3,5-Diiodo-L-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver.

Recent reports demonstrated that 3,5-diiodo-l-thyronine (T(2)) was able to prevent lipid accumulation in the liver of rats fed a high-fat diet (HFD). In this study, we investigated how the rat liver responds to HFD and T(2) treatment by assessing the transcription profiles of some genes involved in the pathways of lipid metabolism: oxidation, storage and secretion. The mRNA levels of the peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ), and of their target enzymes acyl-CoA oxidase and stearoyl-CoA desaturase were evaluated by real-time RT-PCR. Moreover, the expression of the adipose triglyceride lipase involved in lipid mobilisation, of the main PAT proteins acting in lipid droplet (LD) turnover, and of apoprotein B (apo B), the major protein component of very low-density lipoproteins (VLDLs) were analysed. Overall, our data demonstrated that T(2) administration to HFD rats counteracts most of the hepatic transcriptional changes that occurred in response to the excess exogenous fat. In particular, our results suggest that T(2) may prevent the pathways leading to lipid storage in LDs, promote the processes of lipid mobilisation from LDs and secretion as VLDL, in addition to the stimulation of pathways of lipid oxidation. In conclusion, our findings might give an insight into the mechanisms underlying the anti-steatotic ability of T(2) and help to define the potential therapeutic role of T(2) for preventing or treating liver steatosis

Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells

AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis. METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 mol/L) of silybin as phytosome complex with Vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays. RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-B). Incubation of steatotic cells with silybin 50 mol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-B activation

Clinical outcomes of ultrasound-assisted coagulation monitoring-adjusted catheter-directed thrombolysis for acute pulmonary embolism

BACKGROUND Ultrasound-assisted catheter-directed thrombolysis (USAT) may reverse right ventricular dysfunction due to acute pulmonary embolism (PE) with a favorable safety profile. METHODS We studied intermediate-high- and high-risk acute PE patients who underwent USAT at the University Hospital Zurich, 2018-2022. The USAT regimen included alteplase 10 mg per catheter over 15 h, therapeutic-dosed heparin, and dosage adaptations based on routinely monitored coagulation parameters, notably anti-factor Xa activity and fibrinogen. We focused on the mean pulmonary arterial pressure (mPAP) and the National Early Warning Score (NEWS) before and after USAT, and reported the incidence of hemodynamic decompensation, PE recurrence, major bleeding, and death over 30 days. RESULTS We included 161 patients: 96 (59.6 %) were men and the mean age was 67.8 (SD 14.6) years. Mean PAP decreased from a mean of 35.6 (SD 9.8) to 25.6 (SD 8.2) mmHg, whereas the NEWS decreased from a median of 5 (Q1-Q3 4-6) to 3 (Q1-Q3 2-4) points. No cases of hemodynamic decompensation occurred. One (0.6 %) patient had an episode of recurrent PE. Two (1.2 %) major bleeding events occurred, including one (0.6 %) intracranial, fatal hemorrhage in a patient with high-risk PE, severe heparin overdosing, and a recent head trauma (with negative CT scan of the brain performed at baseline). No other deaths occurred. CONCLUSIONS USAT resulted in a rapid improvement of hemodynamic parameters among patients with intermediate-high risk acute PE and selected ones with high-risk acute PE, without any recorded deaths related to PE itself. A strategy including USAT, therapeutic-dosed heparin, and routinely monitored coagulation parameters may partly explain the overall very low rate of major bleeding

Long term effectiveness on prescribing of two multifaceted educational interventions: Results of two large scale randomized cluster trials

Introduction: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Objectives: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. Methods: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach - TEA, with information materials on osteoporosis or prostatic hyperplasia - and a single drug oriented approach - SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. Results: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. Interpretation: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. Trial Registration: Controlled-Trials.com ISRCTN05866587

Recovery of distal coronary flow reserve in LAD and LCx after Y-Graft intervention assessed by transthoracic echocardiography

<p>Abstract</p> <p>Background</p> <p>Y- graft (Y-G) is a graft formed by the Left Internal Mammary Artery (LIMA) connected to the Left Anterior Descending Artery (LAD) and by a free Right Internal Mammary Artery (RIMA) connected to LIMA and to a Marginal artery of Left Circumflex Artery (LCx). Aim of the work was to study the flow of this graft during a six months follow-up to assess whether the graft was able to meet the request of all the left coronary circulation, and to assess whether it could be done by evaluation of coronary flow reserve (CFR).</p> <p>Methods</p> <p>In 13 consecutive patients submitted to Y-G (13 men), CFR was measured in distal LAD and in distal LCx from 1 week after , every two months, up to six months after operation (a total of 8 tests for each patient) by means of transthoracic echocardiography (TTE) and Adenosine infusion (140 mcg/kg/min for 3-6 min). A Sequoia 256, Acuson-Siemens, was used. Contrast was used when necessary (Levovist 300 mg/ml solution at a rate of 0,5-1 ml/min). Max coronary flow diastolic velocity post-/pre-test ≥2 was considered normal CFR.</p> <p>Results</p> <p>Coronary arteriography revealed patency of both branches of Y-G after six months. Accuracy of TTE was 100% for LAD and 85% for LCx. Feasibility was 100% for LAD and 85% for LCx. CFR improved from baseline in LAD (2.21 ± 0.5 to 2.6 ± 0.5, p = 0.03) and in LCx (1.7 ± 1 to 2.12 ± 1, p = 0.05). CFR was under normal at baseline in 30% of patients <it>vs </it>8% after six months in LAD (p = 0.027), and in 69% of patients <it>vs </it>30% after six months in LCx (p = 0.066).</p> <p>Conclusion</p> <p>CFR in Y-G is sometimes reduced in both left territories postoperatively but it improves at six months follow-up. A follow-up can be done non-invasively by TTE and CFR evaluation.</p

Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1G93A), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1G93A background (SOD1G93AGrm1crv4/+), by crossing the SOD1G93A mutant mouse with the Grm1crv4/+ mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1G93AGrm1crv4/+ mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1G93A mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1G93AGrm1crv4/+compared to SOD1G93A mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors

Common laboratory tests and their correlation with the clinical presentation and prognosis of lemierre syndrome

INTRODUCTION Lemierre syndrome is a thromboembolic complication following an acute bacterial infection of the head/neck area, often due to anaerobes. Data on the prognostic role of laboratory parameters is lacking. METHODS We analyzed individual-patient level data from a multinational cohort of patients with Lemierre-syndrome. Patients had an infection in the head/neck area, and contiguous vein thrombosis or septic embolism, irrespective of the causal pathogen. We studied the patterns of white blood cell count, platelet count, and C-reactive protein concentration investigating their association with baseline characteristics and in-hospital clinical outcomes (septic embolism, major bleeding, all-cause death). RESULTS A total of 447 (63%) patients had complete data for analysis. White blood cells were elevated across all subgroups (median 17 × 10$^{3}$/μL; Q1-Q3:12-21). Median platelet count was 61 × 10$^{3}$/μL (Q1-Q3:30-108) with decreasing levels with increasing age. Males, patients with renal failure or cardiopulmonary impairment, and those with typical Lemierre syndrome (tonsillitis, septic thromboembolism, positivity for Fusobacterium spp.) had the lowest platelet count. Median C-reactive protein was 122 (Q1-Q3:27-248) mg/L with higher values in patients who also had more severe thrombocytopenia. The overall risk of complications was similar across subgroups of patients stratified according to white blood cell and C-reactive protein levels. Patients in the lowest third of platelet count (<42 × 10$^{3}$/μL) had the highest rate of complications (26%), as opposed to those in the highest third (11%), notably septic embolic events. CONCLUSIONS Common laboratory tests correlate with the clinical presentation of Lemierre syndrome. However, extreme values did not appear to be prognostically relevant for in-hospital complications and potentially able to improve clinical management

Postępowanie w niewydolności serca u osób starszych

Wstęp: Celem pracy był przegląd aktualnie dost&#234;pnej wiedzy dotyczącej objawów oraz cech klinicznych i post&#234;powania w niewydolności serca (HF) u osób starszych. Metody: Autorzy dokładnie przeszukali kilka źródeł informacji opartych na dowodach naukowych, obejmujących Cochrane Database of Systemic Reviews, Clinical Evidence, wytyczne oparte na dowodach naukowych z National Guidelines Clearinghouse, zaś w bazie MEDLINE sprawdzili takie terminy, jak "niewydolność serca", "osoby starsze" oraz "postępowanie". Wyniki: Różne cechy związane z procesem starzenia mogą predysponowa&#230; osoby starsze do HF i upośledzać ich zdolność do reakcji na uszkodzenie. Inną cechą charakterystyczną u starszych pacjentów jest rosnąca częstość występowania wielu towarzyszących chorób przewlekłych i zespołów geriatrycznych, które mogą wikłać obraz kliniczny i rozwój HF. Kryteria diagnostyczne nie zmieniają się u osób starszych, mimo że rozpoznanie może stanowić wyzwanie z powodu często atypowych objawów i manifestacji klinicznej, a choroby towarzyszące mogą naśladować lub wikłać obraz kliniczny. Farmakoterapia nie różni się znacząco od tej zalecanej u młodszych pacjentów i w dużym stopniu pozostaje empiryczna, ponieważ zwykle wyklucza się osoby starsze oraz osoby z chorobami współistniejącymi z prób klinicznych. Programy postępowania mogą potencjalnie przyczynią się do zmniejszenia chorobowości i śmiertelności pacjentów z HF. Wnioski: Niewydolność serca jest najczęstszą przyczyną hospitalizacji i rehospitalizacji osób starszych. Wykazuje ona szczególne cechy u starszych pacjentów i jest zwykle powikłana chorobami towarzyszącymi, stanowiąc na całym świecie ogromne obciążenie finansowe. Pomimo to osoby starsze zwykle wykluczano z prób klinicznych i dlatego postępowanie w dużym stopniu pozostaje empiryczne i oparte na dowodach naukowych dotyczących osób z młodszych grup wiekowych