Development and assessment of nano drug delivery systems for combined delivery of rosuvastatin and ezetimibe.

Worldwide, cardiovascular disease is the main cause of death, which accordingly increased by hyperlipidemia. Hyperlipidemia therapy can include lifestyle changes and medications to control cholesterol levels. Statins are the medications of the first choice for dealing with lipid abnormalities. Rosuvastatin founds to control high lipid levels by hindering liver production of cholesterol and to achieve the targeted levels of low-density lipoprotein cholesterol, another lipid lowering agents named ezetimibe may be used as an added therapy. Both rosuvastatin and ezetimibe have low bioavailability which will stand as barrier to decrease cholesterol levels, because of such depictions, formulations of this combined therapy in nanotechnology will be of a great assistance. Our study demonstrated preparations of nanoparticles of this combined therapy, showing their physical characterizations, and examined their behavior in laboratory conditions and vivo habitation. The mean particle size was uniform, polydispersity index and zeta potential of formulations were found to be in the ranges of (0.181-0.72) and (-13.4 to -6.24), respectively. Acceptable limits of entrapment efficiency were affirmed with appearance of spherical and uniform nanoparticles. In vitro testing showed a sustained release of drug exceeded 90% over 24 h. In vivo study revealed an enhanced dissolution and bioavailability from loaded nanoparticles, which was evidenced by calculated pharmacokinetic parameters using triton for hyperlipidemia induction. Stability studies were performed and assured that the formulations are kept the same up to one month. Therefore, nano formulations is a suitable transporter for combined therapy of rosuvastatin and ezetimibe with improvement in their dissolution and bioavailability.

Formulation, optimization and full characterization of mirtazapine loaded aquasomes: a new technique to boost antidepressant effects.

OBJECTIVE: The development of Mirtazapine (MRT)-loaded aquasomes by co-precipitation sonication technique to boost the antidepressant potential of MRT. METHODOLOGY: MRT-loaded aquasomes formulations were prepared using Box-Behnken design to investigate the effect of independent factors including sonication time (X1), sonication temperature (X2), and sugar concentration (X3) on the dependent variables as particle size and drug loading efficiency. The formulation of the optimized formula was verified by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and X-ray Powder Diffraction (XRPD). Furthermore, the morphology of the formula was evaluated by Transmission Electron Microscopy (TEM). The optimum MRT- loaded aquasomes was assessed for physiochemical properties, in vitro MRT release and in vivo antidepressant effects in mice model. RESULTS: The results revealed that the optimized formula showed a small particle size of 202.7 ± 3.7 nm and a high loading efficiency of 77.65 ± 2.6%. Thermal DSC and XRPD studies demonstrated the amorphous nature of MRT-loaded aquasomes. The in vitro study demonstrated sustained release of F (opt) 88.16% after 8 h, compared with plain MRT release of 63.06% after 1 h. Mice treated with MRT-loaded aquasomes demonstrated reduced immobility time in behavioral analysis to 37% with MRT-loaded aquasomes, while plain MRT reduced it to 55%. CONCLUSION: These results confirmed that the antidepressant effect of MRT was significantly boosted in formulated aquasomes, and thereby they provide a promising carrier nano vesicular system for effective delivery of MRT.

Optical effect of rapid sintering protocols on different types of zirconia.

STATEMENT OF PROBLEM: Rapid sintering protocols are available for the fabrication of zirconia restorations, but whether rapid sintering influences color or translucency is unclear. PURPOSE: The purpose of this in vitro study was to investigate the effect of different rapid sintering protocols on the color and translucency of cubic and tetragonal zirconias. MATERIAL AND METHODS: Sixty disk-shaped specimens of 1-mm-thick cubic (DD CubeX2) and tetragonal (DD Bio ZX2) zirconia were investigated. Specimens of each type of zirconia were divided into three groups: conventional, speed, and superspeed sintering protocols. The conventional group of each zirconia type served as the control for calculating color differences. Translucency for each group was assessed by the translucency parameter and contrast ratio. Two-way analysis of variance was used for statistical analysis of the data (α=.05). RESULTS: The translucency of cubic and tetragonal zirconia decreased after speed and superspeed sintering (P<.001). Superspeed sintering resulted in a greater color change than speed sintering (P<.001). CONCLUSIONS: Rapid sintering protocols produced a significant effect on the color and translucency of cubic and tetragonal zirconias.

Impact of educational programme on patient's health outcomes following open heart surgeries.

BACKGROUND: Postcardiac surgery, numerous factors have been shown to predict postoperative harm of QoL, such as age, female sex, history of hypertension, chronic obstructive pulmonary disease, education level, marital status, and also psychological factors such as the presence of mood disorders. So, the essential key to self-management is behavioural change, which is necessary to improve the quality of life of patients and Health outcomes. AIM: The aim of this study is to evaluate the impact of the education programme on patients' health outcomes following open heart surgeries. PATIENTS AND METHODS: Quasi-experimental research design carried out in intensive care for open heart surgery in Suez Canal university hospitals at Ismailia Governate on all available both sex patients performing open heart surgery for 6-month period (60) using the following four tools: the first tool for patient's risk stratification model Euro Scale sheet; the second tool New York Heart Association scale for assessing functional abilities; the third tool for health outcomes sheet for assessing patient's quality of life and health status; and the fourth tool for assessing Hospital Anxiety and Depression Scale. RESULTS: There was no significant difference found in the patient's vital signs before and after the educational programme. On the other hand, there was no statistically significant difference between overall quality of life and socio-demographic characteristics before and after the educational programme. CONCLUSION: This study concluded that the educational programme has a positive effect on patients' quality of life in patients' educational programme; improve patient's health status as indicated by improved patient outcomes. RELEVANCE TO CLINICAL PRACTICE: The most important finding was the value of the educational training programme to address the needs of open heart surgery patients, indicating that after heart surgery, patient education by training can be helpful in self-care, and nurses can use a programme containing preparatory information to enhance results, alleviate patients problems, and improve the quality of life in patients with CABG.

Regulation of IGF2BP1 by miR-186 and its impact on downstream lncRNAs H19, FOXD2-AS1, and SNHG3 in HCC.

AIM: We have previously characterized oncogenic properties of IGF2BP1 in HCC, and its regulation by short noncoding RNAs (ncRNAs). Recent evidence suggests that IGF2BP1 itself may regulate long ncRNAs (lncRNAs). Therefore, this study aimed at exploring the interplay between IGF2BP1 and various upstream and downstream ncRNAs and its link to HCC pathogenesis. MATERIALS AND METHODS: Bioinformatic analysis was used to identify up- and downstream ncRNAs interacting with IGF2BP1. Huh-7 cells were transfected with siRNAs against IGF2BP1 and microRNA mimics. Relative gene expression was determined using RTqPCR and IGF2BP1 protein was quantified by western blot. Luciferase binding assay was used to explore the targeting of IGF2BP1 3'UTR. HCC tumorigenesis was measured by MTT assay, BrdU-incorporation assay, colony-forming assay, and scratch assay. KEY FINDINGS: Bioinformatic analysis identified three oncogenic lncRNAs - namely H19, FOXD2-AS1, and SNHG3 - potentially regulated by IGF2BP1. Knockdown of IGF2BP1 decreased the expression of all three oncogenic lncRNAs and inhibited malignant cell behaviors. miR-186 was revealed as a possible upstream regulator of IGF2BP1. miR-186 mimics decreased IGF2BP1 mRNA and protein levels. miR-186 was significantly lower while IGF2BP1 was elevated in cancerous tissues from ten HCC patients compared to five healthy controls. In addition, miR-186 mimics caused a downregulation of the oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 and a concomitant decrease in cell viability, proliferation, migration, and clonogenicity. SIGNIFICANCE: miR-186 may exert tumor suppressor effects in HCC by repressing oncogenic lncRNAs H19, SNHG3, and FOXD2-AS1 through its effect on IGF2BP1.

Knowledge, Attitudes, and Practices of Community Pharmacy Professionals on Poultry Antibiotic Dispensing, Use, and Bacterial Antimicrobial Resistance in Zambia: Implications on Antibiotic Stewardship and WHO AWaRe Classification of Antibiotics.

Globally, the inappropriate dispensing and use of antibiotics in animals has contributed to the development of bacterial antimicrobial resistance (AMR). In Zambia, there is insufficient information among community pharmacy professionals on antibiotic use (ABU) and AMR in food-producing animals. This study assessed community pharmacy professionals' knowledge, attitudes, and practices regarding poultry antibiotic dispensing, use, and bacterial AMR in the Lusaka district of Zambia. A cross-sectional study was conducted among 178 community pharmacy professionals between February and April 2022 using a semi-structured questionnaire. Data were analyzed using Stata version 17. Of the total participants (n = 178), 51.1% (n = 91) were pharmacists. The most dispensed antibiotic was oxytetracycline, a Watch antibiotic, mainly without prescriptions. Good knowledge of ABU and AMR was associated with work experience for more than one year (p = 0.016), while good practices were associated with male gender (p = 0.039) and work experience of more than one year (p = 0.011). The study found moderate knowledge, positive attitudes, and moderate practices of pharmacy professionals on poultry ABU and AMR. There was high dispensing of poultry antibiotics without prescriptions, which calls for strict implementation of antimicrobial stewardship and surveillance programs in poultry production in Zambia to reduce AMR.

Prevalence and Molecular Identification of Schistosoma haematobium among Children in Lusaka and Siavonga Districts, Zambia.

Schistosomiasis remains a public health concern in Zambia. Urinary schistosomiasis caused by Schistosoma haematobium is the most widely distributed infection. The aim of the current study was to determine the prevalence and risk factors of urinary schistosomiasis and identify the strain of S. haematobium among children in the Siavonga and Lusaka districts in Zambia. Urine samples were collected from 421 primary school children and S. haematobium eggs were examined under light microscopy. A semi-structured questionnaire was used to obtain information on the socio-demographic characteristics and the potential risk factors for urinary schistosomiasis. DNA of the parasite eggs was extracted from urine samples and the internal transcribed spacer gene was amplified, sequenced and phylogenetically analysed. The overall prevalence of S. haematobium was 9.7% (41/421) (95% CI: 7.16-13.08), male participants made up 6.2% (26/232) (95% CI: 4.15-9.03), having a higher burden of disease than female participants who made up 3.5% (15/421) (95% CI: 2.01-5.94). The age group of 11-15 years had the highest overall prevalence of 8.3% (35/421) (5.94-11.48). Participants that did not go fishing were 0.008 times less likely to be positive for schistosomiasis while participants whose urine was blood-tinged or cloudy on physical examination and those that lived close to water bodies were 9.98 and 11.66 times more likely to test positive for schistosomiasis, respectively. A phylogenetic tree analysis indicated that S. haematobium isolates were closely related to pure S. haematobium from Zimbabwe and hybrids of S. haematobium × S. bovis from Benin, Senegal and Malawi. The current study shows that urinary schistosomiasis is endemic in the study areas and is associated with water contact, and S. haematobium isolated is closely related to hybrids of S. bovis × S. haematobium strain, indicating the zoonotic potential of this parasite.

Self-efficacy among patients with hemodialysis during the COVID-19 pandemic.

Patients with hemodialysis face various problems with self-care behavior. Therefore, these patients need to control and manage adherence to enhance self-care, especially during the COVID-19 pandemic, which has particularly high morbidity in the elderly and co-morbid peoples. Self-efficacy was identified as a number of psychological factors that improve adherence and treatment outcomes among hemodialysis patients. This study aimed to investigate self-efficacy among patients with hemodialysis during the COVID-19 pandemic. A comparative descriptive research design was used to conduct the study. A convenience sample of 95 hemodialysis patients (male and females) was selected from Port-Said city, Egypt, and 115 hemodialysis patients (male and females) were selected from Saudi Arabia. Data collection included a structured interview with three parts assessing socio-demographic characteristics, anthropometric measurements, and self-efficacy. This study revealed a statistically significant difference between Egyptian and Saudi hemodialysis patients, mainly in the main score and levels of self-efficacy (p=0.001). There is a significant relationship between socio-demographic characteristics and chronic disease self-efficiency among Egyptian hemodialysis patients in terms of sex, age, marital status, work, and level of education.

Effects of Electronic Devices and Internet Addiction on Sleep and Academic Performance Among Female Egyptian and Saudi Nursing Students: A Comparative Study.

INTRODUCTION: The widespread availability of Internet access and increasing rate of electronic device usage has helped enlighten the world community through copious applications, information resources, and other benefits. However, both the lack of controlled behavior and excessive Internet usage have resulted in a variety of difficulties that can hinder user achievement in many areas. OBJECTIVES: This study investigated the prevalence of Internet and electronic device addiction among Egyptian and Saudi nursing students, with the aim of identifying any effects on sleep and academic performance. METHODS: A cross-sectional comparative research design was employed among a systematic random sample comprised of 920 Egyptian and Saudi female nursing students. All participants completed the Young-Internet Addiction Test (IAT), Mobile Phone Involvement Questionnaire (MPIQ), and Epworth Sleepiness Scale (ESS). RESULTS: Severe Internet Addiction (IA) detected in 42.69% and 10.31% of Saudi and Egyptian participants, respectively. However, Saudi participants were more likely to report high rates of mobile phone usage (P < 0.001), while Egyptian participants tended to score higher on the ESS (17.47 ± 3.99 vs. 16.8 ± 3.83; P = 0.024). For all participants, IAT and MPIQ scores were correlated with ESS results, while IA was specifically associated with poor academic performance. Finally, MPIQ scores were inversely correlated with academic performance for Saudi participants. CONCLUSION: Smartphone and Internet addiction were notable problems for the Egyptian and Saudi nursing students investigated in this study. Importantly, these conditions adversely affect academic performance and other activity engagement in addition to inducing excessive daytime sleepiness.

Near-Infrared Light Increases Functional Connectivity with a Non-thermal Mechanism.

Although techniques for noninvasive brain stimulation are under intense investigation, an approach that has received limited attention is transcranial photobiomodulation (tPBM), the delivery of near-infrared light to the brain with a laser or light-emitting diode directed at the scalp. Here we employed functional magnetic resonance imaging to measure the blood-oxygenation-level-dependent signal in n = 20 healthy human participants while concurrently stimulating their right frontal pole with a near-infrared laser. Functional connectivity with the illuminated region increased by up to 15% during stimulation, with a quarter of all connections experiencing a significant increase. The time course of connectivity exhibited a sharp rise approximately 1 min after illumination onset. Brain-wide connectivity increases were also observed, with connections involving the stimulated hemisphere showing a significantly larger increase than those in the contralateral hemisphere. We subsequently employed magnetic resonance thermometry to measure brain temperature during tPBM (separate cohort, n = 20) and found no significant temperature differences between active and sham stimulation. Our findings suggest that near-infrared light synchronizes brain activity with a nonthermal mechanism, underscoring the promise of tPBM as a new technique for stimulating brain function.

Epigallocatechin gallate (EGCG) and miR-548m reduce HCV entry through repression of CD81 receptor in HCV cell models.

Epigallocatechin gallate (EGCG) is the most abundant component in green tea extract, that has powerful antioxidant and antiviral effects. It has been previously reported to inhibit HCV entry via several mechanisms. Hence, this study aimed at further investigating the potential impact of EGCG on HCV entry through regulation of the expression of tetraspanin receptor CD81 by the novel predicted miR-548m. Liver biopsies were obtained from 29 HCV patients and 10 healthy controls for expression profiling. Huh7 cells were stimulated with EGCG and subsequently miR-548m expression was assessed. Naïve, HCV- ED43/JFH-1 and HCV-JFH-1 infected Huh7 cells were transfected by miR-548m mimics and inhibitors. Consequently, CD81 protein and mRNA levels were assessed using flow cytometry and qRT-PCR, respectively. Additionally, these cells were used to investigate HCV permissiveness into Huh7 cells using qRT-PCR for viral quantification. Direct binding confirmation of miR-548m to CD81 was done using luciferase reporter assay. In-silico analysis revealed miR-548m to have two potential binding sites in the 3'UTR of CD81 mRNA. EGCG boosted miR-548m expression in Huh7 cells. Additionally, miR-548m caused a downregulation of CD81 protein and mRNA levels as well as reduction in HCV infectivity of Huh7 cells. Luciferase binding assay confirmed the binding of miR-548m to CD81 mRNA at the two predicted binding sites. Intriguingly, miR-548m expression was not detected in healthy liver biopsies but was found in liver biopsies of HCV patients. This study shows that EGCG might act as an anti-HCV agent that reduces cellular infectivity via enhancing miR-548m expression and repressing CD81 receptor.

Correlation of Appearance of MRI Perinidal T2 Hyperintensity Signal and Eventual Nidus Obliteration Following Photon Radiosurgery of Brain AVMs: Combined Results of LINAC and Gamma Knife Centers.

BACKGROUND: A wide variety of radiologic changes occur within and adjacent to the nidus of arteriovenous malformations (AVMs) after stereotactic radiosurgery (SRS). Our objective was to study the magnetic resonance imaging(MRI)-defined changes following photon radiosurgery of AVMs and specifically to correlate the appearance of a perinidal T2 hyperintensity signal with the eventual angiographic obliteration of an AVM nidus in response to SRS treatment. MATERIAL AND METHODS: This retrospective study was conducted on 62 patients with brain AVMs who received photon SRS treatments between 2004 and 2017, using either a technique based on a linear accelerator at the Alexandria LINAC Radiosurgery Center in Egypt (21 patients/AVMs) or a technique based on a gamma unit at the Koto Memorial Gamma Knife Center in Japan (41 patients/AVMs). All patients included in the study had serial clinical and radiologic follow-ups for ≥ 2 years after SRS treatments. RESULTS: In the combined study series of 62 patients/AVMs treated with photon SRS, the follow-up MRIs revealed that 50 AVMs (80.6%) showed nonvisualized nidus and 12 AVMs (19.4%) showed decreased nidus size. Radiation-induced changes, defined as appearance of perinidal T2 hyperintensities in post-SRS MRIs, occurred in 34 patients (54.8%). Of the 35 patients with available follow-up angiographic studies, 30 AVMs (85.7%) demonstrated complete nidus obliteration at a mean of 36 months (range: 8-66 months) after SRS. Of the 30 AVMs with both MRI evidence of a nonvisualized nidus and angiographic verification of complete nidus obliteration, 20 AVMs (66.7%) were associated with prior MRI evidence of the appearance of a perinidal T2 hyperintensity signal at an average of 12 months (range: 6-45 months) after SRS. Of the five AVMs with both MRI evidence of decreased nidus size and angiographic verification of partial nidus obliteration, four AVMs (80%) showed perinidal T2 hyperintensity signal on post-SRS follow-up MRIs. Lower Spetzler-Martin grade (p = 0.013), smaller AVM volume (p = 0.017), and appearance of post-SRS perinidal T2 hyperintensity signal (p = 0.007) were the statistically significant independent predictors of AVM obliteration. The appearance of perinidal T2 hyperintensity signal in the post-SRS MRIs had a sensitivity of 66.7%, a specificity of 20%, and an overall accuracy of 60% in predicting the eventual obliteration of the AVM nidus. CONCLUSIONS: The present study may help improve our current understanding of the mechanisms behind the radiation-induced tissue changes following AVM SRS. Because the SRS-induced hemodynamic changes within the AVM nidus initiate the cascade of the subsequent formation of perinidal vasogenic brain edema, the appearance of perinidal high T2 signal in the follow-up MRIs after SRS would be a valuable indicator of the AVM response to SRS. The development of perinidal hyperintensity was the strongest predictive factor of AVM obliteration (p = 0.007), with relatively high sensitivity (66.7%) and accuracy (60%) and fairly low specificity (20%), as a prognostic sign of eventual complete angiographic obliteration of the AVM nidus following SRS.

Lycopene ameliorates atrazine-induced oxidative damage in adrenal cortex of male rats by activation of the Nrf2/HO-1 pathway.

Atrazine (ATZ) is one of the most commonly used herbicides contaminating plants, soil and water resources. Several strategies have been used to counteract ATZ toxicity. Here, we tested the hypothesis that lycopene could ameliorate ATZ-induced toxicity in the adrenal cortex. For this purpose, 35 adult male albino rats were randomized into five equal groups: untreated control, vehicle control (received 0.5 mL corn oil/day), lycopene (treated with lycopene dissolved in 0.5 mL corn oil, 10 mg/kg b.w./day), ATZ (received ATZ dissolved in 0.5 mL corn oil 300 mg/kg b.w./day), and ATZ + lycopene (treated with ATZ and lycopene at the same previously mentioned doses). All treatments were given by oral gavage for 4 weeks. We found that ATZ exposure significantly increased relative adrenal weight, plasma ACTH levels, and adrenal oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content and depressed antioxidant enzyme activities in adrenal cortex tissues with respect to control groups. Furthermore, the transcription of adrenal cortex nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B, and caspase-3 genes was increased significantly compared with the control groups. This was accompanied with DNA fragmentation and structural and ultrastructural changes in zona glomerulosa and zona fasiculata of the adrenal cortex. Notably, all these changes were partially ameliorated in rats treated concomitantly with ATZ and lycopene. Our results showed that lycopene exerts protective effects against ATZ-induced toxicity in rat adrenal cortex. These effects may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

Factors affecting nursing students' incivility: As perceived by students and faculty staff.

BACKGROUNDS: Students' incivility in institutions of higher education is a serious issue that faces educators in performing their teaching duties. The negative impacts associated with uncivil classroom behaviors have been found to contribute to the disruption of the learning process and the classroom learning environment, and the deterioration of the faculty-student relationship. OBJECTIVES: This study assays the incivility level among nursing students, investigates factors affecting student nurses' incivility, and explores the relationship between students' uncivil behavior and factors affecting its occurrence based on the perceptions of students and faculty staff. A descriptive comparative research design included all nursing students (n=186) and faculty staff (n=66) in the Faculty of Nursing, Port Said University. A structured questionnaire was used to collect the data. RESULTS: The results of the study reflected that less than two thirds of students (60.2%) reported irresponsible behaviors, more than half (55.9%) expressed that they behave inappropriately, and 47.8% of them believed that they behave aggressively. The highest percentage of students (55.4%) recorded a high level of uncivil behavior, while faculty staff recorded a lower level regarding aggressive uncivil student behaviors. Both faculty staff and students agreed that a high level of incivility is affected by the studied factors, including issues related to environmental and study climate, faculty policies, political atmosphere, and faculty staff. CONCLUSION: Uncivil students' behavior interferes with academic achievement and leads to a declined curve of ethics for nursing students, who are to be considered a symbol of ethics when dealing with their patients. Based on the study results, activated implementation of faculty policies on uncivil behaviors is recommended. Also, there is an obvious need to train faculty staff members to deal with uncivil and bullying students.

The Virtual Brain: Modeling Biological Correlates of Recovery after Chronic Stroke.

There currently remains considerable variability in stroke survivor recovery. To address this, developing individualized treatment has become an important goal in stroke treatment. As a first step, it is necessary to determine brain dynamics associated with stroke and recovery. While recent methods have made strides in this direction, we still lack physiological biomarkers. The Virtual Brain (TVB) is a novel application for modeling brain dynamics that simulates an individual's brain activity by integrating their own neuroimaging data with local biophysical models. Here, we give a detailed description of the TVB modeling process and explore model parameters associated with stroke. In order to establish a parallel between this new type of modeling and those currently in use, in this work we establish an association between a specific TVB parameter (long-range coupling) that increases after stroke with metrics derived from graph analysis. We used TVB to simulate the individual BOLD signals for 20 patients with stroke and 10 healthy controls. We performed graph analysis on their structural connectivity matrices calculating degree centrality, betweenness centrality, and global efficiency. Linear regression analysis demonstrated that long-range coupling is negatively correlated with global efficiency (P = 0.038), but is not correlated with degree centrality or betweenness centrality. Our results suggest that the larger influence of local dynamics seen through the long-range coupling parameter is closely associated with a decreased efficiency of the system. We thus propose that the increase in the long-range parameter in TVB (indicating a bias toward local over global dynamics) is deleterious because it reduces communication as suggested by the decrease in efficiency. The new model platform TVB hence provides a novel perspective to understanding biophysical parameters responsible for global brain dynamics after stroke, allowing the design of focused therapeutic interventions.

Repressing PU.1 by miR-29a∗ in NK cells of HCV patients, diminishes its cytolytic effect on HCV infected cell models.

OBJECTIVES: Natural killer cells are immune safeguards against HCV infection. PU.1 is a pivotal transcription factor in the development of NK cells. This study aimed at studying the regulatory effect of miRNAs on both development and function of NK cells isolated from HCV patients. METHODS: NK cells were isolated from 17 chronic HCV patients and 12 healthy controls; after which miRNA and mRNA were quantified using qRT-PCR. Manipulating miRNA expression using mimics and antagomirs, was performed followed by investigating downstream targets as well as viral abundance. RESULTS: PU.1 expression levels were upregulated in NK cells of HCV patients. In silico analysis revealed PU.1 to be a potential downstream target of miR-29a(∗), where miR-29a(∗) overexpression in NK cells caused a significant downregulation in PU.1 mRNA. Forcing miR-29a(∗) caused a downregulation of the cytotoxicity determinant NK activating receptor (NKG2D) via upregulation of miR-155. Moreover, perforin-1 mRNA was found to be downregulated upon forcing the expression of miR-29a(∗) in NK cells of HCV patients. This decrease in NK cytolytic function was accompanied by an 80% viral load increase in cocultured HCVcc cell models. CONCLUSIONS: This study showed that HCV infection might abrogate NK cytotoxic potential through altering PU.1, NKG2D receptor and perforin molecules.

Fracture and Fatigue Resistance of Cemented versus Fused CAD-on Veneers over Customized Zirconia Implant Abutments.

PURPOSE: To evaluate the fracture mechanics of cemented versus fused CAD-on veneers on customized zirconia implant abutments. MATERIALS AND METHODS: Forty-five identical customized CAD/CAM zirconia implant abutments (0.5 mm thick) were prepared and seated on short titanium implant abutments (Ti base). A second scan was made to fabricate 45 CAD-on veneers (IPS Empress CAD, A2). Fifteen CAD-on veneers were cemented on the zirconia abutments (Panavia F2.0). Another 15 were fused to the zirconia abutments using low-fusing glass, while manually layered veneers served as control (n = 15). The restorations were subjected to artificial aging (3.2 million cycles between 5 and 10 kg in a water bath at 37°C) before being axially loaded to failure. Fractured specimens were examined using scanning electron microscopy to detect fracture origin, location, and size of critical crack. Stress at failure was calculated using fractography principles (alpha = 0.05). RESULTS: Cemented CAD-on restorations demonstrated significantly higher (F = 72, p < 0.001) fracture load compared to fused CAD-on and manually layered restorations. Fractographic analysis of fractured specimens indicated that cemented CAD-on veneers failed due to radial cracks originating from the veneer/resin interface. Branching of the critical crack was observed in the bulk of the veneer. Fused CAD-on veneers demonstrated cohesive fracture originating at the thickest part of the veneer ceramic, while manually layered veneers failed due to interfacial fracture at the zirconia/veneer interface. CONCLUSIONS: Within the limitations of this study, cemented CAD-on veneers on customized zirconia implant abutments demonstrated higher fracture than fused and manually layered veneers.

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.

Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.