Clinical and ultrasound characteristics of deep endometriosis affecting sacral plexus.

OBJECTIVE: To describe the sonomorphological changes and appearance of deep endometriosis (DE) affecting the nervous tissue of the sacral plexus (SP). METHODS: This was a retrospective study of symptomatic patients who underwent radical resection of histologically confirmed DE affecting the SP and who had undergone preoperative transvaginal sonography (TVS) between 2019 and 2023. Lesions were described based on the terms and definitions of the International Deep Endometriosis Analysis (IDEA), International Ovarian Tumor Analysis (IOTA) and Morphological Uterus Sonographic Assessment (MUSA) groups. A diagnosis of DE affecting the SP on TVS was made when the sonographic criteria of DE were visualized in conjunction with fibers of the SP and the presence of related symptoms corresponding to sacral radiculopathy. Clinical symptoms, ultrasound features and histological confirmation were analyzed for each patient included. RESULTS: Twenty-seven patients with DE infiltrating the SP were identified in two contributing tertiary referral centers. Median age was 37 (range, 29-45) years and all patients were symptomatic and presented one or more of the following neurological symptoms: dysesthesia in the ipsilateral lower extremity (n = 17); paresthesia in the ipsilateral lower extremity (n = 10); chronic pelvic pain radiating in the ipsilateral lower extremity (n = 9); chronic pain radiating in the pudendal region (n = 8); and motor weakness in the ipsilateral lower extremities (n = 3). All DE lesions affecting the SP were purely solid tumors in the posterior parametrium in direct contact with, or infiltrating, the S1, S2, S3 and/or S4 roots of the SP. The median of the largest diameter recorded for each of the DE nodules was 35 (range, 18-50) mm. Echogenicity was non-uniform in 23 (85%) of the DE nodules, with all but one of these nodules containing hyperechogenic areas. The shape of the lesions was irregular in 24 (89%) cases. Only one lesion exhibited a lobulated form, with all other irregular lesions showing a spiculated appearance. An acoustic shadow was produced in 20 (74%) of the nodules, all of which were internal. On color or power Doppler examination, 21 (78%) of the nodules showed no signal (color score of 1). The remaining six (22%) lesions showed a minimal color content (color score of 2). According to pattern recognition, most DE nodules were purely solid, non-uniform, hypoechogenic nodules containing hyperechogenic areas, with internal shadows and irregular spiculated contours, and were poorly vascularized on color/power Doppler examination. CONCLUSION: The ultrasound finding of a parametrial, unilateral, solid, non-uniform, hypoechogenic nodule with hyperechogenic areas and possible internal shadowing, as well as irregular spiculated contours, demonstrating poor vascularization on Doppler examination in proximity to or involving the structures of the SP, indicates DE affecting the SP. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Visualization of sacral nerve roots and sacral plexus on gynecological transvaginal ultrasound: feasibility study.

OBJECTIVE: To investigate the feasibility of identifying and measuring the normal sacral plexus (SP) on gynecological transvaginal ultrasound (TVS) examination. METHODS: This was a prospective observational study conducted at a single tertiary gynecological referral center, including consecutive women undergoing TVS for various indications between November 2021 and January 2022. A standardized assessment of the pelvic organs was performed and the presence of any congenital or acquired uterine pathology or ovarian abnormality was recorded. Visualization of the right and left SP was attempted in all cases. The success rate and the time needed to identify the SP were recorded and measurements of the SP were made. RESULTS: A total of 326 patients were included in the study. In all women, the SP was identified successfully on at least one side. SP were visualized bilaterally in 317 (97.2% (95% CI, 94.4-98.5%)) women. Only the right SP was seen in 3/326 (0.9% (95% CI, 0.2-2.7%)) and only the left in 6/326 (1.8% (95% CI, 0.6-4.0%)) (P = 0.5048). There was no significant difference in the median time required to visualize the right vs left SP (9.0 (interquartile range (IQR), 8.0-10.0) s  vs 9.0 (IQR, 8.0-10.0) s; P = 0.0770). The median transverse diameter of the right SP was 15.0 (IQR, 14.2-15.6) mm and that of the left SP was 14.9 (IQR, 14.4-15.6) mm. CONCLUSIONS: We describe a novel method which allows for the consistent and rapid identification of the SP on TVS. Integrating assessment of the SP into routine pelvic TVS may be helpful particularly for women suffering from deep endometriosis. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Imaging in gynecological disease (26): clinical and ultrasound characteristics of benign retroperitoneal pelvic peripheral-nerve-sheath tumors.

OBJECTIVE: To describe the clinical and sonographic characteristics of benign, retroperitoneal, pelvic peripheral-nerve-sheath tumors (PNSTs). METHODS: This was a retrospective study of patients with a benign, retroperitoneal, pelvic PNST who had undergone preoperative ultrasound examination at a single gynecologic oncology center between 1 January 2018 and 31 August 2022. All ultrasound images, videoclips and final histological specimens of benign PNSTs were reviewed side-by-side in order to: describe the ultrasound appearance of the tumors, using the terminology of the International Ovarian Tumor Analysis (IOTA), Morphological Uterus Sonographic Assessment (MUSA) and Vulvar International Tumor Analysis (VITA) groups, following a predefined ultrasound assessment form; describe their origin in relation to nerves and pelvic anatomy; and assess the association between their ultrasound features and histotopography. A review of the literature reporting benign, retroperitoneal, pelvic PNSTs with preoperative ultrasound examination was performed. RESULTS: Five women (mean age, 53 years) with a benign, retroperitoneal, pelvic PNST were identified, four with a schwannoma and one with a neurofibroma, of which all were sporadic and solitary. All patients had good-quality ultrasound images and videoclips and final biopsy of surgically excised tumors, except one patient managed conservatively who had only a core needle biopsy. In all cases, the findings were incidental. The five PNSTs ranged in maximum diameter from 31 to 50 mm. All five PNSTs were solid, moderately vascular tumors, with non-uniform echogenicity, well-circumscribed by hyperechogenic epineurium and with no acoustic shadowing. Most of the masses were round (n = 4 (80%)), and contained small, irregular, anechoic, cystic areas (n = 3 (60%)) and hyperechogenic foci (n = 5 (100%)). In the woman with a schwannoma in whom surgery was not performed, follow-up over a 3-year period showed minimal growth (1.5 mm/year) of the mass. We also summarize the findings of 47 cases of benign retroperitoneal schwannoma and neurofibroma identified in a literature search. CONCLUSIONS: On ultrasound examination, no imaging characteristics differentiate reliably between benign schwannomas and neurofibromas. Moreover, benign PNSTs show some similar features to malignant retroperitoneal tumors. They are solid lesions with intralesional blood vessels and show degenerative changes such as cystic areas and hyperechogenic foci. Therefore, ultrasound-guided biopsy may play a pivotal role in their diagnosis. If confirmed to be benign PNSTs, these tumors can be managed conservatively, with ultrasound surveillance. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Addendum to the consensus opinion from the International Deep Endometriosis Analysis (IDEA) group: sonographic evaluation of the parametrium.

Preoperative sonographic staging in patients with suspected parametrial endometriosis is essential to plan the surgical intervention and to anticipate the need for a multidisciplinary approach, and hence optimize surgical outcome. The results of a recent metanalysis suggest that defining more accurately the ultrasonographic criteria of parametrial involvement in endometriosis is needed. The aim of this addendum to the IDEA-consensus is to highlight the sonographic characteristics of the parametrium and identify ultrasound techniques to diagnose deep endometriosis in this area. This article is protected by copyright. All rights reserved.

Surface nanostructures on Nb-doped SrTiO3irradiated with swift heavy ions at grazing incidence.

A single crystal of SrTiO3doped with 0.5 wt% niobium (Nb-STO) was irradiated with 200 MeV Au32+ions at grazing incidence to characterize the irradiation-induced hillock chains. Exactly the same hillock chains are observed by using atomic force microscopy (AFM) and scanning electron microscopy (SEM) to study the relation between irradiation-induced change of surface topography and corresponding material property changes. As expected, multiple hillocks as high as 5-6 nm are imaged by AFM observation in tapping mode. It is also found that the regions in between the adjacent hillocks are not depressed, and in many cases they are slightly elevated. Line-like contrasts along the ion paths are found in both AFM phase images and SEM images, indicating the formation of continuous ion tracks in addition to multiple hillocks. Validity of preexisting models for explaining the hillock chain formation is discussed based on the present results. In order to obtain new insights related to the ion track formation, cross-sectional transmission electron microscopy (TEM) observation was performed. The ion tracks in the near-surface region are found to be relatively large, whereas buried ion tracks in the deeper region are relatively small. The results suggest that recrystallization plays an important role in the formation of small ion tracks in the deep region, whereas formation of large ion tracks in the near-surface region is likely due to the absence of recrystallization. TEM images also show shape deformation of ion tracks in the near-surface region, suggesting that material transport towards the surface is the reason for the absence of recrystallization.

Accuracy of sonography for non-invasive detection of ovarian and deep endometriosis using #Enzian classification: prospective multicenter diagnostic accuracy study.

OBJECTIVE: To compare the preoperative detection of endometriosis using transvaginal sonography (TVS) supplemented by transabdominal sonography (TAS) with surgical assessment of disease, using the #Enzian classification for endometriosis. METHODS: This was a prospective multicenter diagnostic accuracy study of women undergoing TVS/TAS and radical surgery for deep endometriosis (DE) at different tertiary referral centers. The localization and grade of severity of the endometriotic lesions and adhesions were described according to the criteria of the #Enzian classification, both at preoperative ultrasound examination and during surgery. According to the #Enzian classification, the small pelvis is divided into three compartments for DE: A (rectovaginal septum and vagina); B (uterosacral and cardinal ligaments, parametrium and pelvic sidewalls); and C (rectum). In addition, further locations (F) are classified as adenomyosis (FA), urinary bladder involvement (FB) and ureteric involvement with signs of obstruction (FU). Other intestinal locations (FI) and other extragenital locations (FO) are also included. Ovarian endometriosis and adhesions at the level of the tubo-ovarian unit are listed as O and T, respectively. The #Enzian grade of severity (Grade 1-3) was determined for #Enzian compartments O, T, A, B and C based on the size of the lesion or the severity of the adhesions. Concordance between preoperative assessment using TVS/TAS and evaluation at surgery was assessed. The sensitivity, specificity, positive and negative predictive values and accuracy of TVS/TAS in the detection of endometriotic lesions/adhesions in the different #Enzian compartments were calculated. RESULTS: In total, 745 women were included in the analysis. Preoperative TVS/TAS and surgical findings showed a concordance rate ranging between 86% and 99% for the presence or absence of endometriotic lesions/adhesions, depending on the evaluated #Enzian compartment. The concordance rate between TVS and surgery ranged between 71% and 92% for different severity grades, in #Enzian compartments O, T, A, B and C. Determining the presence or absence of adhesions at the level of the tubo-ovarian unit and classifying them accurately as Grade 1, 2 or 3 on TVS was more difficult than determining the presence and severity of endometriotic lesions in #Enzian compartments O, A, B and C. The sensitivity of TVS/TAS for the detection of endometriotic lesions ranged from 50% (#Enzian compartment FI) to 95% (#Enzian compartment A), specificity from 86% (#Enzian compartment Tleft ) to 99% (#Enzian compartment FI) and 100% (#Enzian compartments FB, FU and FO), positive predictive value from 90% (#Enzian compartment Tright ) to 100% (#Enzian compartment FO), negative predictive value from 74% (#Enzian compartment Bleft ) to 99% (#Enzian compartments FB and FU) and accuracy from 88% (#Enzian compartment Bright ) to 99% (#Enzian compartment FB). CONCLUSIONS: The localization and severity of endometriotic lesions/adhesions, as described and classified according to the #Enzian classification, can be diagnosed accurately and non-invasively using TVS/TAS. The #Enzian classification provides a uniform classification system for describing endometriotic lesions, which can be used both at TVS/TAS and during surgical evaluation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Improving biogas production performance of dairy activated sludge via ultrasound disruption prior to microwave disintegration.

In this study, ultrasound disruption was employed to enhance the efficiency of microwave disintegration of dairy sludge. Results revealed that ultrasound specific energy input of 1,500 kJ/kg TS was found to be optimum with limited cell lysis at the end of the disruption phase. Biodegradability study suggested an enhancement in suspended solids reduction (16%) and biogas production (180 mL/gVS) in floc disrupted (deflocculated) samples when compared to sole microwave pretreatment (8.3% and 140 mL/gVS, respectively). Energy assessment to attain the 15% optimum solubilization revealed a positive net production of 26 kWh per kg sludge in deflocculated samples compared to 18 kWh in flocculated (sole microwave) samples. Thus, ultrasound disruption prior to microwave disintegration of dairy sludge was considered to be a feasible pretreatment technique.

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat.

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.

Origin and compensation of imaging artefacts in localization-based super-resolution microscopy.

Interpretation of high resolution images provided by localization-based microscopy techniques is a challenge due to imaging artefacts that can be categorized by their origin. They can be introduced by the optical system, by the studied sample or by the applied algorithms. Some artefacts can be eliminated via precise calibration procedures, others can be reduced only below a certain value. Images studied both theoretically and experimentally are qualified either by pattern specific metrics or by a more general metric based on fluorescence correlation spectroscopy.

Patterns of impaired oral health-related quality of life dimensions.

How dental patients are affected by oral conditions can be described with the concept of oral health-related quality of life (OHRQoL). This concept intends to make the patient experience measurable. OHRQoL is multidimensional, and Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact were suggested as its four dimensions and consequently four scores are needed for comprehensive OHRQoL assessment. When only the presence of dimensional impact is measured, a pattern of affected OHRQoL dimensions would describe in a simple way how oral conditions influence the individual. By determining which patterns of impact on OHRQoL dimensions exist in prosthodontic patients and general population subjects, we aimed to identify in which combinations oral conditions' functional, painful, aesthetical and psychosocial impact occurs. Data came from the Dimensions of OHRQoL Project with Oral Health Impact Profile (OHIP)-49 data from 6349 general population subjects and 2999 prosthodontic patients in the Learning Sample (N = 5173) and the Validation Sample (N = 5022). We hypothesised that all 16 patterns of OHRQoL dimensions should occur in these individuals who suffered mainly from tooth loss, its causes and consequences. A dimension was considered impaired when at least one item in the dimension was affected frequently. The 16 possible patterns of impaired OHRQoL dimensions were found in patients and general population subjects in both Learning and Validation Samples. In a four-dimensional OHRQoL model consisting Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact, oral conditions' impact can occur in any combination of the OHRQoL dimensions.

Alcoholic hepatitis and HCV interactions in the modulation of liver disease.

Most HCV-infected patients regularly consume alcohol. Alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection together are the most common causes of liver disease worldwide. Although both factors independently cause liver disease, they synergistically promote rapid liver disease progression with devastating outcomes for patients. This review focuses on the prevalence, clinical characteristics and molecular pathophysiologic mechanisms of HCV infection associated with alcohol abuse. Recent findings have centred on the synergistic effect of alcohol and HCV on viral replication, hepatocyte apoptosis, oxidative stress, alcohol-induced 'leaky gut', miR-122 and immune dysregulation. Clinical and basic research findings presented here summarize key scientific findings with the aim of highlighting potential areas for new therapies and identifying ways of optimizing current treatments for alcoholics with HCV infection.

Characterization of degenerative human facet joints and facet joint capsular tissues.

OBJECTIVE: Lumbar facet joint degeneration (FJD) may be an important cause of low back pain (LBP) and sciatica. The goal of this study was to characterize cellular alterations of inflammatory factor expression and neovascularization in human degenerative facet joint capsular (FJC) tissue. These alterations in FJC tissues in pain stimulation were also assessed. DESIGN: FJs were obtained from consented patients undergoing spinal reconstruction surgery and cadaveric donors with no history of back pain. Histological analyses of the FJs were performed. Cytokine antibody array and quantitative real-time polymerase chain reaction (qPCR) were used to determine the production of inflammatory cytokines, and western blotting analyses (WB) were used to assay for cartilage-degrading enzymes and pain mediators. Ex vivo rat dorsal root ganglion (DRG) co-culture with human FJC tissues was also performed. RESULTS: Increased neovascularization, inflammatory cell infiltration, and pain-related axonal-promoting factors were observed in degenerative FJCs surgically obtained from symptomatic subjects. Increased VEGF, (NGF/TrkA), and sensory neuronal distribution were also detected in degenerative FJC tissues from subjects with LBP. qPCR and WB results demonstrated highly upregulated inflammatory cytokines, pain mediators, and cartilage-degrading enzymes in degenerative FJCs. Results from ex vivo co-culture of the DRG and FJC tissue demonstrated that degenerative FJCs increased the expression of inflammatory pain molecules in the sensory neurons. CONCLUSION: Degenerative FJCs possess greatly increased inflammatory and angiogenic features, suggesting that these factors play an important role in the progression of FJD and serve as a link between joint degeneration and neurological stimulation of afferent pain fibers.

Exploratory factor analysis of the Oral Health Impact Profile.

Although oral health-related quality of life (OHRQoL) as measured by the Oral Health Impact Profile (OHIP) is thought to be multidimensional, the nature of these dimensions is not known. The aim of this report was to explore the dimensionality of the OHIP using the Dimensions of OHRQoL (DOQ) Project, an international study of general population subjects and prosthodontic patients. Using the project's Learning Sample (n = 5173), we conducted an exploratory factor analysis on the 46 OHIP items not specifically referring to dentures for 5146 subjects with sufficiently complete data. The first eigenvalue (27·0) of the polychoric correlation matrix was more than ten times larger than the second eigenvalue (2·6), suggesting the presence of a dominant, higher-order general factor. Follow-up analyses with Horn's parallel analysis revealed a viable second-order, four-factor solution. An oblique rotation of this solution revealed four highly correlated factors that we named Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact. These four dimensions and the strong general factor are two viable hypotheses for the factor structure of the OHIP.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Addition of vardenafil into storage solution protects the endothelium in a hypoxia-reoxygenation model.

OBJECTIVE: Based upon the well known protective effect of intracellular cyclic guanosine monophosphate (cGMP) accumulation, we tested the hypothesis that storage solution enriched with optimal concentration of the phosphodiestherase-5 inhibitor vardenafil could provide better protection of vascular grafts against reperfusion injury after long-term cold ischaemic storage. METHODS: Isolated thoracic aorta obtained from rats underwent 24-h cold ischaemic preservation in physiological saline or vardenafil (10(-11) M)-supplemented saline solution. Reperfusion injury was simulated by hypochlorite (200 µM) exposure for 30 minutes. Endothelium-dependent vasorelaxation was assessed, and histopathological and molecular-biological examination of the aortic tissue were performed. RESULTS: Compared with the control group, the saline group showed significantly attenuated endothelium-dependent maximal relaxation (Rmax) to acetylcholine after hypoxia-reoxygenation, which was significantly improved by vardenafil supplementation (Rmax control: 98 ± 1%; saline: 48 ± 6%; vardenafil: 75 ± 4%; p < .05). Vardenafil treatment significantly reduced DNA strand breaks (control: 10.6 ± 6.2%; saline: 72.5 ± 4.0%; vardenafil: 14.2 ± 5.2%; p < .05) and increased cGMP score in the aortic wall (control: 8.2 ± 0.6; saline: 4.5 ± 0.3; vardenafil: 6.7 ± 0.6; p < .05). CONCLUSIONS: Our results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction induced by cold storage warm reperfusion, which can be effectively reversed by pharmacological phosphodiesterase-5 inhibition.

New pool of cortical interneuron precursors in the early postnatal dorsal white matter.

The migration of cortical γ-aminobutyric acidergic interneurons has been extensively studied in rodent embryos, whereas few studies have documented their postnatal migration. Combining in vivo analysis together with time-lapse imaging on cortical slices, we explored the origin and migration of cortical interneurons during the first weeks of postnatal life. Strikingly, we observed that a large pool of GAD65-GFP-positive cells accumulate in the dorsal white matter region during the first postnatal week. Part of these cells divides and expresses the transcription factor paired box 6 indicating the presence of local transient amplifying precursors. The vast majority of these cells are immature interneurons expressing the neuronal marker doublecortin and partly the calcium-binding protein calretinin. Time-lapse imaging reveals that GAD65-GFP-positive neurons migrate from the white matter pool into the overlying anterior cingulate cortex (aCC). Some interneurons in the postnatal aCC express the same immature neuronal markers suggesting ongoing migration of calretinin-positive interneurons. Finally, bromodeoxyuridine incorporation experiments confirm that a small fraction of interneurons located in the aCC are generated during the early postnatal period. These results altogether reveal that at postnatal ages, the dorsal white matter contains a pool of interneuron precursors that divide and migrate into the aCC.

The unfolding web of innate immune dysregulation in alcoholic liver injury.

Inflammatory cell and cytokine cascade activation is present in humans with alcoholic liver disease as well as in animal models of alcohol-induced liver damage. Gut-derived lipopolysaccharide (LPS), a ligand of the Toll-like receptor 4 (TLR4), plays a central role in triggering and maintaining activation of Kupffer cells in alcoholic hepatitis. In this mini-review, we describe molecular mechanisms that lead to increased inflammatory cell activation by alcohol and LPS and discuss the mechanism for activation in alcohol-exposed macrophages. In alcohol-induced liver disease we discuss the role of MyD88-independent but IRF3-mediated TLR4 signaling in alcohol-related liver inflammation and liver damage.

PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels.

OBJECTIVE: Atherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood. METHODS: Male Apoe-/- mice on a western diet were treated with the PARP inhibitor INO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks. RESULTS: Inhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by Il12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3α (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL in vitro. Moreover, serum IgM antibody levels to oxLDL were significantly lower in INO-1001 treated mice (p = 0.03). CONCLUSIONS: Functional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL.

A computer model of early diastolic filling through the mitral valve.

The current paper presents a computer model of early diastolic (E-wave) left ventricular filling through the mitral valve. It is believed that this lumped-parameter model will be clinically useful, for example in the diagnosis of diastolic dysfunction. The model is based on the solution of the ordinary differential equations describing flow through the mitral valve, as well as equations that model the intrinsic and extrinsic behaviour of a mitral valve with variable orifice area (mimicking the opening and closing of the valve leaflets). The model was developed and calibrated using porcine data. The model has now been further validated in 12 canine trials. Values are reported of canine atrial and ventricular stiffness, active relaxation characteristics, valve natural frequency, damping coefficient, and effective orifice area measured by solving the inverse problem to obtain a best-fit match between canine empirical and simulated waveforms. The best fit was determined by minimizing the error between the simulated and empirical pressure and velocity waveforms using a minimized sum-of-squares figure of merit. The paper also presents human data addressing the feasibility of using the model in man, with Doppler velocity waveforms as the primary input to the model. The paper reports parameters measured in human patients by solving the inverse problem.

Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6.

The discovery that a common polymorphism (5-HTTLPR, short variant) in the human serotonin transporter gene (SLC6A4) can influence personality traits and increase the risk for depression in adulthood has led to the hypothesis that a relative increase in the extracellular levels of serotonin (5-HT) during development could be critical for the establishment of brain circuits. Consistent with this idea, a large body of data demonstrate that 5-HT is a strong neurodevelopmental signal that can modulate a wide variety of cellular processes. In humans, serotonergic fibers appear in the developing cortex as early as the 10th gestational week, a period of intense neuronal migration. In this study we hypothesized that an excess of 5-HT could affect embryonic cortical interneuron migration. Using time-lapse videometry to monitor the migration of interneurons in embryonic mouse cortical slices, we discovered that the application of 5-HT decreased interneuron migration in a reversible and dose-dependent manner. We next found that 5-HT6 receptors were expressed in cortical interneurons and that 5-HT6 receptor activation decreased interneuron migration, whereas 5-HT6 receptor blockade prevented the migratory effects induced by 5-HT. Finally, we observed that interneurons were abnormally distributed in the cerebral cortex of serotonin transporter gene (Slc6a4) knockout mice that have high levels of extracellular 5-HT. These results shed new light on the neurodevelopmental alterations caused by an excess of 5-HT during the embryonic period and contribute to a better understanding of the cellular processes that could be modulated by genetically controlled differences in human 5-HT homeostasis.