Endocannabinoids and liver disease--review.

AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.     

Hemochromatosis: pathophysiology,evaluation, and management of hepatic iron overload with a focus on MRI

Introduction: Hereditary hemochromatosis (HH) is an autosomal recessive disorder that occurs in approximately 1 in 200–250 individuals. Mutations in the HFE gene lead to excess iron absorption. Excess iron in the form of non-transferrin-bound iron (NTBI) causes injury and is readily uptaken by cardiomyocytes, pancreatic islet cells, and hepatocytes. Symptoms greatly vary among patients and include fatigue, abdominal pain, arthralgias, impotence, decreased libido, diabetes, and heart failure. Untreated hemochromatosis can lead to chronic liver disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Many invasive and noninvasive diagnostic tests are available to aid in diagnosis and treatment. MRI has emerged as the reference standard imaging modality for the detection and quantification of hepatic iron deposition, as ultrasound (US) is unable to detect iron overload and computed tomography (CT) findings are nonspecific and influenced by multiple confounding variables. If caught and treated early, HH disease progression can significantly be altered.

Area covered: The data on Hemochromatosis, iron overload, and MRI were gathered by searching PubMed.

Expert commentary: MRI is a great tool for diagnosis and management of iron overload. It is safe, effective, and a standard protocol should be included in diagnostic algorithms of future treatment guidelines.     

The Emerging Threat of Antifungal Resistance in Transplant Infectious Diseases

Purpose of Review

The global emergence of antifungal resistance among Candida spp. and Aspergillus spp. will disproportionately affect transplantation recipients, who are prone to invasive fungal disease.

Recent Findings

Invasive candidiasis is increasingly caused by non-albicans Candida species with reduced susceptibility to first-line antifungals. Echinocandin resistance in Candida glabrata is increasing in some settings. Candida auris has rapidly emerged as a global concern due to multidrug resistance and efficient nosocomial spread in healthcare settings. Azole-resistant Aspergillus fumigatus is already an important concern in some European countries and is increasingly reported elsewhere, possibly driven by agricultural use of triazole fungicides.

Summary

Antifungal resistance is anticipated to expand among these and other common fungal pathogens. Culture-independent detection methods will become more important for rapid diagnosis and to guide empiric therapy. Antifungal stewardship is of critical importance to conserve our limited antifungal armamentarium for transplantation recipients and other vulnerable patients.

     

Impact of age on coronary artery plaque progression and clinical outcome: A PARADIGM substudy

BackgroundThe association of age with coronary plaque dynamics is not well characterized by coronary computed tomography angiography (CCTA).MethodsFrom a multinational registry of patients who underwent serial CCTA, 1153 subjects (61 ± 5 years old, 61.1% male) were analyzed. Annualized volume changes of total, fibrous, fibrofatty, necrotic core, and dense calcification plaque components of the whole heart were compared by age quartile groups. Clinical events, a composite of all-cause death, acute coronary syndrome, and any revascularization after 30 days of the initial CCTA, were also analyzed. Random forest analysis was used to define the relative importance of age on plaque progression.ResultsWith a 3.3-years’ median interval between the two CCTA, the median annual volume changes of total plaque in each age quartile group was 7.8, 10.5, 10.8, and 12.1 mm³/year and for dense calcification, 2.5, 4.6, 5.4, and 7.1 mm³/year, both of which demonstrated a tendency to increase by age (p-for-trend = 0.001 and < 0.001, respectively). However, this tendency was not observed in any other plaque components. The annual volume changes of total plaque and dense calcification were also significantly different in the propensity score-matched lowest age quartile group versus the other age groups as was the composite clinical event (log-rank p = 0.003). In random forest analysis, age had comparable importance in the total plaque volume progression as other traditional factors.ConclusionsThe rate of whole-heart plaque progression and dense calcification increases depending on age. Age is a significant factor in plaque growth, the importance of which is comparable to other traditional risk factors.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifiers: NCT02803411.     

Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.     

A real-life setting evaluation of the effect of remdesivir on viral load in COVID-19 patients admitted to a large tertiary centre in Israel

ObjectivesThe effectiveness of remdesivir, a Food and Drug Administration-approved drug for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been repeatedly questioned during the current coronavirus disease 2019 (COVID-19) pandemic. Most of the recently reported studies were randomized controlled multicentre clinical trials. Our goal was to test the efficiency of remdesivir in reducing nasopharyngeal viral load and hospitalization length in a real-life setting in patients admitted to a large tertiary centre in Israel.MethodsA total of 142 COVID-19 patients found to have at least three reported SARS-CoV-2 quantitative RT-PCR tests during hospitalization were selected for this study. Of these, 29 patients received remdesivir, while the remaining non-treated 113 patients served as controls.ResultsAmong the tested parameters, the control and remdesivir groups differed significantly only in the intubation rates. Remdesivir treatment did not significantly affect nasopharyngeal viral load, as determined by comparing the differences between the first and last cycle threshold values of the SARS-CoV-2 quantitative RT-PCR tests performed during hospitalization (cycle threshold 7.07 ± 6.85 vs. 7.08 ± 7.27, p 0.977 in the control and treated groups, respectively). Remdesivir treatment shortened hospitalization length by less than a day compared with non-treated controls and by 3.1 days when non-intubated patients from both groups were compared. These differences, however, were not statistically significant, possibly because of the small size of the remdesivir group.DiscussionRemdesivir was not associated with nasopharyngeal viral load changes, but our study had a significant disease severity baseline imbalance and was not powered to detect viral load or clinical differences.     

Prevalence of Periapical Lesions in Patients with Osteoporosis

IntroductionOsteoporosis is a major systemic disease that can significantly deteriorate the quality of life of the affected individuals. It is more common in women, particularly after menopause. Osteoporosis may be associated with alterations in oral health. Treatment of osteoporotic patients mainly involves the administration of bisphosphonates (BPs). Nitrogen-containing BPs are more potent therapeutically and more commonly used. The purpose of this study was to assess the prevalence of periapical lesions in patients with osteoporosis and to evaluate the difference in the prevalence of periapical lesions in patients treated with alendronate and risedronate, 2 nitrogen-containing types of BPs.MethodsIntegrated data of hospital patients were used. Data from the corresponding diagnosis codes for osteoporosis and periapical periodontitis were retrieved by searching the appropriate query in the database. The odds ratio (OR) of periapical lesions, its association with osteoporosis, and the use of 2 BP medications were calculated and analyzed statistically.ResultsOf 1,644,953 hospital patients, 8715 presented with periapical lesions. A total of 42,292 patients were diagnosed with osteoporosis. A total of 754 patients diagnosed with osteoporosis presented with periapical lesions. The prevalence of periapical lesions in patients with osteoporosis was 1.78% compared with 0.52% in the general patient population of the hospital. The OR for the prevalence of periapical lesions in patients with osteoporosis was 3.36 and was statistically significant (P < .0001). Patients with osteoporosis treated with any type of BPs showed a prevalence of periapical lesions in 1.25% of cases compared with 0.52% in the general patient population of the hospital. The difference in the OR was statistically significant (P < .0001). The OR for the presence of periapical lesions in the osteoporosis group treated with BPs was 2.35 compared with 3.52 in the osteoporosis group not treated with BP. The difference in the OR was statistically significant (P < .0001). Patients treated with alendronate showed an OR of 1.6 for the prevalence of periapical lesions, and the difference in the OR was statistically significant (P < .0001). Patients treated with risedronate showed an OR of 1.34 for the prevalence of periapical lesions, and the difference in the OR was not statistically significant (P = .3502).ConclusionsUnder the conditions of this study, it appears that the prevalence of periapical lesions is significantly higher in osteoporotic patients. Osteoporotic patients treated with BPs showed a marked reduction in the prevalence of periapical lesions, especially when risedronate was used.     

Prevalence of Periapical Abscesses in Patients with Hypertension: A Cross-sectional Study of a Large Hospital Population

IntroductionHypertension is a common major systemic disease and 1 of the most significant causes of mortality worldwide. Persistent hypertension is 1 of the risk factors for stroke, heart attack, heart failure, and arterial aneurysm and is a leading cause of chronic kidney failure. Common medications used to treat hypertension include beta blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. The purpose of this study was to assess the prevalence of periapical abscesses in patients with different types of hypertension conditions and to evaluate the effect of commonly used antihypertensive medications on the prevalence of periapical abscesses.MethodsThe integrated data of hospital patients were used. Data from the corresponding diagnosis codes for hypertensive conditions and periapical abscess were retrieved by searching the appropriate query in the database. The odds ratio (OR) of periapical abscesses, its association with hypertensive conditions, and the intake of 4 antihypertensive medications were calculated and analyzed statistically.ResultsThe prevalence of periapical abscesses in patients with hypertensive conditions was 1.2% compared with 0.558% in the general patient population of the hospital. The OR for the prevalence of periapical lesions in patients with hypertension was 2.32. For primary hypertension, the OR was 2.02; for hypertensive heart disease, the OR was 2.68; for hypertensive chronic kidney disease, the OR was 2.1; for hypertensive heart and chronic kidney diseases, the OR was 4.16; for secondary hypertension, the OR was 4.16; and for hypertension crisis, the OR was 5.64. For patients treated with beta blockers, the OR was 2.58; for patients treated with angiotensin-converting enzyme inhibitors, the OR was 2.73; for patients treated with angiotensin II receptor blockers, the OR was 1.93; and for patients treated with calcium channel blockers, the OR was 2.79. The differences were statistically significant (P < .0001). The OR for the prevalence of periapical abscesses in patients treated with angiotensin II receptor blockers was significantly lower than that of patients treated with either beta blockers or calcium channel blockers (P < .00001).ConclusionsUnder the conditions of this study, it appears that the prevalence of perapical abscesses is significantly higher in hypertensive patients. The prevalence of periapical abscesses is higher in patients with secondary hypertension than in those with primary hypertension. Angiotensin II receptor blockers may significantly lower the prevalence of periapical abscesses in hypertensive patients.     

Sequence Homology at the 5′-Termini of Insect Messenger RNAs

Treatment of insect polyribosomes with 1 M KCl released a messenger ribonucleoprotein with a pronounced 16S peak. Phenol extraction resulted in a defined peak of 10S RNA, which was judged as mRNA by the following criteria: it showed specificity for binding to ribosomes, and the formation of initiation complex was dependent on protein initiation factors, GTP, mRNA, and aminoacyl-tRNA. The complex directed protein synthesis upon the addition of elongation factors. mRNA was treated with phosphatase and phosphorylated at the 5'-end with [(32)P]cyanoethylphosphate. [(32)P]mRNA was digested by T1 ribonuclease to completion and chromatographed on DEAE-cellulose. The only fragment with (32)P was 15 nucleotides long; it was treated with pancreatic ribonuclease and fingerprinted. Fractions of AC, AAC, and AAAC were found. Initiation signal AUG or GUG in these mRNAs does not begin immediately at the 5'-end and may be at a distance greater than 15 nucleotides. Alkaline hydrolysis of mRNAs labeled in vivo with [(14)C]adenosine revealed Ap and pppAp. Alkaline hydrolysis of mRNA labeled with (32)P at the 5'-terminus resulted in pAp. Hence, these results suggest that in a heterogeneous population of mRNAs from insects, all start with A and have sequence homology at the 5'-termini. This sequence may reflect the signal for RNA polymerase on the gene or may promote the binding of mRNA to ribosomes.