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To determine incidence and clinically relevant risk factors for diabetic amputation in a large cohort study of diabetic foot ulceration patients in China, we investigated a total of 669 diabetic foot ulceration patients, who were assessed at baseline for demographic information, medical and social history, peripheral neuropathy screening, periphery artery disease screening, assessment of nutritional status and diabetic control, physical examination including foot deformity in 15 Grade III-A hospitals. Of the 669 patients, 435 were male and 201 were female, with the mean age being 64.0 years. Of all patients, 110 had neuropathic ulcers, 122 had ischemic ulcers, 276 had neuroischemic ulcers, and 12 cases were unclassified. Wagner classification showed 61 cases were grade I, 216 cases grade II, 159 cases grade III, 137 cases grade IV, and 7 cases grade V. The overall amputation rate among diabetic foot patients was 19.03%, and major and minor amputation rates were 2.14% and 16.88%, respectively. By univariate analysis, statistically significant differences were found in smoking, rest pain, ulcer history, revascularization history, amputation history, gangrene, infection, Wagner grades, duration of diabetes, and postprandial blood glucose, aldehyde, total protein, globulin, albumin, white blood cell (WBC), hemoglobin, HbA1c, ulcer property, body mass index, as well as creatinine. Binary logistic regression model showed that increased WBC (odds ratio 1.25) and ulcer history (odds ratio 6.8) were associated with increased risks from diabetic foot ulcer to major amputation; increased duration of diabetes (odds ratio 1.004), WBC (odds ratio 1.102), infection (odds ratio 2.323), foot deformity (odds ratio 1.973), revascularization history (odds ratio 2.662), and decreased postprandial blood sugar (odds ratio 0.94) were associated with increased risks from diabetic foot ulcer to minor amputation. It is of great importance to give better management to diabetic patients at early stages. Following a diagnosis of DFU more intensive surveillance and aggressive care may improve outcome.

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. Enhanced excitability and suppression of A-type K ϩ current of pancreas-specific afferent neurons in a rat model of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 291: G424 -G431, 2006. First published April 27, 2006 doi:10.1152/ajpgi.00560.2005.-Chronic pancreatitis (CP) is a relatively common disorder, characterized by glandular insufficiency and chronic, often intractable, pain. The mechanism of pain in CP is poorly understood. We have previously developed a model of trinitrobenzene sulphonic acid (TNBS)-induced CP that results in nociceptive sensitization in rats. This study was designed to examine changes in the excitability and alteration of voltage-gated K ϩ currents of dorsal root ganglia (DRG) neurons innervating the pancreas. CP was induced in adult rats by an intraductal injection of TNBS. DRG neurons innervating the pancreas were identified by 1,1Ј-dioleyl-3,3,3Ј,3-tetramethylindocarbocyanine methanesulfonate fluorescence labeling. Perforated patch-clamp recordings were made from acutely dissociated DRG neurons from control and TNBS-treated rats. Pancreas-specific DRG neurons displayed more depolarized resting potentials in TNBS-treated rats than those in controls (P Ͻ 0.02). Some neurons from the TNBS-treated group exhibited spontaneous firings. TNBS-induced CP also resulted in a dramatic reduction in rheobase (P Ͻ 0.05) and a significant increase in the number of action potentials evoked at twice rheobase (P Ͻ 0.05). Under voltage-clamp conditions, neurons from both groups exhibited transient A-type (I A) and sustained outward rectifier K ϩ currents (IK). Compared with controls, the average I A but not the average IK density was significantly reduced in the TNBS-treated group (P Ͻ 0.05). The steadystate inactivation curve for I A was displaced by ϳ20 mV to more hyperpolarized levels after the TNBS treatment. These data suggest that TNBS treatment increases the excitability of pancreas-specific DRG neurons by suppressing I A density, thus identifying for the first time a specific molecular mechanism underlying chronic visceral pain and sensitization in CP.dorsal root ganglion; inflammation; visceral pain; trinitrobenzene sulfonic acid; membrane properties PAIN is a cardinal feature of chronic pancreatitis (CP) and remains the most important clinical challenge in these patients (5, 34). Despite much speculation, little is known about the underlying mechanisms responsible for this symptom. By definition, CP is an inflammatory condition and is therefore expected to produce significant functional changes in the nociceptive system serving this organ, as has been observed in other forms of visceral inflammation such as cystitis, gastric ulcers, and ileitis (4,21,29,40). However, until now, it has been difficult to demonstrate this in CP, in large part due to the lack of an appropriate animal model. We (35) have recently developed a novel and robust model of pain behavior and sensitization after the induction of CP with an intraductal injection of trinitrobenzene sulfonic acid (TNBS) in t...

Background and aimsExercise training is considered a cornerstone in the management of type 2 diabetes, which is associated with impaired endothelial function. However, the association of exercise training with endothelial function in type 2 diabetes patients has not been fully understood. This meta-analysis aimed to investigate their associations with focus on exercise types.MethodsDatabases were searched up to January 2018 for studies evaluating the influences of exercise training with durations ≥ 8 weeks on endothelial function assessed by flow-mediated dilation (FMD) among type 2 diabetes patients or between type 2 diabetics and non-diabetics. Data were pooled using random-effects models to obtain the weighted mean differences (WMDs) and 95% confidence intervals (CIs).ResultsSixteen databases were included. Exercise training resulted in an overall improvement in FMD by 1.77% (95% CI 0.94–2.59%) in type 2 diabetes patients. Specifically, both aerobic and combined aerobic and resistance exercise increased FMD by 1.21% (95% CI 0.23–2.19%) and 2.49% (95% CI 1.17–3.81%), respectively; but resistance exercise only showed a trend. High-intensity interval aerobic exercise did not significantly improve FMD over moderate-intensity continuous exercise. Notably, the improvement in FMD among type 2 diabetes patients was smaller compared with non-diabetics in response to exercise training (WMD − 0.72%, 95% CI − 1.36 to − 0.08%) or specifically to aerobic exercise (WMD − 0.65%, 95% CI − 1.31 to 0.01%).ConclusionsExercise training, in particular aerobic and combined exercise, improves endothelial function in type 2 diabetes patients, but such an improvement appears to be weakened compared with non-diabetics.Trial registration PROSPERO CRD42018087376Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0711-2) contains supplementary material, which is available to authorized users.

Background Human studies show that fetal membranes have a limited lifespan and undergo telomere-dependent cellular senescence that is augmented by oxidative stress and mediated by p38 mitogen activated protein kinase (MAPK). Further, these studies suggest that fetal membranes are anatomically physiologically positioned to transmit senescence signals that may initiate parturition at term. Methods Longitudinal evaluation of feto-maternal tissues from mouse pregnancies was undertaken to determine the molecular progression of senescence during normal pregnancy. On days 10–18 of gestation, C57BL/6 mice were euthanized. Fetal membranes, placenta, and decidua/uterus were collected. Tissues were examined for Telomere length (TL) and the presence of Phosphorylated (P) p38MAPK and p53, p21 and senescence associated β-Galactosidase (SA- β-Gal). Findings Telomere length negatively correlated with gestational age in fetal membranes (β= − 0.1901 ± 0.03125, p < 0.0001), placenta (−0.09000 ± 0.03474, p=0.0135), and decidua/uterus (− 0.1317 ± 0.03264, p=0.0003). Progressive activation p38MAPK was observed in all tissues from days 10 to day18, with the highest activation observed in fetal membranes. Activation of p53 was progressive in fetal membranes. In contrast, active p53 was constitutive in placenta and decidua/uterus throughout gestation. Detection of p21 indicated that pro-senescent change was higher in all compartments on day 18 as compared to other days. The number of SA-β-Gal positive cells increased in fetal membranes as gestation progressed. However, in placenta and uterus and decidua/uterus SA-β-Gal was seen only in days 15 and 18. Conclusions Telomere dependent p38 and p53 mediated senescence progressed in mouse fetal membranes as gestation advanced. Although senescence is evident, telomere dependent events were not dominant in placenta or decidua/uterus. Fetal membrane senescence may significantly contribute to mechanisms of parturition at term.

BackgroundWe have shown functional expression of several TRP channels on human synovial cells, proposing significance in known calcium dependent proliferative and secretory responses in joint inflammation. The present study further characterizes synoviocyte TRP expression and activation responses to thermal and osmotic stimuli after pre-treatment with proinflammatory mediator tumor necrosis factor alpha (TNF-α, EC50 1.3221 × 10-10g/L).ResultsFluorescent imaging of Fura-2 loaded human SW982 synoviocytes reveals immediate and delayed cytosolic calcium oscillations elicited by (1) TRPV1 agonists capsaicin and resiniferatoxin (20 – 40% of cells), (2) moderate and noxious temperature change, and (3) osmotic stress TRPV4 activation (11.5% of cells). TNF-alpha pre-treatment (1 ng/ml, 8 – 16 hr) significantly increases (doubles) capsaicin responsive cell numbers and [Ca2+]i spike frequency, as well as enhances average amplitude of temperature induced [Ca2+]i responses. With TNF-alpha pre-treatment for 8, 12, and 16 hr, activation with 36 or 45 degree bath solution induces bimodal [Ca2+]i increase (temperature controlled chamber). Initial temperature induced rapid transient spikes and subsequent slower rise reflect TRPV1 and TRPV4 channel activation, respectively. Only after prolonged TNF-alpha exposure (12 and 16 hr) is recruitment of synoviocytes observed with sensitized TRPV4 responses to hypoosmolarity (3–4 fold increase). TNF-alpha increases TRPV1 (8 hr peak) and TRPV4 (12 hr peak) immunostaining, mRNA and protein expression, with a TRPV1 shift to membrane fractions.ConclusionTNF-α provides differentially enhanced synoviocyte TRPV1 and TRPV4 expression and [Ca2+]i response dependent on the TRP stimulus and time after exposure. Augmented relevance of TRPV1 and TRPV4 as inflammatory conditions persist would provide calcium mediated cell signaling required for pathophysiological responses of synoviocytes in inflammatory pain states.

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