Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation ...of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway.
The putative binding mode of five FQs ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells.
CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells.
These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.
Oral health is closely related to both physical and psychological well-being, as it enables individuals to eat, speak, and socialize. The number of teeth is the most used indicator of oral health. ...Several reports document a relationship of dental status with a variety of indicators of general health but longitudinal studies employing standardized physical performance tests are infrequent in the scientific literature. The Italian elderly participating in the Pro.V.A. longitudinal Study (3099 subjects aged 65+ at baseline, 2196 at the 5-year follow-up 1 and 1641 at the 7-year follow- up 2) underwent detailed interview and extensive clinical and instrumental examination that included validated physical performance measures. Participants were classified into 4 groups according to the number of remaining teeth: 0, 1-7, 8-19, and 20+. To explore the association of the number of remaining teeth with physical function and disability, we performed logistic regression analyses with models progressively adjusted for a wide number of covariates, namely anthropometric (gender, age, BMI), comorbidity (cardio-vascular, osteoarticular, and neurological diseases including depression), muscle strength (assessed for upper and lower limbs), lifestyle (smoking status, alcohol use, leisure time activities) and socioeconomical status (education, income, marital status, loneliness). Dental status correlated with most comorbidities, lifestyle, and socio-economic variables at the univariate analysis at baseline and at follow-ups. A good dental status was significantly associated with better physical functioning and lower disability. The presence of 20+ teeth resulted significantly protective (reference group: 0 teeth) versus mobility-related disability (OR = 0.67), disability (OR = 0.54) and inability to perform heavy duties (OR = 0.62), at follow up 1 and low physical performance score (OR = 0.59) at follow up 2. Conversely, the detrimental effect of edentulism, explored in subjects with or without dentures, was present but not as straightforward. Conclusion. The assessment of a geriatric patient should include an oral evaluation as a good dental status is a crucial component of successful aging.
Mitral valve prolapse (MVP) may present with ventricular arrhythmias and sudden cardiac death (SCD) even in the absence of hemodynamic impairment. The structural basis of ventricular electric ...instability remains elusive.
The cardiac pathology registry of 650 young adults (≤40 years of age) with SCD was reviewed, and cases with MVP as the only cause of SCD were re-examined. Forty-three patients with MVP (26 females; age range, 19-40 years; median, 32 years) were identified (7% of all SCD, 13% of women). Among 12 cases with available ECG, 10 (83%) had inverted T waves on inferior leads, and all had right bundle-branch block ventricular arrhythmias. A bileaflet involvement was found in 70%. Left ventricular fibrosis was detected at histology at the level of papillary muscles in all patients, and inferobasal wall in 88%. Living patients with MVP with (n=30) and without (control subjects; n=14) complex ventricular arrhythmias underwent a study protocol including contrast-enhanced cardiac magnetic resonance. Patients with either right bundle-branch block type or polymorphic complex ventricular arrhythmias (22 females; age range, 28-43 years; median, 41 years), showed a bileaflet involvement in 70% of cases. Left ventricular late enhancement was identified by contrast-enhanced cardiac magnetic resonance in 93% of patients versus 14% of control subjects (P<0.001), with a regional distribution overlapping the histopathology findings in SCD cases.
MVP is an underestimated cause of arrhythmic SCD, mostly in young adult women. Fibrosis of the papillary muscles and inferobasal left ventricular wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark and correlates with ventricular arrhythmias origin. Contrast-enhanced cardiac magnetic resonance may help to identify in vivo this concealed substrate for risk stratification.
In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never ...been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy‐eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI‐INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI‐BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20‐40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 μmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value >133 μmol/L. The rate of adverse events was lower in the TERLI‐INF group (35.29%) than in the TERLI‐BOL group (62.16%, P < 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI‐INF group than in the TERLI‐BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P < 0.05). Conclusion: Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration. (Hepatology 2016;63:983–992)
Postsurgical recurrence of Crohn's disease (CD) is very frequent and, to date, only infliximab has been shown to be useful in preventing it. The efficacy of adalimumab (ADA) is poorly known. We ...evaluated whether the administration of ADA after resective intestinal surgery reduces postoperative CD recurrence.
We randomly assigned 51 patients with CD who had undergone ileocolonic resection to receive after 2 weeks from surgery ADA at the dose of 160/80/40 mg every two weeks, azathioprine (AZA) at 2 mg/kg/day, or mesalamine at 3 g/day, and they were followed up for 2 years. The primary end point was the proportion of patients with endoscopic and clinical recurrence. Secondary end point was the assessment of quality of life by means of a previously validated questionnaire.
The rate of endoscopic recurrence was significantly lower in ADA (6.3%) compared with the AZA (64.7%; odds ratio (OR)=0.036 (95% confidence interval (CI) 0.004-0.347)) and mesalamine groups (83.3%; OR=0.013 (95% CI 0.001-0.143)). There was a significantly lower proportion of patients in clinical recurrence in the ADA group (12.5%) compared with the AZA (64.7%; OR=0.078 (95% CI 0.013-0.464)) and mesalamine groups (50%; (OR=0.143 (95% CI 0.025-0.819)). The quality of life was higher in the ADA (202) than in the AZA (90; OR=0.028 (95% CI 0.004-0.196)) and mesalamine groups (98; OR=0.015 (95% CI 0.002-0.134)).
The administration of ADA after intestinal resective surgery was greatly effective in preventing endoscopic and clinical recurrence of CD. Further larger studies are necessary to confirm the therapeutic advantage and to show the economic implications of biologic therapy in this field.
Background
Microscopic esophagitis (ME) is common in patients with non-erosive reflux disease (NERD), and dilation of intercellular spaces (DIS) has been regarded as the potential main mechanism of ...symptom generation. We aimed to compare these histological abnormalities in healthy volunteers (HVs) and patients with erosive esophagitis (EE), NERD, and functional heartburn (FH).
Methods
Consecutive patients with heartburn prospectively underwent upper endoscopy and impedance-pH off-therapy. Twenty EE patients and fifty-seven endoscopy-negative patients (NERD), subclassified as 22 with pH-POS (positive for abnormal acid exposure), 20 with hypersensitive esophagus (HE; normal acid/symptom association probability SAP+ or symptom index SI+), and 15 with FH (normal acid/SAP-/SI-/ proton pump inhibitor PPI test-), were enrolled. Twenty HVs were also included. In each patient/control, multiple specimens (
n
= 5) were taken from the distal esophagus and histological alterations were evaluated. ME was diagnosed when the global histological score was >0.35.
Results
The prevalence of ME was higher (
p
< 0.0001) in EE (95 %), pH-POS (77 %), and HE (65 %) NERD patients than in FH patients (13 %) and HVs (15 %). Also, basal cell hyperplasia (
p
< 0.0023), DIS (
p
< 0.0001), and papillae elongation (
p
< 0.0002) showed similar rates of prevalence in the above populations (
p
< 0.0001). ME, including each histological lesion, had similar low frequencies in FH and HVs (
p
= 0.9990). Considering the histological abnormalities together, they permitted us to clearly differentiate EE and NERD from FH and HVs (
p
< 0.0001 and
p
< 0.0001, respectively).
Conclusions
The lack of ME in the esophageal distal biopsies of FH patients indicates a limited role of these histological abnormalities in symptom generation in them. ME can be considered as an accurate and reliable diagnostic marker for distinguishing FH patients from GERD patients and has the potential to be used to guide the correct therapy.
To investigate the outcomes of hearing preservation surgery (HPS) for acoustic neuroma and quantify tumor and patient characteristics predictive of hearing preservation after surgery.
Retrospective ...study.
Tertiary referral center.
A total of 100 consecutive patients diagnosed with acoustic neuroma from 2000 to 2012.
Hearing preservation surgery through microscopic retrosigmoid approach combined with a retrolabyrinthine meatotomy.
Pre- and postoperative hearing stratified according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Tokyo classifications. The most accurate cutoff was identified for each tumor and patients' variable affecting the outcome by calculating the Youden index. A multivariable analysis was undertaken at these cutoffs to identify prognostic factors for hearing preservation.
Preoperative hearing class was preserved after surgery in 31% (AAO-HNS), and 39% (Tokyo classification) of patients. According to the AAO-HNS classification, the tumor size in the cerebello-pontine angle, pure-tone average (PTA), and speech discrimination score cutoffs for predicting good postoperative hearing function were 7 mm, 21 dB, and 90%, respectively. With the Tokyo classification, only the PTA cutoff differed, with 27 dB. On multivariable analysis, tumor size and PTA were independent prognostic factors for postoperative hearing with high model's goodness of fit (area under the curve = 0.784; 95% CI = 0.68-0.88 and area under the curve = 0.813; 95% CI = 0.72-0.90), according to both the hearing classifications.
The estimated cutoffs for tumor size and PTA were independently associated with HPS. These factors should be prospectively investigated before they are adopted as selection criteria for HPS.
Small pretreatment laryngeal biopsies may not fully represent a tumor’s biological profile. This study on laryngeal squamous cell carcinoma (LSCC) aimed to investigate the prognostic role of CD105- ...and CD31-assessed microvessel density (MVD) in paired biopsies and surgical specimens and the association and discrepancy between CD105- and CD31-assessed MVD in biopsies and surgical specimens. CD105- and CD31-assessed MVD was analyzed in paired biopsies and surgical specimens of 45 consecutive cases of LSCC. In the LSCC biopsies and surgical specimens, median CD105-assessed MVD was significantly higher in N+ than in N0 cases (p = 0.0008, and p = 0.0002, respectively). Disease-free survival (DFS) was associated with CD105- and CD31-assessed MVD in both biopsies and surgical specimens (p < 0.0001 for all specimens). Multivariable Cox’s regression showed that pathological grade (p < 0.0001) and CD105-assessed MVD in LSCC biopsies (p = 0.0209) predicted DFS. Lin’s concordance coefficient showed that CD31 overestimated MVD compared with CD105 in LSCC biopsies and surgical specimens. CD105-assessed MVD should be further investigated in larger LSCC series as a potential prognostic marker for identifying: patients at higher risk of recurrence who might warrant more aggressive therapy; and cN0 patients requiring elective neck dissection for a significant risk of regional metastasis.
Preterm birth is a risk factor for a child's neurological development. Preterm children have unusual neurodevelopmental profiles with executive, visual-motor functions, fine and gross motor skills, ...language and behavior that affect learning. In this study, we analyzed the neurodevelopmental outcomes of a cohort of very low birth weight infants admitted to the Treviso Neonatal Intensive Care Unit (NICU) between 2014 and 2016 and followed up to preschool childhood.
This is a prospective cohort study. Infants were followed at birth and after NICU discharge at two- and four-year follow-ups. The two-year assessment was conducted with Bayley III, and at four years with the Wechsler Preschool and Primary Scale of Intelligence - III scales and Movement Assessment Battery for Children - 2.
The cohort consisted of 207 subjects with a mean gestational age of 28.9 weeks, and a mean birth weight of 1097.2 g. At two years of age, children without disabilities were 90 (59.6%), those with minor disabilities 47 (31.1%), and those with major disabilities 14 (9.3%); at four years, 58.4% of children without previous disabilities, presented problems with verbal tests and manual dexterity: aiming, grasping and balance at movement assessment. There was significant alteration in processing speed (p < 0.001). Furthermore, there was a strong correlation between processing speed and manual dexterity (p < 0.001) and between processing speed and aiming and grasping (p = 0.0059).
We found that more than half the children free of disability at two years, at four years had deficit often involving the oculo-motor coordination and processing speed. These motor profile alterations limit the expression of cognitive abilities and the achievement of expected school performance, thus resulting in behavioral disorders, typical of preterm children. Early professional follow-up could improve the expected educational outcomes.
To evaluate the spontaneous change in size over the time of idiopathic full-thickness macular holes (IFTMHs) using optical coherence tomography (OCT).
This retrospective observational study included ...24 eyes of 24 consecutive patients waiting for IFTMH surgery. On OCT horizontal B-scan passing through the center of the fovea, the minimum linear diameter (MLD), the basal diameter (BD), and the presence of vitreomacular adhesion (VMA) were evaluated. The mean total and daily MLD and BD variations were calculated as both absolute and percentage values.
The MLD and BD size increase was statistically significant (P < 0.0001). The MLD size increase was significantly greater for small (<250 μm) versus both medium (≥250 to ≤400 μm) and large (>400 μm) IFTMHs in all analysis: the total absolute (P = 0.0248), the daily absolute (P = 0.0186), the total percentage (P = 0.0020), and the daily percentage (P = 0.0008) variations. For the BD, the significance between the same groups was achieved only in the daily percentage change (P = 0.0220). The presence of VMA did not influence the amount of MLD and BD increase. The rate of increase was dependent on the size of hole at presentation (MLD: small: 1.67 microns per day; medium: 0.61 microns per day; large: 0.44 microns per day).
Both MLD and BD increase over the time in IFTMHs. There is a significantly greater rate of increase in hole size in smaller holes compared with larger. Therefore, prioritisation for small IFTMH may be justified.
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