Naturally occurring polyphenolic inhibitors of amyloid beta aggregation.

Alzheimer's disease is the most common neurodegenerative disease and is one of the main causes of death in developed countries. Consumption of foods rich in polyphenolics is strongly correlated with reduced incidence of Alzheimer's disease. Our study has investigated the biological activity of previously untested polyphenolic compounds in preventing amyloid ß aggregation. The anti-aggregatory potential of these compounds was assessed using the Thioflavin-T assay, transmission electron microscopy, dynamic light scattering and size exclusion chromatography. Two structurally related compounds, luteolin and transilitin were identified as potent inhibitors of Aß fibril formation. Computational docking studies with an X-ray derived oligomeric structure offer a rationale for the inhibitory activity observed and may facilitate development of improved inhibitors of Aß aggregation and toxicity.

Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-ß peptide.

Alzheimer's disease is the most common form of dementia in humans and is related to the accumulation of the amyloid-ß (Aß) peptide and its interaction with metals (Cu, Fe, and Zn) in the brain. Crystallographic structural information about Aß peptide deposits and the details of the metal-binding site is limited owing to the heterogeneous nature of aggregation states formed by the peptide. Here, we present a crystal structure of Aß residues 1-16 fused to the N-terminus of the Escherichia coli immunity protein Im7, and stabilized with the fragment antigen binding fragment of the anti-Aß N-terminal antibody WO2. The structure demonstrates that Aß residues 10-16, which are not in complex with the antibody, adopt a mixture of local polyproline II-helix and turn type conformations, enhancing cooperativity between the two adjacent histidine residues His13 and His14. Furthermore, this relatively rigid region of Aß (residues, 10-16) appear as an almost independent unit available for trapping metal ions and provides a rationale for the His13-metal-His14 coordination in the Aß1-16 fragment implicated in Aß metal binding. This novel structure, therefore, has the potential to provide a foundation for investigating the effect of metal ion binding to Aß and illustrates a potential target for the development of future Alzheimer's disease therapeutics aimed at stabilizing the N-terminal monomer structure, in particular residues His13 and His14, and preventing Aß metal-binding-induced neurotoxicity.

Subtle vaginal evisceration resulting in small bowel evisceration: a case report.

BACKGROUND: Evisceration of bowel contents through the vagina is a rare event that may be complicated by bowel obstruction. OBJECTIVE: We report a case of vaginal evisceration with small bowel obstruction which, in contrast to previous, more dramatic case reports in the literature, is a more subtle and, in fact, characteristic clinical presentation for this unusual occurrence. CASE REPORT: A 72-year-old woman with a previous history of pelvic surgery presented to the Emergency Department with lower abdominal discomfort and a prolapsing mass from her vagina. She was initially discharged home after bedside reduction of the mass, but returned 48 h later with worsening symptoms. A computed tomography scan on her repeat visit confirmed evisceration of bowel into the vaginal vault with obstruction of distal bowel loops. Surgical and gynecologic services were consulted and the patient underwent partial small bowel resection and vaginal cuff repair in the operating room. CONCLUSION: Early recognition of subtle presentations of vaginal evisceration is crucial for preserving bowel viability and preventing morbidity from bowel ischemia or infarction. Risk factors for this rare condition include postmenopausal status, previous pelvic surgery, and presence of an enterocele.

Oligomerization and toxicity of Aß fusion proteins.

This study has found that the Maltose binding protein Aß42 fusion protein (MBP-Aß42) forms soluble oligomers while the shorter MBP-Aß16 fusion and control MBP did not. MBP-Aß42, but neither MBP-Aß16 nor control MBP, was toxic in a dose-dependent manner in both yeast and primary cortical neuronal cells. This study demonstrates the potential utility of MBP-Aß42 as a reagent for drug screening assays in yeast and neuronal cell cultures and as a candidate for further Aß42 characterization.

Facile Green, Room-Temperature Synthesis of Gold Nanoparticles Using Combretum erythrophyllum Leaf Extract: Antibacterial and Cell Viability Studies against Normal and Cancerous Cells.

We herein report a facile, green, cost-effective, plant-mediated synthesis of gold nanoparticles (AuNPs) for the first time using Combretum erythrophyllum (CE) plant leaves. The synthesis was conducted at room temperature using CE leaf extract serving as a reducing and capping agent. The as-synthesized AuNPs were found to be crystalline, well dispersed, and spherical in shape with an average diameter of 13.20 nm and an excellent stability of over 60 days. The AuNPs showed broad-spectrum antibacterial activities against both pathogenic Gram-positive (Staphylococcus epidermidis (ATCC14990), Staphylococcus aureus (ATCC 25923), Mycobacterium smegmatis (MC 215)) and Gram-negative bacteria (Proteus mirabilis (ATCC 7002), Escherichia coli (ATCC 25922), Klebsiella pneumoniae (ATCC 13822), Klebsiella oxytoca (ATCC 8724)), with a minimum inhibition concentration of 62.5 µg/mL. In addition, the as-synthesized AuNPs were highly stable with exceptional cell viability towards normal cells (BHK- 21) and cancerous cancer cell lines (cervical and lung cancer).

Graphene Oxide-Gold Nanorods Nanocomposite-Porphyrin Conjugate as Promising Tool for Cancer Phototherapy Performance.

The cancer mortality rate has increased, and conventional cancer treatments are known for having many side effects. Therefore, it is imperative to find a new therapeutic agent or modify the existing therapeutic agents for better performance and efficiency. Herein, a synergetic phototherapeutic agent based on a combination of photothermal and photodynamic therapy is proposed. The phototherapeutic agent consists of water-soluble cationic porphyrin (5,10,15,20-tetrakis(N-methylpyridinium-3-yl)porphyrin, TMePyP), and gold nanorods (AuNRs) anchored on graphene-oxide (GO) sheet. The TMePyP was initially synthesized by Adler method, followed by methylation, while GO and AuNRs were synthesized using Hummer's and seed-mediated methods, respectively. The structural and optical properties of TMePyP were confirmed using UV-Vis, zeta analyzer, PL, FTIR and NMR. The formation of both GO and AuNRs was confirmed by UV-Vis-NIR, FTIR, TEM and zeta analyzer. TMePyP and AuNRs were anchored on GO to form GO@AuNRs-TMePyP nanocomposite. The as-synthesized nanocomposite was stable in RPMI and PBS medium, and, on irradiation, produced high heat than the bare AuNRs, with high photothermal efficiency. In addition, the nanocomposite produced higher singlet oxygen than TMePyP with high biocompatibility in the absence of light. These results indicated that the as-synthesized nanocomposite is a promising dual photodynamic and photothermal agent for cancer therapy.

Radiological imaging of the GI tract after bariatric surgery.

BACKGROUND: Obesity is becoming epidemic in proportion and is leading to considerable morbidity and mortality in the community. Bariatric surgery offers one tested solution to sustained weight loss and comorbidity reduction. However, it is associated with a significant number of complications. OBJECTIVE: The objective of this article is to review the utility of radiological techniques in the diagnosis of surgical complications after bariatric surgery. DESIGN: Literature-based review and pictorial illustration in the use of imaging techniques in the diagnosis of complications after bariatric surgery. CONCLUSIONS: Radiology plays a critical role in the diagnosis of complications after bariatric surgery. Upper GI contrast study and CT are the most commonly used imaging modalities in this regard. They are complementary in their diagnostic abilities and should be used in concert for the complete evaluation of symptomatic patients. All other radiological imaging modalities are also used in the diagnosis of complications after bariatric surgery, but much less commonly.

A new method to measure cellular toxicity of non-fibrillar and fibrillar Alzheimer's Abeta using yeast.

The 42 amino acid amyloid-beta (Abeta) can exist in multiple physical states including oligomers and fibrils. This study shows that fibril formation is hastened by the biological buffers required to support the growth of mammalian cells, but is prevented if Abeta is maintained in water. Here we describe a method to produce Abeta in oligomeric form and the comparison of stable fibrillar and non-fibrillar forms in cell toxicity studies in water, achieved through the use of yeast. We show that extracellular, non-fibrillar Abeta causes a dose dependent loss of cell viability while fibrillar Abeta has low toxicity.

CT-guided intervention with low radiation dose: feasibility and experience.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of performing CT-guided interventional procedures with a very low radiation dose. MATERIALS AND METHODS: We performed 291 CT-guided interventional procedures using a low dose of radiation. The subjects were 165 men and 126 women 22-89 years old with a mean age of 65 years. CT fluoroscopy was not used. The procedures were 201 percutaneous biopsies and 90 percutaneous aspiration or drainage procedures. Before the procedure, images were obtained with standard mAs of 175-250 mAs. All subsequent CT was performed at a reduced mAs. Technical success of catheter placement and biopsy was calculated, and the results were compared with those of procedures performed over the previous 12 months with standard radiation doses. Patient weight, lesion size, and number of CT acquisitions needed to complete the procedure were recorded. RESULTS: All but three aspiration or drainage procedures performed at 30 mAs were successful, for a success rate of 96.7%. The technical success rate of biopsy performed at 30 mAs was 93.5%. In the cases of 13 patients undergoing biopsy, the masses were not identified with low-dose technique, and these procedures were completed at a higher dose. Results were independent of patient weight and lesion size. The technical success rate was 98% for percutaneous drainage performed at a standard radiation dose in the 12 months before introduction of the low-dose technique. The technical success rate was 87.5% for biopsy performed at a standard radiation dose in the 12 months before introduction of the low-dose technique. The complication rate of the low-dose technique was comparable to that of the standard-dose technique. CONCLUSION: Low-dose radiation technique using 30 mAs results in technical success for both catheter placement and percutaneous biopsy comparable to standard radiation dose.

Accuracy of MDCT in the diagnosis of choledocholithiasis.

OBJECTIVE: Our purpose was to evaluate the diagnostic performance of contrast-enhanced and unenhanced MDCT, performed for various indications, in detecting choledocholithiasis. CONCLUSION: Unenhanced and contrast-enhanced MDCT images, interpreted in PACS workstations with axial images, are moderately sensitive and specific for showing choledocholithiasis.

Sixty-four multi-detector row computed tomography in multitrauma patient imaging: early experience.

Sixty-four multi-detector row computed tomography (64-MDCT) offers the possibility of increasing the application of CT in multitrauma imaging. 64-MDCT affords significant increases in imaging speed while allowing for subisotropic voxel slice thicknesses. We have recently installed two 64-MDCT scanners in our Level I trauma center. Our routine protocols using these new scanners are detailed. Additionally, this new technology has made possible several novel protocols. These include an increased use of CT angiography in trauma imaging. The acquisition speed and table lengths available with 64-MDCT allow for whole-body scout images. These scout images may be used to plan complex, multistep CT studies incorporating pelvic and extremity angiography, when indicated, into a single study. Imaging speeds afforded by 64-MDCT allow for imaging in any number of phases, over any area to be imaged, all with a single initial bolus of contrast. Image quality afforded by 64-MDCT allows for increasing roles of MPR and 3D reformations. These alternatives to axial images are currently used both for primary interpretation by our trauma radiologists as well as for communication and use by our clinical colleagues. Technical challenges presented by 64-MDCT include further increases in the number of images generated. Currently, datasets may exceed 4,000 images when angiography is included in routine trauma protocols. Radiation doses are also an ever present concern. With the opportunity to image from head to toe in seconds with submillimeter slice thicknesses, radiologists must be constantly vigilant in their efforts to limit radiation. Novel techniques such as automated dose modulation currently offer means of reducing radiation doses. Though several technical challenges are faced, 64-MDCT represents an evolution in multitrauma imaging.

Spontaneous hemoperitoneum: causes and significance.

Spontaneous hemoperitoneum is an uncommon cause of acute abdominal pain. When it occurs, it may be catastrophic. There are a myriad of causes for spontaneous hemoperitoneum and an underlying cause should always be looked for if the patient survives the initial event. This article describes the imaging findings of spontaneous hemoperitoneum and discusses the relative merits of multiple imaging modalities used for the diagnosis of the hemoperitoneum and an underlying cause. In addition, we outline the etiology of spontaneous hemoperitoneum, which includes hepatic, splenic, gynecologic, and vascular causes, and bleeding disorders.

Evaluation of simethicone-coated cellulose as a negative oral contrast agent for abdominal CT.

RATIONALE AND OBJECTIVES: Because of the increased clinical use of computed tomography (CT) for imaging the abdominal vasculature and urinary tract, there is a need for negative contrast agents. The authors undertook this study to assess the suitability of simethicone-coated cellulose (SCC), which is approved for use as an oral contrast agent in sonography, for use as a negative oral contrast agent in abdominal CT. MATERIALS AND METHODS: This prospective study involved 40 adult patients scheduled to undergo abdominal CT for the evaluation of hematuria. Prior to scanning, 20 subjects received 800 mL of SCC and 20 received 800 mL of water as an oral contrast agent. Imaging was performed with a multi-detector row helical scanner in two phases, according to the abdominal CT protocol used for hematuria evaluation at the authors' institution. The first, "early" phase began an average of 15 minutes after the ingestion of contrast material; the second, "late" phase began an average of 45 minutes after the ingestion of contrast material. Blinded analysis was performed by three abdominal radiologists separately, using a three-point scale (0 = poor, 1 = acceptable, 2 = excellent) to assess the effectiveness of SCC for marking the proximal, middle, and distal small bowel. Average scores for enhancement with SCC and with water were obtained and compared. Statistical analysis was performed with a Wilcoxon signed-rank test. RESULTS: SCC was assigned higher mean scores than water for enhancement in each segment of the bowel, both on early-phase images (0.8-1.35 for SCC vs 0.6-1.1 for water) and on late-phase images (1.1-1.4 vs 0.81-0.96). Bowel marking with SCC, particularly in the jejunum and ileum, also was rated better than that with water in a high percentage of patients. The differences between the scores for water and for SCC, however, were not statistically significant (P > .05). CONCLUSION: SCC is effective as a negative oral contrast agent for small bowel marking at CT.

Correlation of patient weight and cross-sectional dimensions with subjective image quality at standard dose abdominal CT.

OBJECTIVE: We evaluated the association between patients' weight and abdominal cross-sectional dimensions and CT image quality. MATERIALS AND METHODS: We prospectively evaluated 39 cancer patients aged more than 65 years with multislice CT scan of abdomen. All patients underwent equilibrium phase contrast-enhanced abdominal CT with 4 slices (from top of the right kidney) obtained at standard tube current (240-280 mA). All other scanning parameters were held constant. Patients' weight was measured just prior to the study. Cross-sectional abdominal dimensions such as circumference, area, average anterior abdominal wall fat thickness and, anteroposterior and transverse diameters were measured in all patients. Two subspecialty radiologists reviewed randomized images for overall image quality of abdominal structures using 5- point scale. Non-parametric correlation analysis was performed to determine the association of image quality with patients' weight and cross-sectional abdominal dimensions. RESULTS: A statistically significant negative linear correlation of 0.46, 0.47, 0.47, 0.58, 0.56, 0.54, and 0.56 between patient weight, anterior abdominal fat thickness, anteroposterior and transverse diameter, circumference, cross-sectional area and image quality at standard scanning parameters was found (p<0.01). CONCLUSION: There is a significant association between image quality, patients' weight and cross-sectional abdominal dimensions. Maximum transverse diameter of the abdomen has the strongest association with subjective image quality.

Mouse Minute Virus (MMV) Contamination--A Case Study: Detection, Root Cause Determination, and Corrective Actions.

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA) The production of biologic drugs using mammalian cell production systems offers the benefits of high yield, proper protein folding, and faithful post-translational modifications. However, mammalian cell culture is vulnerable to contamination with adventitious agents, including mouse minute virus (MMV). The case study presented here demonstrates that MMV is a ubiquitous threat to CHO (Chinese hamster ovary) cell-based production of biologic drugs and that animal-free media components can be a contamination source. Compounding the risk posed by MMV, the contamination may be "silent," with no impact on cell viability and product titers. Furthermore, contamination may not be detected using in vitro virus assays, and assays based on PCR (polymerase chain reaction) are required for reliable detection. The development of effective corrective and preventative action (CAPA) was greatly aided by the identification of the source of the contamination as an animal-free recombinant media additive. The execution of a CAPA that included disposal of contaminated materials, decontamination of the facility, and replacement of the contaminated raw material allowed the resumption of MMV-free production.

Cardiovascular biology of interleukin-6.

Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine that is tightly regulated and expressed at low levels in healthy individuals. Increased IL-6 expression has been associated with a variety of diseases, including inflammatory conditions such as atherosclerosis and cardiovascular disease (obesity, myocardial infarction and type II diabetes). Cytokines including IL-6 and tumour necrosis factor alpha as well as acute phase proteins such as C-reactive protein (CRP) and fibrinogen are key biochemical risk factors for the development of these disease conditions. IL-6 is the key cytokine responsible for the stimulus of synthesis and secretion of CRP. IL-6 activates cell surface signalling via the assembly of IL-6, the IL-6 receptor (IL-6R) and the signalling receptor gp130. Assembly of the (hexameric) signalling complex of IL-6, IL-6R and gp130 occurs in a sequential manner and therefore this signalling complex lends itself to several potential sites for drug targeting. This review discusses some of the mechanisms of IL-6 signalling on various aspects of cardiovascular biology as well as some recent developments in drug targeting of this complex.

Alzheimer's Abeta fused to green fluorescent protein induces growth stress and a heat shock response.

The 42 amino acid Alzheimer's Abeta peptide is involved in the progression of Alzheimer's disease. Here we describe the effects of intracellular Abeta, produced through its attachment to either end of a green fluorescent protein, in yeast. Cells producing Abeta exhibited a lower growth yield and a heat shock response, showing that Abeta fusions promote stress in cells and supporting the notion that intracellular Abeta is a toxic molecule. These studies have relevance in understanding the role of Abeta in the death of neuronal cells, and indicate that yeast may be a new tractable model system for the screening for inhibitors of the stress caused by Abeta.

Spontaneous hemoperitoneum: a bloody mess.

Spontaneous hemoperitoneum may be a life-threatening occurrence. It most frequently presents with acute abdominal pain. Computed tomography (CT) is the most commonly used modality in the initial work up of these patients, but sonography and magnetic resonance imaging (MRI) play a role in the diagnosis. The etiology is varied, yet may be broadly classified into gynecologic, hepatic, splenic, vascular, and coagulopathic causes. This review will describe the common imaging findings of spontaneous hemoperitoneum, as it presents through the emergency room, and will detail the underlying causes and significance of spontaneous hemoperitoneum.

Blunt splenic trauma: delayed-phase CT for differentiation of active hemorrhage from contained vascular injury in patients.

PURPOSE: To retrospectively evaluate delayed-phase computed tomography (CT) in the differentiation of active splenic hemorrhage requiring emergent treatment from contained vascular injuries (pseudoaneurysms or arteriovenous fistulas) that can be treated electively or managed conservatively. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study; the informed consent requirement was waived. Forty-seven patients with blunt splenic injury diagnosed at CT after blunt abdominal trauma were evaluated. Abdominal and pelvic dual-phase CT was performed; images were obtained 60-70 seconds and 5 minutes after contrast material injection. Scans were reviewed in consensus by two radiologists. Splenic injuries were graded with the American Association for the Surgery of Trauma Splenic Injury Scale. Patients with intrasplenic hyperattenuating foci on portal venous phase images were classified as having active splenic hemorrhage (group 1) or a contained vascular injury (group 2) on the basis of delayed-phase imaging findings. Findings suggestive of active hemorrhage included areas that remained hyperattenuating or increased in size on delayed-phase images. The clinical outcome of these patients was determined by reviewing their medical records. Relationships between several factors were tested with the Fisher exact test, including (a) the presence or absence of hyperattenuating foci and management and (b) the presence of contained vascular injury or active extravasation and management. RESULTS: Portal venous phase CT revealed a focal high-attenuation parenchymal contrast material collection in 19 patients: nine patients were classified as group 1 and 10 were classified as group 2. All patients in group 1 underwent emergent splenectomy, and all patients in group 2 were initially treated without surgery. Significant differences in management were noted on the basis of whether hyperattenuating foci were seen on portal venous phase images (P < .001) and whether hyperattenuating foci seen at portal venous phase imaging were further characterized as active splenic hemorrhage or a contained vascular injury at delayed-phase CT (P < .001). CONCLUSION: In blunt splenic injury, delayed-phase CT helps differentiate patients with active splenic hemorrhage from those with contained vascular injuries.

Blunt abdominal trauma: utility of 5-minute delayed CT with a reduced radiation dose.

PURPOSE: To retrospectively evaluate the utility of 5-minute delayed computed tomography (CT) of the abdomen and pelvis by using a reduced radiation dose in patients with blunt abdominal trauma. MATERIALS AND METHODS: Institutional review board consent was obtained, and written informed consent was waived. The study was HIPAA compliant. A total of 662 patients (497 men, 165 women; mean age, 40.5 years; range, 18-94 years) were identified who were evaluated with CT after blunt abdominal trauma during a 1-year period. Delayed CT scans were acquired 5 minutes after intravenous contrast material injection by using a decreased tube current of 100 mAs. Injury was identified in 106 patients. Two radiologists blinded to initial CT scan interpretation reviewed these cases to determine the quality and utility of delayed scans. Disagreement was settled by consensus. Delayed scans were considered useful when they aided in (a) characterizing initial CT findings, (b) identifying findings not present at initial CT, (c) excluding injury suggested at initial CT, and (d) increasing reader confidence with regard to initial CT findings. RESULTS: All delayed scans were diagnostic. Delayed scans were useful in 27% (12 of 44) of patients with solid organ injury, 5.9% (one of 17) of patients with bowel or mesenteric injury, 4.5% (one of 22) of patients with pelvic fractures, and in none of the patients with free fluid only. Overall, delayed CT was useful in 2.1% (14 of 662) of all patients (95% confidence interval: 1.0, 3.2) referred for evaluation following blunt abdominal trauma. Utility increased to 13.2% (14 of 106) (95% confidence interval: 6.8, 19.7) in the group of patients with injury or suspected of having injury after initial CT. CONCLUSION: If delayed CT scans are acquired when patients with blunt abdominal trauma are evaluated, selective, rather than routine, acquisition is recommended and a reduced radiation dose seems adequate.