strips. Results βTC6-F7 cells contained 60±8pmol of IGF-II-LI per 10 6 cells compared to 340±44pmol insulin-LI per 10 6 cells. IGF-II immunoreactive fractions were found to contain an IGF-II-like molecule with a molecular mass of 6847.6Da. The protein was found to be a two-chain insulin-like product of Igf2 that corresponds to mouse des(37–40)IGF-II, which we termed ‘vesiculin'. This molecule was also detectable in βTC6-F7 cells by intact-cell mass spectrometry. Mouse vesiculin evoked concentration-dependent stimulation of muscle glycogen synthesis ex vivo with an EC 50 value of 131nM±1.35. Conclusions Vesiculin, des(37–40)IGF-II, is a novel two-chain insulin-like hormone and the major "IGF-II-like" peptide found in purified mouse βTC6-F7 secretory granules. It stimulated ex vivo muscle glycogen synthesis with an efficacy greater than or equal to the intrinsic potency of IGF-II when compared to insulin derived from the same species.

Treatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress. Rats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transition-metal-targeted treatments: d-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine. Diabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevating the urinary albumin/creatinine ratio. Diabetes also lowered total antioxidant potential and heparan sulphate levels in cardiac and arterial tissues, and serum ferroxidase activity, whereas it elevated urinary heparan sulphate excretion. TETA treatment rectified or partially rectified all these defects, whereas the other three experimental treatments were ineffectual. By contrast, none of the four drug treatments lowered diabetes-mediated elevations of plasma glucose or lipid concentrations. TETA may limit the cardiac and renal/vascular damage inflicted by diabetes through its actions to reinforce antioxidant defence mechanisms, probably acting through selective chelation of ‘loosely-bound’/chelatable Cu(II). It may also improve heparan sulphate homeostasis and bolster antioxidant defence by increasing vascular extracellular superoxide dismutase activity. Urinary albumin/creatinine ratio might prove useful for monitoring TETA treatment.

Background There have been several reports of ischaemic complications after routine laparoscopy. The aim of this review was to investigate the relationship between this oxidative stress and pneumoperitoneum. Methods Medline, Medline in-process, The Cochrane Library, PubMed and EMBASE were searched for papers on oxidative stress and pneumoperitoneum, from 1947 to March 2008 with no language restriction or restriction on trial design. Papers that did not investigate pneumoperitoneum as a causative factor, or did not report outcome measures related to oxidative stress, were excluded. Results A total of 73 relevant papers were identified: 36 animal studies, 21 human clinical trials, nine case reports, five review articles and two comments. Pneumoperitoneum causes a reduction in splanchnic blood flow, resulting in biochemical evidence of oxidative stress in a pressure- and time-dependent manner. There is evidence that the use of carbon dioxide for insufflation is contributory. Several measures proposed to minimize the oxidative stress have shown promise in animal studies, but few have been evaluated in the clinical setting. Conclusion There is an increasing body of evidence, mainly from animal studies, that pneumoperitoneum decreases splanchnic perfusion with resulting oxidative stress. It is now appropriate to investigate the clinical significance of pneumoperitoneum-associated oxidative stress.

Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.

beta-Cell granules contain proteins involved in fuel regulation, which when altered, contribute to metabolic disorders including diabetes mellitus. We analyzed proteins present in purified granules from the INS-1E beta-cell model. Fifty-one component proteins were identified by LC-MS/MS including hormones, granins, protein processing components, cellular trafficking components, enzymes implicated in cellular metabolism and chaperone proteins. These findings may increase understanding of granule secretion and the processes leading to protein aggregation and beta-cell death in type-2 diabetes.