The importance of the 'uterine factor' in recurrent pregnancy loss: a retrospective cohort study on women screened through 3D transvaginal ultrasound.

STUDY QUESTION: What is the prevalence of congenital and acquired anomalies of the uterus in women with recurrent pregnancy loss (RPL) of unknown etiology examined using 3D transvaginal ultrasound (US)? SUMMARY ANSWER: Depending on the adopted diagnostic criteria, the prevalence of partial septate uterus varies between 7% and 14% and a T-shaped uterus is 3% or 4%, while adenomyosis is 23%, at least one of type 0, type 1 or type 2 myoma is 4%, and at least one endometrial polyp is 4%. WHAT IS KNOWN ALREADY: ESHRE and the Royal College of Obstetricians and Gynaecologists guidelines on RPL recommend the adoption of the 3D transvaginal US to evaluate the 'uterine factor'. Nevertheless, there are no published studies reporting the prevalence of both congenital and acquired uterine anomalies as assessed by 3D transvaginal US and diagnosed according to the criteria proposed by the most authoritative panels of experts in a cohort of women with RPL. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study including 442 women with at least two previous first-trimester spontaneous pregnancy losses (i.e. non-viable intrauterine pregnancies), who referred to the obstetrics and gynecology unit of two university hospitals between July 2020 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Records of eligible women were reviewed. Women could be included in the study if: they were between 25 and 42 years old; they had no relevant comorbidities; they were not affected by infertility, and they had never undergone ART; they and their partner tested negative to a comprehensive RPL diagnostic work-up; and they had never undergone metroplasty, myomectomy, minimally invasive treatments for uterine fibroids or adenomyomectomy. Expert sonographers independently re-analyzed the stored 2- and 3D transvaginal US images of all included patients. Congenital uterine anomalies (CUAs) were reported according to the American Society for Reproductive Medicine (ASRM) 2021, the ESHRE/European Society for Gynaecological Endoscopy (ESGE) and the Congenital Uterine Malformation by Experts (CUME) criteria. Acquired uterine anomalies were reported according to the International Federation of Gynecology and Obstetrics (FIGO) and the Morphological Uterus Sonographic Assessment (MUSA) criteria. MAIN RESULTS AND THE ROLE OF CHANCE: The partial septate uterus was diagnosed in 60 (14%; 95% CI: 11-17%), 29 (7%; 95% CI: 5-9%), and 47 (11%; 95% CI: 8-14%) subjects, according to the ESHRE/ESGE, the ASRM 2021, and the CUME criteria, respectively. The T-shaped uterus was diagnosed in 19 women (4%; 95% CI: 3-7%) according to the ESHRE/ESGE criteria and in 13 women (3%; 95% CI: 2-5%) according to the CUME criteria. The borderline T-shaped uterus (diagnosed when two out of three CUME criteria for T-shaped uterus were met) was observed in 16 women (4%; 95% CI: 2-6%). At least one of FIGO type 0, type 1, or type 2 myoma was detected in 4% of included subjects (95% CI: 3-6%). Adenomyosis was detected in 100 women (23%; 95% CI: 19-27%) and was significantly more prevalent in women with primary RPL and in those with three or more pregnancy losses. At least one endometrial polyp was detected in 4% of enrolled women (95% CI: 3-7%). LIMITATIONS, REASONS FOR CAUTION: The absence of a control group prevented us from investigating the presence of an association between both congenital and acquired uterine anomalies and RPL. Second, the presence as well as the absence of both congenital and acquired uterine anomalies detected by 3D US was not confirmed by hysteroscopy. Finally, the results of the present study inevitably suffer from the intrinsic limitations of the adopted classification systems. WIDER IMPLICATIONS OF THE FINDINGS: The prevalence of CUAs in women with RPL varies depending on the classification system used. For reasons of clarity, the US reports should always state the name of the uterine anomaly as well as the adopted classification and diagnostic criteria. Adenomyosis seems to be associated with more severe forms of RPL. The prevalence rates estimated by our study as well as the replicability of the adopted diagnostic criteria provide a basis for the design and sample size calculation of prospective studies. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Murine left atrium and left atrial appendage structure and function: echocardiographic and morphologic evaluation.

Aim of this study was to provide an echocardiographic protocol for the description of the normal murine venous reservoir (atrium, appendage and pulmonary veins) and to investigate the possibility to use this approach to discriminate changes on left atrium (LA) and left atrial appendage (LAA) in a stress-induced model such us myocardial infarction. Global left ventricular function and the venous reservoir were assessed by a Vevo2100 in 20 female C57BL/6N. LA and LAA were also studied in 10 CD-1 and 10 FVB mice, whereas modifications investigated in 15 C57BL/6N subjected to coronary artery ligation. Left ventricle function was evaluated as well as pulsed Doppler mitral valve, pulmonary vein, and LAA velocities. From 2D view monoplane LA volumes were obtained and LAA long axis measured. Macroscopic inspection with casts and immunohistochemistry were performed. Results show that compared to humans, in C57BL/6N mice left atrium was disproportionately smaller (5.2±1.4 µL) than the left ventricle (53±8 µL) and connected through a duct by a large LAA and posteriorly to three pulmonary veins. The LA volume increased 2-fold during reservoir with two distinct phases, early and late divided by a short pause. LAA long axis (4.1±0.5 mm) was almost 2 times longer than the LA. LAA flow volume together with LA volume reservoir account for about 36% of stroke volume and the rest was provided by conduit flow. Linear regressions showed that stroke volume was strongly influenced by LAA flow, LA early filling volume and left ventricle base descent. Moreover, we also report the ability to assess LA and LAA in other mice strains and discriminate size increase following myocardial infarction. In conclusion, we performed a complete characterization of murine left venous reservoir establishing an optimized protocol that can be used in both investigative and pharmacological studies requiring rapid and serial determination of cardiac structure and function.

Expression of dual nucleotides/cysteinyl-leukotrienes receptor GPR17 in early trafficking of cardiac stromal cells after myocardial infarction.

GPR17 is a G(i) -coupled dual receptor activated by uracil-nucleotides and cysteinyl-leukotrienes. These mediators are massively released into hypoxic tissues. In the normal heart, GPR17 expression has been reported. By contrast, its role in myocardial ischaemia has not yet been assessed. In the present report, the expression of GPR17 was investigated in mice before and at early stages after myocardial infarction by using immunofluorescence, flow cytometry and RT-PCR. Before induction of ischaemia, results indicated the presence of the receptor in a population of stromal cells expressing the stem-cell antigen-1 (Sca-1). At early stages after ligation of the coronary artery, the receptor was expressed in Sca-1(+) cells, and cells stained with Isolectin-B4 and anti-CD45 antibody. GPR17(+) cells also expressed mesenchymal marker CD44. GPR17 function was investigated in vitro in a Sca-1(+)/CD31(-) cell line derived from normal hearts. These experiments showed a migratory function of the receptor by treatment with UDP-glucose and leukotriene LTD4, two GPR17 pharmacological agonists. The GPR17 function was finally assessed in vivo by treating infarcted mice with Cangrelor, a pharmacological receptor antagonist, which, at least in part, inhibited early recruitment of GPR17(+) and CD45(+) cells. These findings suggest a regulation of heart-resident mesenchymal cells and blood-borne cellular species recruitment following myocardial infarction, orchestrated by GPR17.

Outcome following selective fetal reduction in monochorionic and dichorionic twin pregnancies discordant for structural, chromosomal and genetic disorders.

BACKGROUND: To investigate the indications for offering selective fetal reduction in monochorionic (MC) and dichorionic (DC) twins and to correlate obstetric outcome with the antenatal procedure. METHODS: All cases of MC and DC twins discordant for structural anomalies and for chromosomal/genetic abnormalities were included. Selective reductions performed for twin-to-twin transfusion syndrome or growth restriction were excluded. For DC twins, feticide was achieved using intracardiac injection of potassium chloride (KCl). For MC twins, bipolar cord occlusion (BCO), interstitial laser or radiofrequency ablation (RFA) was used. RESULTS: There were 121 twin pregnancies discordant for structural and chromosomal abnormalities. Only 88 (56 were MC twins and 32 were DC twins) had selective reduction. For both MC and DC twins, the leading indication for selective reduction was structural anomalies with CNS malformations the most common. For all MC fetal reduction techniques, the overall pregnancy loss rate (<24 weeks) was 8.9% with RFA having the lowest procedure loss rate (7.7%). The preterm delivery rate was lowest with reduction in DC pregnancies. The live birth rates for MC twins were >87% and 100% for DC twins. CONCLUSIONS: Selective reduction in MC pregnancies carries an increased procedure-related and preterm delivery rate compared with DC pregnancies. The main indication for selective reduction was structural malformations, with a predominance of CNS anomalies.

Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease.

BACKGROUND: Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe(-/-) mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia. METHODS AND PRINCIPAL FINDINGS: Myocardial biopsies from Apoe(-/-) mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C(4) synthase (LTC(4)S) and CysLT1 expression in the myocardium of Apoe(-/-) mice. Acute bouts of hypoxia further induced LTC(4)S expression, increased LTC(4)S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe(-/-) mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC(4)S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling. CONCLUSION: Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.

Feasibility of quantitative analysis of regional left ventricular function in the post-infarct mouse by magnetic resonance imaging with retrospective gating.

We aimed testing feasibility of identification of regional left ventricular (LV) endocardial motion abnormalities in mice undergoing coronary ligation (MI), using cine magnetic resonance with retrospective gating and computation of regional fractional area change (RFAC), by comparison with histological "gold standard" evaluation. ROC analysis determined the optimal RFAC cut-off values for detecting regional ischemic injury. This approach was tested on 18 MI and 10 sham mice. Automated regional LV motion interpretation and bull's eye display allowed non-invasive localization of the induced infarction. Possible applications to future studies assessing the effectiveness of pharmacological treatments or regenerative medicine are expected.

12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms.

Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15-lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovascular symptoms and risk factors. The Biobank of Karolinska Endarterectomies (BiKE) collection of human carotid plaque tissue and associated clinical data was utilized (n=132). Lesion mRNA levels were analyzed by TaqMan qPCR (n=132) and microarray hybridization (n=77). Of the investigated mRNAs, only ALOX15B (15-LOX-2; epidermis-type 15-LOX) was readily detected in all plaque samples by qPCR, and thus suitable for quantitative statistical evaluation. ALOX12, ALOX12B, ALOX15 and ALOXE3 were detected with lower frequency and at lower levels, or virtually undetected. Microarray analysis confirmed ALOX15B as the most abundant 12- or 15-lipoxygenase mRNA in carotid lesions. Comparing plaques with or without attributable cerebrovascular symptoms (amaurosis fugax, transient ischemic attack, or stroke), ALOX15B mRNA levels were higher in symptomatic than asymptomatic plaques (1.31 [1.11-1.56], n=102; and 0.79 [0.55-1.15], n=30, respectively; p=0.008; mean [95% CI], arbitrary units). Multiple regression analysis confirmed symptomatic/asymptomatic status as a significant determinant of ALOX15B mRNA levels, independently of potentially confounding factors. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue. In summary, we observed associations between high ALOX15B expression in carotid lesions and a history of cerebrovascular symptoms. These findings suggest a link between ALOX15B and atherothrombotic events that merits further investigation.

Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats.

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1ß, transforming growth factor ß, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

Use of the Internet by women seeking information about potentially teratogenic agents.

OBJECTIVE: The aim of this study was to evaluate if the Internet provides evidence-based information to women seeking information about teratogenic risk factors and women's risk perception. Furthermore, we evaluated the possible risk related to teratogen exposure in the study sample and analysed age, gravidity, educational level, geographic location, marital status and type of exposure compared to a control group made up of women who did not use the Internet to search for teratogen-related information. STUDY DESIGN: Between October 2008 and June 2009, a questionnaire was administered to pregnant women calling our Teratology Information Service concerning a suspected teratogenic exposure. RESULTS: Fifty-seven percent (n=116) of callers had used the Internet to find medical information about their exposure, while 43% (n=87) had not. Internet users had a medium-high level of education and consulted the Internet because of its convenience, usually early in their pregnancy. We verified the accuracy of the information the women obtained from the Internet and found that 59.5% (n=69) of women received evidence-based answers; 18.1% (n=21) were informed that their exposure was dangerous when it was not; 4.3% (n=5) were wrongly reassured; and the rest (n=18) were not able to interpret the data they found or found no relevant information. CONCLUSIONS: Internet use during pregnancy is a widespread phenomenon as the Internet offers the opportunity to share apprehensions and doubts with other women, but it can often lead to increased and unjustified anxiety. Medical information published on websites cannot be considered a substitute for informed medical advice, and patients should not take any action before consulting with a health care professional.

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, increases survival in stroke-prone rats by preventing systemic inflammation and endothelial dysfunction: comparison with aspirin and rosuvastatin.

This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Salt-loaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B(2) levels, terutroban significantly increased survival (p < 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p < 0.001), and a delayed increase of proteinuria (p < 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1beta, transforming growth factor-beta, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.

Magnetic resonance imaging of human endothelial progenitors reveals opposite effects on vascular and muscle regeneration into ischaemic tissues.

AIMS: The assessment of progenitor cell survival and efficacy after transplantation is one of the major challenges in cardiovascular cell therapy. Translation of currently used imaging techniques to patients is not immediate. Possible options include iron oxide particle loading into cells to be tracked using magnetic resonance (MR) and by MR-based water diffusion anisotropy analysis. The aim of the present study was to assess, using these techniques, the localization and survival of human 'early' endothelial progenitor cells (EPCs) and their effects on vascular and skeletal muscle regeneration in a mouse model of hind limb ischaemia. METHODS AND RESULTS: A paramagnetic iron oxide particle loading protocol of human peripheral blood-derived early EPCs was devised. The iron+ EPCs maintained their phenotype and in vitro functional activity. In addition, the presence of iron+ cells was observed by MR until 7 days after injection into a pharmacologically immunosuppressed mouse model of hind limb ischaemia. Immunohistochemistry with human major histocompatibility complex antibodies revealed the absence of human cells at 7 days post-ischaemia. EPC death was confirmed by staining of iron+ cells with an anti-mouse CD68 antibody and by qPCR performed on DNA extracted from injected ischaemic limbs, at different times following injection. Surprisingly, early EPC injection enhanced arteriogenesis but caused a significant increase in ischaemic tissue inflammation and a retarded muscle regeneration, as evidenced by water diffusion anisotropy analysis and histology. CONCLUSION: In line with recent reports, our results show that the use of iron-based contrast agents does not allow detection of long-term EPC engraftment into ischaemic tissues. They further show that early EPCs exert a potent arteriogenic effect on ischaemic tissues that is not dependent on their prolonged survival. Unexpectedly, injection of these cells elicited a long-term inflammatory response that reflected a delayed muscle healing process.

S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function.

S 35171 is one of a family of compounds that have been designed to protect mitochondrial function. We tested the hypothesis that S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats (SHRSPs), an animal model developing spontaneous brain damage preceded by proteinuria and systemic inflammation revealed by the urinary accumulation of acute-phase proteins (APPs) originating in the liver. Male SHRSPs fed a permissive diet received vehicle or S 35171 (10 mg/kg/day) started simultaneously with a high-sodium diet (group A) or after the establishment of proteinuria (group B). The drug delayed urinary APPs accumulation and the appearance of magnetic resonance imaging (MRI)-monitored brain lesions (after 62+/-3 days in group A, and 51+/-2 days in controls, P<0.01). The delay was more pronounced in group B as 30% of the animals survived the entire 90-day experimental period without brain abnormality. Proteomic analysis showed no significant alteration in the expression pattern of brain mitochondrial proteins, but the liver mitochondrial levels of carbamoylphosphate synthase I (CPS-I), an enzyme involved in urea metabolism) and the antioxidant peroxiredoxin-3 spot were affected by hypertension and S 35171. Stress reduces CPS-I and induces the peroxiredoxin-3 spot, whereas S 35171 brought about normal CPS-I expression and a 12-fold higher level of the peroxiredoxin-3 spot. As both enzymes are involved in maintaining mitochondrial functions, their increased expression after S 35171 treatment may be responsible for delaying the pathological condition that leads to the development of brain damage in SHRSPs.

Paternal exposure and counselling: experience of a Teratology Information Service.

We describe paternal exposure and counselling in a selected population calling to an Italian Teratology Information Service (TIS). The majority of callers asked for paternal drug exposure (76%, drugs except chemotherapy) and treatment for cancer (17%, chemotherapy and/or radiotherapy). Others asked for exposure to diagnostic radiations (4%), recreational drugs (2%) and occupational chemicals (1%). Among paternal drugs neurological compounds, immunosuppressive drugs and antiviral agents were the main reasons for calling. In humans, there are no evidences of birth defects after paternal exposures, but to minimize any possible risk, counselling in men exposed to radio and chemotherapy should recommend delaying conception for at least 3 months after the end of the therapy. Male patients treated with drugs, whose teratogenic potential has been well assessed or suspected for maternal exposure, should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy.

Prenatal drug exposure and teratological risk: one-year experience of an Italian Teratology Information Service.

BACKGROUND: Concern about exposure to drugs, radiation, or infection during pregnancy occur often because pregnancy is not always planned. A teratology information service offers rapid scientific counseling to all those worried about prenatal exposure. The aim of this study is to present data on the most common pharmaceutical products responsible for teratogenic risk in the one-year experience of a teratology information service in Italy. MATERIAL/METHODS: The survey was conducted among 8664 callers who contacted our Teratology Information Service in Rome between January and December 2006. Data on maternal age, gravidity, parity, maternal health status, and details of exposure (dose and timing) were collected and stored in a specific data base. Scientific counseling on prenatal exposure was given to the caller by a specialized service operator, specifying the type of risk and suggesting appropriate tests for prenatal diagnosis. RESULTS: Most of the people called regarding drug exposure; increased risk was present in only 5% of the pregnant women calling during pregnancy. Selective serotonin reuptake inhibitors (SSRIs) are the first category that are actually considered of increased risk to the fetus. The second category is represented by antiepileptic drugs. CONCLUSIONS: This experience confirms previous data that there is a high teratological risk perception among both women and physicians. The drugs estimated to present increased risk are medications used for chronic neurological diseases, mainly mood disorders and epilepsy. Preconceptional counseling for these women could be an effective strategy to prevent such exposure and to improve maternal and fetal outcome.

Statins: multiple mechanisms of action in the ischemic brain.

Although substantial epidemiological studies have failed to find a correlation between cholesterol levels and stroke, clinical trials have shown that HMG-CoA reductase inhibitors (or statins, the most potent hypocholesterolemic drugs available) greatly reduce the incidence of stroke. These clinical observations have opened the way to a number of studies of the non-cholesterol-dependent (or pleiotropic) effects in animal models of stroke, indicating that the neuroprotection is attributable to multiple activities. One of the main protective mechanisms elicited by statin administration is the increase in nitric oxide bioavailability that regulates cerebral perfusion and improves endothelial function, but others include antioxidant properties, the inhibition of inflammatory responses, immunomodulatory actions, the regulation of progenitor cells, and the stabilization of atherosclerotic plaques. Many of these effects are due to the inhibited synthesis of isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. This article describes the mechanisms involved in the neuroprotective effects of statins.

Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats.

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.

Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment.

We investigated the effects of simvastatin treatment on the expression of IL-1beta and MCP-1, the activity of NF-kB, and the signaling pathways related to NF-kB activation in a rat model of permanent middle cerebral artery occlusion (pMCAO). IL-1beta and MCP-1 expression, determined using RT-PCR, was enhanced by pMCAO; this effect was inhibited by the administration of simvastatin before ischemia. Pre-treatment with simvastatin abolished the ischemia-induced activation of NF-kB observed in vehicle-treated animals. The evaluation of signal transduction pathways, including extracellular signal-regulated kinase (ERK1/2), SAPK/JNK 46/54 and p38, indicated that only ERK1/2 phosphorylation was enhanced by ischemia, and this activation was prevented by simvastatin. ERK1/2-inhibitor, U0126, reduced brain ischemia but not cytokine induction. These results provide evidence that the HMG-CoA reductase inhibitor induces its effect in the protection of ischemic brain damage with a more complex mechanism which also involve anti-inflammatory properties rather than simple inhibition of ERK1/2 signaling pathway.

Anti-inflammatory properties of drugs acting on the renin-angiotensin system.

It is now well established that the activation of the renin-angiotensin system (RAS) is involved in the onset and progression of cardiovascular and renal diseases, and that its main effector, angiotensin II (Ang II) has major pro-inflammatory activity that induces the expression of cytokines, chemokines, adhesion molecules, growth factors and reactive oxygen species. By means of these actions, Ang II induces vascular inflammation, endothelial dysfunction and fibrosis, and participates in destabilizing atherosclerotic plaque and establishing chronic kidney diseases. Blocking the RAS by inhibiting Ang II generation or blocking angiotensin receptors reduces the morbidity and mortality associated with cardiovascular and renal disease beyond the levels due to the lowering of blood pressure, and these benefits are at least partially due to the reduction/prevention of both local and systemic inflammatory processes. The aim of this review is to describe the role of the RAS (and particularly Ang II) in initiating and maintaining these processes, and to summarize experimental and clinical evidence supporting the role of drugs acting on the RAS in preventing or modulating inflammation.

Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects.

OBJECTIVE: Brain abnormalities, preceded by a systemic inflammation, develop in spontaneously hypertensive stroke-prone rats (SHRSP). In this model, we investigated whether the hydrophilic statin, rosuvastatin, influences the development of inflammation associated with brain abnormalities. Because differences in hydrophilicity/hydrophobicity contribute to the differences in statin pharmacology, we also evaluated the effects of simvastatin, a lipophilic molecule METHODS AND RESULTS: SHRSP, fed a high-salt diet, were treated long-term with vehicle or rosuvastatin (1 and 10 mg/kg per day). Brain abnormalities developed after 40+/-5 days and after 60+/-5 days of salt loading, in vehicle-treated and in rosuvastatin-treated (1 mg/kg per day) SHRSP, respectively. After 100 days of treatment, no damage was detectable in 30% of the rats treated with the highest dose of the drug. In comparison with vehicle-treated SHRSP, rosuvastatin treatment attenuated the transcription of monocyte chemoattractant protein-1, transforming growth factor-beta1, IL-1beta, and tumor necrosis factor-alpha in the kidney, and of P-selectin in brain vessels and increased the transcription of endothelial nitric oxide synthase mRNA in the aorta. Urinary excretion of acute-phase proteins increased with time in vehicle-treated animals but remained negligible in drug-treated animals. These effects are independent of changes in physiological parameters. Treatment of SHRSP with simvastatin (2 to 20 mg/kg per day) did not exert any protective effect. CONCLUSIONS: Rosuvastatin attenuates inflammatory processes associated with cerebrovascular disease.