Synthesis and in vitro anti-Helicobacter pylori activity of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles

A new series of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles (6a–h) were synthesized and evaluated by the disc diffusion method against Helicobacter pylori. Four compounds which exhibited strong anti-H. pylori activity at concentration of 8–32 μg/disc (average of inhibition zone >20 mm) were further tested against 20 clinical isolates of H. pylori at lower concentrations. The averages of inhibition zone diameters indicated that all selected compounds exhibit better anti-H. pylori activity profile against clinical isolates of H. pylori with respect to standard drug metronidazole. Compound 6c, containing the 3-chlorobenzylthio moiety, was the most potent compound tested.     

Development of a tissue-engineered bypass graft seeded with stem cells

The gold standard conduit for bypass of diseased small-diameter arteries remains autologous vascular tissue. In the absence of such tissue, patients are offered bypass with prosthetic material, with far less durable results. Vascular tissue engineering, the creation of a vascular conduit by seeding a tubular scaffold with various cells, may offer an alternative approach to this difficult situation. Herein we review some of the significant challenges that remain in designing an ideal vascular conduit and outline potential solutions offered by a graft created by seeding natural vascular tissue (decellularized vein allograft) with readily available autologous cells (adipose-derived stem cells).     

Regular physical activity postpones age of occurrence of first-ever stroke and improves long-term outcomes

Neurological Sciences - Few data are available on the associations between the level of pre-stroke physical activity and long-term outcomes in patients with stroke. This study is designed to assess...     

Immunomodulatory effects of IP-10 chemokine along with PEI600-Tat delivery system in DNA vaccination against HPV infections

Although DNA vaccines represent an attractive approach for generating antigen-specific immunity, improvement of their potency is highly demanded. In the present study, three strategies including linkage to immunostimulatory molecules (N-terminal of gp96), co-administration of chemokines (IP-10 or RANTES) and PEI600-Tat as non-viral gene delivery system have been applied to enhance DNA vaccine efficacy against HPV infections. We found that C57BL/6 immunization with E7-NT-gp96 fusion gene led to increased level of IFN-γ compared to E7 alone. The fused genes showed considerable protective potency in tumor mice model. In addition, E7-NT-gp96 delivered with PEI600-Tat was more protective against E7-expressing tumors comparing with E7-NT-gp96 alone. Our results showed that co-administration of IP-10 with E7-NT-gp96 delivered by PEI600-Tat elicits significant IFN-γ production and consequently a strong preventive response against TC-1 tumor cells in contrast to increased tumor growth by RANTES co-delivery. Also in therapeutic experiment, our data showed that co-immunization of IP-10 at the same inoculation site of TC-1 along with E7-NT-gp96 delivery by PEI600-Tat is able to significantly suppress TC-1 tumor growth. The successful treatment by this immunization protocol was associated with the elevated levels of IFN-γ and IL-2 production in the lymph nodes. These data indicated that fusion of NT-gp96 to E7 in combination with IP-10 co-administration and PEI600-Tat delivery system can synergistically enhance the potency of HPV DNA vaccines. Therefore, this approach suggests a combinational therapeutic strategy against cervical and other HPV-related cancers.     

Effects of berberine on β-secretase activity in a rabbit model of Alzheimer's disease

Introduction

Relevant aspects of Alzheimer''s disease (AD) can be modeled by aluminium-maltolate injection into specific regions of the brain. The possible role of berberine chloride (BC) as an anti-inflammatory agent in the brain has been previously addressed.

Material and methods

Rabbits were divided into control (C), untreated lesion (L) and BC-treated + lesion (L + BC) groups. Animals in L + BC received BC (50 mg/ kg) orally 1 day after surgery and daily for 2 weeks. The lesion was induced by injection of 100 µl of either vehicle or water containing 25 mM aluminium-maltol into intraventricular fissure. Weight loss, ataxia, paralysis and tremor were monitored. For histopathology, Bielschowsky silver and H&E staining were employed. β-Secretase activity in hippocampus was finally assessed.

Results

All L animals died on days 12-15 after lesion. Seven to 10 days after lesion, abnormal symptoms as well as cachexia were seen in over 90% of cases. L rabbits lost an average of 0.5 kg which was significant on days 10 and 12 (p < 0.05); this was not completely prevented by BC. Up to day 15, all L animals had lost their lives (p < 0.001). BC treatment protected the hippocampus from degeneration, altered the behavior and decreased the activity of β-site amyloid precursor protein cleaving enzyme-1 (BACE-1).

Conclusions

Considering the findings in regard to physiological abilities, histological changes and BACE-1 activity in hippocampus changes, it is concluded that BC treatment could be an effective therapy in restoring Al maltol-induced behavioral derangements in the rabbit model of AD.     

The role of hollow magnetic nanoparticles in drug delivery

The increasing number of scientific publications focusing on nanomaterials in the biomedical field indicates growing interest from the broader scientific community. Nanomedicine is a modern science, and research continues into the application of nanoscale materials for the therapy and diagnosis of damaged tissues. In this regard, substantial progress has been made in the synthesis of magnetic materials with desired sizes, morphologies, chemical compositions, and surface chemistry. Among these, magnetic iron oxide nanoparticles have demonstrated great promise as unique carriers in the delivery of chemical drugs due to their combinations of hollow structures. Importantly, due to the combination of the ability to respond to an external magnetic field and the rich possibilities of their coatings, magnetic materials are universal tools for the magnetic separation of small molecules, biomolecules, and cells. This review provides an overview of the synthesis and biological applications of hollow magnetic nanoparticles in drug delivery systems.

The increasing number of scientific publications focusing on nanomaterials in the biomedical field indicates growing interest from the broader scientific community.     

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD and are known to have high densities of PACAP receptors. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.Posttraumatic stress disorder (PTSD) is an anxiety disorder estimated to affect 7% of the population (1), with symptoms that are highly debilitating and associated with a range of major physical health conditions (2, 3). PTSD disproportionally affects women over men (1, 4), and mechanisms for this sex difference have not yet been defined. We recently identified a single nucleotide polymorphism (SNP) in the gene coding for the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1) that predicts PTSD in women and not men (5–9). This SNP, rs2267735, is located on a canonical estrogen response element, indicating that estrogen levels may influence expression of the receptor. The ADCYAP1R1 polymorphism has been shown to predict exaggerated arousal responses characteristic of PTSD in autonomic psychophysiology (5, 10), but no study has yet examined the extent to which this polymorphism influences fear responses in the human brain. The current study tests the hypothesis that ADCYAP1R1 polymorphism influences brain regions that underlie emotional arousal, using functional MRI (fMRI) in a sample of women who have experienced civilian trauma.PTSD symptom clusters include hyperarousal, reexperiencing, avoidance, and numbing (11). Recently, evidence has accumulated to support the idea that hyperarousal is predictive of PTSD after trauma, whereas other symptoms are products of the disorder (12). In particular, pretrauma reactivity of the amygdala—a brain region responsible for coordinating and maintaining multiple components of emotional arousal (13)—appears to be a predisposing risk factor for the maintenance of PTSD symptoms (14–16). Additional brain regions implicated in the pathophysiology of PTSD include the ventromedial and dorsolateral prefrontal cortex, the anterior cingulate cortex, the hippocampus, and the insula (17, 18), each of which plays a role in regulating aspects of the emotional response.Genetic profiles appear to be the initiating predictor of vulnerability to psychiatric disorders. In the case of PTSD, however, environmental factors play a similarly critical role, with a major example being the specific traumatic experience that is a necessary component of the disorder. The combined influences of genetics and the environment are also apparent in twin studies indicating that genetic factors account for 30–70% of PTSD risk, with higher estimates for women than men (19, 20), and the remaining variance is attributable to experience. Such interacting genetic and environmental influences create complex symptom profiles that can vary greatly from individual to individual (19, 21), introducing wide error margins in predicting initial vulnerability, progress of symptoms over time, or effective therapeutic courses for the individual.Relative to genetic predictors or specific experiences, neurobiological phenotypes may provide greater power to predict psychopathology, as brain structure and function reflect an aggregate of genetic and environmental factors. Identifying such intermediate phenotypes, whose action falls between risk factors and psychiatric outcomes, will be critical to our ability to predict and understand disorders such as PTSD, helping to link multiple levels of research from proteins and cellular mechanisms to patient outcomes (21). Here we investigated the effects of an ADCYAP1R1 polymorphism on amygdala and hippocampal function, in a sample of adult women who have experienced moderate to high levels of civilian trauma. To disentangle genetic effects from the complex effects of PTSD and other psychiatric symptoms, genotype groups were matched for childhood and adult trauma levels and PTSD and depression symptom severity.Our primary hypotheses focused on the amygdala because of its role in regulating emotional arousal and as a possible predisposing factor in PTSD. We also examined the hippocampus, another brain region that plays a central role in PTSD (22), where PACAP binding sites are particularly dense (23) and where PACAP has been shown to act in a neuroprotective or neurotrophic manner (24–26) and may facilitate synaptic plasticity (25, 27). We predicted that individuals with the risk polymorphism would show exaggerated amygdala responses to threat stimuli and decreased functional connectivity between the amygdala and the hippocampus and medial prefrontal cortex, regions that regulate amygdala reactivity (28, 29).     

Confident non-invasive diagnosis of pseudolesions of the liver using diffusion-weighted imaging at 3T MRI

Purpose

Pseudolesions of the liver including focal steatosis or non-steatosis and THID (transient hepatic intensity differences) are often challenging, especially when imaging patients with underlying malignant disease. We evaluated the efficacy of diffusion-weighted imaging (DWI) in the diagnostic work-up of pseudolesions.

Materials and methods

Forty-eight patients with pseudolesions of the liver were consecutively examined and the images were retrospectively analyzed. MRI was performed on a clinical 3 T scanner using T1-GRE in-phase and opposed phase images, T2-TSE-FS, diffusion-weighted sequences (b-value 50, 300, 600), ADC mapping, and dynamic post-contrast T1-VIBE-FS sequences (32 patients received Gd-EB-DTPA and 16 patients received gadolinium chelates). All images were analyzed by two experienced radiologists in consensus. As a standard of reference, we used the T1-w GRE, in-phase and out of phase, and the contrast enhanced series, as well as long-term follow-up.

Results

In the 48 patients, a total of 116 liver lesions were found. Of these, 40 were benign and eleven were malignant focal lesions. Benign lesions included one FNH, 26 simple cysts, and twelve hemangiomas. In addition, 65 pseudolesions (20 focal steatosis, 13 focal non-steatosis, and 32 THIDs) were found. All pseudolesions could be identified either on the T1-GRE in-phase and opposed phase images or on the contrast-enhanced series, or on both. However, none of them were visible on the diffusion-weighted images.

Conclusion

Pseudolesions are invisible on DWI (negative predictive value = 1); therefore, DWI can be used as an additional sequence to significantly increase diagnostic confidence in the differentiation between pseudolesions and other focal liver lesions.