The aggregate of epidemiological studies indicates a significantly elevated risk for cancer in people with a high body mass index (BMI); a “dose–response” effect exists with increasing risk as BMI ...increases from the normal to overweight to obese categories. Successful sustained weight loss decreases future risk. The relationship of being overweight to the risk for leukemia in the aggregate has been supported in several large cohort studies and two meta‐analyses of cohort and case–control studies. One meta‐analysis found an elevated risk for each of the four major subtypes of leukemia. A significant association between the risk for non‐Hodgkin's lymphoma and elevated BMI was supported by a meta‐analysis of 13 cohort and nine case–control studies. The risk for diffuse large B‐cell lymphoma may be especially significant. A high BMI increases the risk for myeloma, as judged by a meta‐analysis of 11 cohort and four case–control studies. The biological relationship of obesity to the risk for cancer (biological plausibility) is unresolved. The two major causal final pathways could be “inductive” or “selective.” The metabolic, endocrinologic, immunologic, and inflammatory‐like changes resulting from obesity may increase the cell mutation rate, dysregulate gene function, disturb DNA repair, or induce epigenetic changes, favoring the induction of neoplastic transformation (inductive). Alternatively, obesity may create an environment in which pre‐existing clones that are dormant are permitted (selected) to emerge.
Studies on obesity and the risk for hematological malignancies are reviewed. The paper includes a discussion of the metabolic effects of obesity and their possible role in linking increased body fat to neoplasia.
Review on the evidence for the neutrophil as a mediator of tissue injury in seven conditions making it a potential therapeutic target.
The neutrophil is an essential component of the innate immune ...system, and its function is vital to human life. Its production increases in response to virtually all forms of inflammation, and subsequently, it can accumulate in blood and tissue to varying degrees. Although its participation in the inflammatory response is often salutary by nature of its normal interaction with vascular endothelium and its capability to enter tissues and respond to chemotactic gradients and to phagocytize and kill microrganisms, it can contribute to processes that impair vascular integrity and blood flow. The mechanisms that the neutrophil uses to kill microorganisms also have the potential to injure normal tissue under special circumstances. Its paradoxical role in the pathophysiology of disease is particularly, but not exclusively, notable in seven circumstances: 1) diabetic retinopathy, 2) sickle cell disease, 3) TRALI, 4) ARDS, 5) renal microvasculopathy, 6) stroke, and 7) acute coronary artery syndrome. The activated neutrophilˈs capability to become adhesive to endothelium, to generate highly ROS, and to secrete proteases gives it the potential to induce local vascular and tissue injury. In this review, we summarize the evidence for its role as a mediator of tissue injury in these seven conditions, making it or its products potential therapeutic targets.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Henry Bence Jones is among the esteemed physicians of the mid-19th century. Eighteen biographical medical journal articles, published between 1952 and 2021, describe his life and contributions to ...medicine. Unmentioned, however, is an island in the waters of Shepherd Bay in northern Canada, now Nunavut, designated Bence Jones Island, by the British explorer John Rae in 1854. Rae had sailed from Great Britain to the regions extending north of Hudson's Bay in search of information regarding Sir John Franklin and 133 other officers and men who departed from the Kingdom of Great Britain in two ships in 1845 to search for the Northwest Passage to the Pacific Ocean; they disappeared. In anticipation of Rae's voyage to search for evidence of Franklin's expedition, Bence Jones provided a special preparation of tea that could be drunk cold, if necessary. It was so meaningful to the crew of Rae's ship that it resulted in Rae naming an island near Boothia Isthmus in Shepherd Bay in recognition of this contribution to the contentment of his men under arduous conditions and in acknowledgment of Bence Jones's professional standing, upon which we comment. Rae's report of his voyage in 1855, cited herein, mentioned the island and showed its position on a map of the region. We have located it on a current map of the waterways and landmasses of Nunavut using Google Earth Pro by showing its position at the approximate coordinates of latitude and longitude cited by Rae.
We have reviewed the literature to identify and characterize reports of warm-antibody type, autoimmune hemolytic anemia in which the standard direct antiglobulin reaction was negative but a ...confirmatory test indicated that the red cells were opsonized with antibody. Three principal reasons account for the absence of a positive direct antiglobulin test in these cases: a) IgG sensitization below the threshold of detection by the commercial antiglobulin reagent, b) low affinity IgG, removed by preparatory washes not conducted at 4°C or at low ionic strength, and c) red cell sensitization by IgA alone, or rarely (monomeric) IgM alone, but not accompanied by complement fixation, and thus not detectable by a commercial antiglobulin reagent that contains anti-IgG and anti-C3. In cases in which the phenotype is compatible with warm-antibody type, autoimmune hemolytic anemia and the direct antiglobulin test is negative, an alternative method to detect low levels of IgG sensitization, use of 4°C, low ionic strength washes to prepare the cells for the direct antiglobulin test reaction to permit retention and identification of low affinity IgG antibodies, and, if the latter are uninformative, testing for sensitization with an anti-IgA, and, if necessary, an anti-IgM reagent identifies cases of warm-antibody type, immune hemolysis not verified by a commercial reagent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their ...therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-5-(2-pyridyl)-2-yl-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB(1) or CB(2) receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzod1,3dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB(1), but not a CB(2), receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.
Enhanced signaling of the endocannabinoid (eCB) system through inhibition of the catabolic enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) has received increasing ...interest for development of candidate analgesics. This study compared effects of MAGL and FAAH inhibitors with effects of ∆9-tetrahydrocannabinol (THC) using a battery of pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to stimulate two behaviors (stretching, facial grimace) and depress two behaviors (rearing, nesting). Nesting and locomotion were also assessed in the absence of IP acid as pain-independent behaviors. THC and a spectrum of six eCB catabolic enzyme inhibitors ranging from MAGL- to FAAH-selective were assessed for effectiveness to alleviate pain-related behaviors at doses that did not alter pain-independent behaviors. The MAGL-selective inhibitor MJN110 produced the most effective antinociceptive profile, with 1.0 mg/kg alleviating IP acid effects on stretching, grimace, and nesting without altering pain-independent behaviors. MJN110 effects on IP acid-depressed nesting had a slow onset and long duration (40 minutes to 6 hours), were blocked by rimonabant, and tended to be greater in females. As inhibitors increased in FAAH selectivity, antinociceptive effectiveness decreased. PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion. THC decreased IP acid-stimulated stretching and grimace at doses that did not alter pain-independent behaviors; however, it did not alleviate IP acid-induced depression of rearing or nesting. These results support further consideration of MAGL-selective inhibitors as candidate analgesics for acute inflammatory pain. SIGNIFICANCE STATEMENT: This study characterized a spectrum of endocannabinoid catabolic enzyme inhibitors ranging in selectivity from monoacylglycerol lipase-selective to fatty acid amide hydrolase-selective in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate analgesics by effectiveness to alleviate pain-related behaviors at doses that do not alter pain-independent behaviors, with inclusion of pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives.
Background and Purpose
Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2‐arachidonoylglycerol (2‐AG), a great need has ...emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3‐hexafluoropropan‐2‐yl 4‐(bis(benzod1,3dioxol‐5‐yl)(hydroxy)methyl)piperidine‐1‐carboxylate).
Experimental Approach
In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac‐induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.
Key Results
KML29 attenuated carrageenan‐induced paw oedema and completely reversed carrageenan‐induced mechanical allodynia. These effects underwent tolerance after repeated administration of high‐dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2‐AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac‐induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ9‐tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose‐dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (−/−) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC‐like subjective effects.
Conclusions and Implications
These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.
Linked Articles
This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cerebrospinal-fluid (CSF) drainage is recommended by current guidelines for spinal protection during open and endovascular repairs of thoracic and thoraco-abdominal aortic aneurysms. In the published ...literature, great variability exists in the rate of CSF-related complications and morbidity. Herein, we perform a systematic review and meta-analysis on the incidence of CSF drainage-related complications, and compare the complication rates between open and endovascular repairs.
The systematic review was conducted according to the Meta-Analysis of Observational Studies in Epidemiology guidelines. Thirty-four studies (4714 patients) were included in the quantitative analysis. The CSF drainage-related complications were categorised as mild, moderate, and severe. Pooled event rates for each complication category were estimated using a random-effect model. Random-effect uni- and multivariable meta-regression analyses were used to assess the effect of aortic-repair approach (open vs endovascular) and the CSF drainage criteria on CSF drainage-related complications.
The pooled event rates were 6.5% 95% confidence interval (CI): 4.3–9.8% for overall complications, 2% (95% CI: 1.1–3.4%) for minor complications, 3.7% (95% CI: 2.5–5.6%) for moderate complications, and 2.5% (95% CI: 1.6–3.8%) for severe complications. The drainage-related-mortality pooled event rate was 0.9% (95% CI: 0.6–1.4%). The uni- and multivariable meta-regression analyses showed no difference in complication rates between the open and endovascular approaches, or between the different CSF drainage protocols.
The complication rate for CSF drainage is not negligible. Our results help define a more accurate risk–benefit ratio for CSF drain placement at the time of repair of thoracic and thoraco-abdominal aneurysms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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