Bidirectional Relationship Between Reduced Blood pH and Acute Pancreatitis: A Translational Study of Their Noxious Combination

Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP

Stereolithography 3D Printing of a Heat Exchanger for Advanced Temperature Control in Wire Myography

We report the additive manufacturing of a heat-exchange device that can be used as a cooling accessory in a wire myograph. Wire myography is used for measuring vasomotor responses in small resistance arteries; however, the commercially available devices are not capable of active cooling. Here, we critically evaluated a transparent resin material, in terms of mechanical, structural, and thermal behavior. Tensile strength tests (67.66 ± 1.31 MPa), Charpy impact strength test (20.70 ± 2.30 kJ/m2), and Shore D hardness measurements (83.0 ± 0.47) underlined the mechanical stability of the material, supported by digital microscopy, which revealed a glass-like structure. Differential scanning calorimetry with thermogravimetry analysis and thermal conductivity measurements showed heat stability until ~250 °C and effective heat insulation. The 3D-printed heat exchanger was tested in thermophysiology experiments measuring the vasomotor responses of rat tail arteries at different temperatures (13, 16, and 36 °C). The heat-exchange device was successfully used as an accessory of the wire myograph system to cool down the experimental chambers and steadily maintain the targeted temperatures. We observed temperature-dependent differences in the vasoconstriction induced by phenylephrine and KCl. In conclusion, the transparent resin material can be used in additive manufacturing of heat-exchange devices for biomedical research, such as wire myography. Our animal experiments underline the importance of temperature-dependent physiological mechanisms, which should be further studied to understand the background of the thermal changes and their consequences

Distinct patterns of serum and urine macrophage migration inhibitory factor kinetics predict death in sepsis: a prospective, observational clinical study

Abstract Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics

The Transient Receptor Potential Vanilloid-1 Channel in Thermoregulation: A Thermosensor It Is Not

The development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel as pain therapeutics has revealed that these compounds cause hyperthermia in humans. This undesirable on-target side effect has triggered a surge of interest in the role of TRPV1 in thermoregulation and revived the hypothesis that TRPV1 channels serve as thermosensors. We review literature data on the distribution of TRPV1 channels in the body and on thermoregulatory responses to TRPV1 agonists and antagonists. We propose that two principal populations of TRPV1-expressing cells have connections with efferent thermoeffector pathways: 1) first-order sensory (polymodal), glutamatergic dorsal-root (and possibly nodose) ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. We further hypothesize that all thermoregulatory responses to TRPV1 agonists and antagonists and thermoregulatory manifestations of TRPV1 desensitization stem from primary actions on these two neuronal populations. Agonists act primarily centrally on population 2; antagonists act primarily peripherally on population 1. We analyze what roles TRPV1 might play in thermoregulation and conclude that this channel does not serve as a thermosensor, at least not under physiological conditions. In the hypothalamus, TRPV1 channels are inactive at common brain temperatures. In the abdomen, TRPV1 channels are tonically activated, but not by temperature. However, tonic activation of visceral TRPV1 by nonthermal factors suppresses autonomic cold-defense effectors and, consequently, body temperature. Blockade of this activation by TRPV1 antagonists disinhibits thermoeffectors and causes hyperthermia. Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed

The hypothermic effect of hydrogen sulfide is mediated by the transient receptor potential ankyrin-1 channel in mice

Hydrogen sulfide (H(2)S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H(2)S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na(2)S) and slow-releasing (GYY4137) H(2)S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1(−/−)) and wild-type (Trpa1(+/+)) mice. Intracerebroventricular administration of Na(2)S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na(2)S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H(2)S donors was significantly (p < 0.001) attenuated in Trpa1(−/−) mice compared to their Trpa1(+/+) littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H(2)S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways