Objective To summarize the information regarding pathogenetic factors of leiomyoma formation and growth, and to make a simple integrated pathogenetic view of this tumor for further thinking to ...establish new therapeutic options. Design PubMed and Google Scholar searches were conducted to identify the relevant studies on pathogenesis of uterine leiomyoma, which are hereby reviewed and discussed. Setting Academic medical center. Patient(s) Not applicable. Intervention(s) Not applicable. Main Outcome Measure(s) Not applicable. Result(s) To date, the pathogenesis of uterine leiomyomas is not well understood. However, genetic alterations (especially MED12 and HMGA2 ) and involvement of epigenetic mechanisms (DNA methylation, histone modifications, and microRNA) in leiomyoma provide the clue of initiator of this tumor. Estrogens and P are considered as promoters of leiomyoma growth, and growth factors, cytokines, and chemokines are thought to be as potential effectors of estrogens and P. Extracellular matrix components are a major structural part of leiomyoma tissue that are abnormally orientated and can modify mechanical stress on cells, which leads to activation of internal mechanical signaling and may contribute to leiomyoma growth. Conclusion(s) Besides many genetics and epigenetic factors, the important link among the sex steroids, growth factors, cytokines, chemokines, and extracellular matrix and their involvement in cell proliferation, fibrotic processes, apoptosis, and angiogenesis are implicating a complex network in leiomyoma formation and growth. Those findings could provide information to establish future therapeutic options for the management of this tumor.
There is an increasing number of nutraceutical combinations (NCs) on the market for hypercholesterolemia, although clinical trials to verify their safety and efficacy are scarce. We selected fourteen ...randomized, placebo-controlled clinical trials (RCTs) on different lipid-lowering NCs in hypercholesterolemic subjects. We described each compound′s mechanism of action and efficacy in the mixtures and summarized the clinical trials settings and NCs safety and efficacy results. Almost all NCs resulted efficient against hypercholesterolemia; only one reported no changes. Interestingly, red yeast rice (RYR) was present in eleven mixtures. It is not clear whether the lipid-lowering efficacy of these combinations derives mainly from the RYR component monacolin K “natural statin” single effect. Up to now, few RCTs have verified the efficacy of every single compound vs. NCs to evaluate possible additive or synergistic effects, probably due to the complexity and the high resources request. In conclusion, to manage the arising nutraceutical tide against hypercholesterolemia, it could be helpful to increase the number and robustness of clinical studies to verify the efficacy and safety of the new NCs.
Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the “usual leiomyoma”, characterized by overexpression of ECM proteins, whereas the ...“cellular type” has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via α-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-15, GM-CSF and IFN-γ) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the “usual type”. Inside the fibroid tissue, we found cells positive for α-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the “usual type”, we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the “cellular type”, stromal fibroblasts were CD34-negative. Finally, we found that TNF-α increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth.
Disorders of lipoprotein metabolism are among the major risk factors for cardiovascular disease (CVD) development. Single nucleotide polymorphisms (SNPs) have been associated with the individual ...variability in blood lipid profile and response to lipid-lowering treatments. Here, we genotyped 34 selected SNPs located in coding genes related to lipid metabolism, inflammation, coagulation, and a polymorphism in the
gene-a microRNA previously linked to CVD-to evaluate the association with lipid trait in subjects with moderate dyslipidemia not on lipid-lowering treatment (Treatment-naïve (TN) cohort,
= 125) and in patients treated with statins (STAT cohort,
= 302). We also explored the association between SNPs and the effect of a novel phytochemical lipid-lowering treatment in the TN cohort. We found that 6 SNPs (in the
, TNFA, CETP, SOD2, and VEGFA genes) were associated with lipid traits in the TN cohort, while no association was found with the response to twelve-week phytochemical treatment. In the STAT cohort, nine SNPs (in the
, CETP, CYP2C9, IL6, ABCC2, PON1, IL10, and VEGFA genes) were associated with lipid traits, three of which were in common with the TN cohort. Interestingly, in both cohorts, the presence of the rs3746444
SNP was associated with a more favorable blood lipid profile. Our findings could add information to better understand the individual genetic variability in maintaining a low atherogenic lipid profile and the response to different lipid-lowering therapies.
Background: Nutraceutical combinations (NCs) against hypercholesterolemia are increasing in the marketplace. However, the availability of NCs without monacolin K is scarce even though the ...statin-intolerant population needs it. Methods: This study is a parallel-group, randomized, placebo-controlled, double-blind trial. We evaluated the effects of the NC containing phytosterols, bergamot, olive fruits, and vitamin K2 on lipid profile and inflammatory biomarkers in 118 subjects (mean age ± SD, 57.9 ± 8.8 years; 49 men and 69 women) with hypercholesterolemia (mean total cholesterol ± SD, 227.4 ± 20.8 mg/dL) without clinical history of cardiovascular diseases. At baseline and 6 and 12 weeks of treatment, we evaluated lipid profile (total, LDL and HDL cholesterol, and triglycerides), safety (liver, kidney, and muscle parameters), and inflammatory biomarkers such as hs-CRP, leukocytes, interleukin-32, and interleukin-38 and inflammatory-microRNAs (miRs) miR-21, miR-126, and miR-146a. Results: Compared to the placebo, at 6 and 12 weeks, NC did not significantly reduce total cholesterol (p = 0.083), LDL cholesterol (p = 0.150), and triglycerides (p = 0.822). No changes were found in hs-CRP (p = 0.179), interleukin-32 (p = 0.587), interleukin-38 (p = 0.930), miR-21 (p = 0.275), miR-126 (p = 0.718), miR-146a (p = 0.206), myoglobin (p = 0.164), and creatine kinase (p = 0.376). Among the two reported, only one adverse event was probably related to the nutraceutical treatment. Conclusions: The evaluated nutraceutical combination did not change serum lipid profile and inflammatory parameters, at least not with the daily dose applied in the present study.
Elevated cholesterol levels and systemic inflammation are considered relevant risk factors for cardiovascular disease (CVD) development and progression. Increasing evidence suggests that ...cholesterol-lowering and inflammation-lowering nutraceuticals are useful in the management of moderate hypercholesterolemia. Here, we describe the study protocol of a clinical trial aimed to evaluate the cholesterol and inflammatory lowering effect of an innovative dietary supplement (BruMeChol™, Mivell S.r.l., Italy), composed of a mixture of extracts of bergamot and olive fruits in association with vitamin K2 in subjects with mild hypercholesterolemia.
The study was planned as a randomized, double-blind, placebo-controlled, parallel group clinical trial for 12 weeks at the Cardiology Unit of the IRCCS INRCA of Ancona, Italy. A total of 125 subjects (age ≥ 40 years) with mild hypercholesterolemia (total serum cholesterol levels ≥ 200 and ≤ 250 mg/dl) will be recruited. Intervention arm participants will take one capsule of dietary supplement two times a day, 15 min before the main meal. Control arm participants will receive one capsule of placebo in the same way. The dietary supplement capsule contains the following ingredients: phytosterols, flavonoid-rich extract of bergamot fruit (Citrus bergamia), flavonoid-rich extract of olive fruit (Olea europaea), and vitamin K2. Participants will undergo a medical evaluation and chemical-clinical examinations, which include lipid profile, glycemia, biomarkers of renal, liver and cardiac/muscular functions, interleukins (IL 6, IL-32, IL-37, and IL-38), and innovative mediators of inflammation such as inflamma-miRs (miR-21 and miR-146a), at baseline, and after 6 and 12 weeks of treatment. The decrease in total cholesterol levels and inflammatory biomarkers will be the primary and secondary endpoints of the study.
This protocol study, planned to verify the effects of BruMeChol™ dietary supplementation in subjects with mild hypercholesterolemia, could also contribute to new study designs for next large-scale multicenter clinical trials.
Australian New Zealand Clinical Trials Registry: ACTRN12619000170123 . Retrospectively registered on 5 February 2019.
: Physical activity is an important predictor of quality of life in older adults with type 2 diabetes (T2D). Unfortunately, most T2D adults adopt a sedentary lifestyle. The randomized, controlled ...TRIPL-A trial aims to verify the effect of a personalized, discontinuous exercise program on a sedentary lifestyle of T2D older adults.
: A total of 305 T2D patients (mean age ± SD: 68.8 ± 3.3 years) were divided into a control arm receiving only behavioral counseling and an intervention arm of an 18-month supervised discontinuous exercise program (ERS). The primary outcomes were the changes in sitting time (ST) and metabolic equivalent (MET) values, both evaluated by the International Physical Activity Questionnaire short form. A repeated measures ANOVA with Bonferroni correction for multiple comparisons was used to compare study outcomes.
: The ST and MET differed significantly during the study compared to the control group (
= 0.028 and
= 0.004, respectively). In the intervention group, a decrease from baseline in ST at 6 months (
= 0.01) and an increase in MET values at 6 months (
= 0.01) up to 12 months (
< 0.01) were found. No significant differences were found for the other variables.
: Beneficial lifestyle changes were found within the first year of intervention. These results align with the theory of change.
Objective To determine the effect of tranilast (an antiallergic drug known to suppress fibrosis or to stabilize mast cells) on extracellular matrix production in human leiomyoma and myometrial cells. ...Design Laboratory study. Setting University-affiliated laboratory. Patient(s) Seven premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Intervention(s) Cells were treated with tranilast (300 μM) for 48 hours to measure extracellular matrix and activin-A expression by real-time reverse-transcription polymerase chain reaction and/or immunocytochemistry. Main Outcome Measure(s) The expression of fibronectin, collagen1A1, versican, and activin-A in myometrial and leiomyoma cells. Result(s) Tranilast decreased fibronectin, collagen 1A1, and versican messenger RNA (mRNA) expression in human primary leiomyoma cell culture. Similar results were found in an immortalized human leiomyoma cell line. Tranilast also decreased the mRNA expression of fibronectin, collagen 1A1, and versican in human primary myometrial cells. The reduced expression of fibronectin and collagen 1 were observed by immunocytochemistry as well. Tranilast also reduced profibrotic growth factor, activin-A mRNA expression in primary myometrial and leiomyoma cells. Conclusion(s) Our results indicate that tranilast reduced fibronectin, collagen 1A1, versican, and activin-A expression in leiomyoma and myometrial cells, demonstrating its potential as an antifibrotic therapy for human leiomyomas.
Context:
Uterine leiomyomas (fibroids or myomas) are benign tumors of the uterus and are clinically apparent in up to 25% of reproductive-age women. Heavy or abnormal uterine bleeding, pelvic pain or ...pressure, infertility, and recurrent pregnancy loss are generally associated with leiomyoma. Although surgical and radiological therapies are frequently used for the management of this tumor, medical therapies are considered the first-line treatment of leiomyoma.
Evidence Acquisition and Synthesis:
A review was conducted of electronic and print data comprising both original and review articles on pathophysiology and medical treatments of uterine leiomyoma retrieved from the PubMed or Google Scholar database up to June 2012. These resources were integrated with the authors' knowledge of the field.
Conclusion:
To date, several pathogenetic factors such as genetic factors, epigenetic factors, estrogens, progesterone, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in leiomyoma development and growth. On the basis of current hypotheses, several medical therapies have been investigated. GnRH agonist has been approved by US Food and Drug Administration for reducing fibroid volume and related symptoms. In addition, the FDA also approved an intrauterine device, levonorgestrel-releasing intrauterine system (Mirena), for additional use to treat heavy menstrual bleeding in intrauterine device users only. Currently, mifepristone, asoprisnil, ulipristal acetate, and epigallocatechin gallate have been shown to be effective for fibroid regression and symptomatic improvement which are all in clinical trial. In addition, some synthetic and natural compounds as well as growth factor inhibitors are now under laboratory investigation, and they could serve as future therapeutic options.
•COVID-19 patients with the worst prognosis are older and more comorbid patients, but very elderly patients are the less studied in clinical trials. This study involve elderly and very elderly ...patients affected by COVID-19.•Increased HS-cTnT value during COVID-19 can be due not only to direct cardiac damage (ischemic or not ischemic) but also to pre-existing cardiovascular diseases or other comorbidities.•High admission HS-cTnT level (≥ 101 pg/ml) is an independent predictor of in-hospital mortality in elderly and very elderly COVID-19 patients.•Admission HS-cTnT level is a simple and not expensive blood test that can help clinicians to stage frailty and then mortality risk of elderly patients. This study has demonstrated the utility of evaluating HS-cTnT at hospitalization for elderly COVID-19 patients.
Elevation of cardiac troponin (cTn) is associated with the worst prognosis not only in cardiovascular disease but also in non-cardiovascular disease. The aim of this study is to verify if cTn has a prognostic role in elderly and very elderly coronavirus disease 2019 (COVID-19) patients.
This study enrolled consecutive COVID-19 elderly patients hospitalized at INRCA hospital, with available admission high sensitivity cardiac troponin T (HS-cTnT) level. Patients were divided into three groups based on HS-cTnT level: group A (Hs-cTnT ≤ 40 pg/ml), group B (Hs-cTnT 41-100 pg/ml), and group C (Hs-cTnT ≥ 101 pg/ml). The correlation between HS-cTnT levels and mortality rates was analyzed.
461 patients (mean age 86 years; 59% female) were divided into group A (261 patients), group B (129 patients), and group C (71 patients). Group C resulted significantly older, more affected by heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and dementia, and with higher levels of creatinine, C-reactive protein, pro-calcitonin, interleukin-6, ferritin, NT-proBNP, D-dimer then group A and group B. Mortality rate increased significantly across groups (group A: 18.4%; group B: 36.4%; group C: 62.0%; p<0.001). Group C had a significant increase in mortality risk compared to group A, both univariate analysis (HR 3.78) and multivariate analysis (model 2 HR 3.10; model 3 HR 3.59; model 4 HR 1.72).
HS-cTnT has demonstrated a prognostic role in elderly and very elderly COVID-19 patients. HS-cTnT is a simple and inexpensive laboratory exam that gives clinicians important information on mortality risk stratification.
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