Search results for: tissue regeneration.

Authors: Anna Perrone, Federico Martinelli

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Olive fruit is well-known for the high content in secondary metabolites with high interest at nutritional, nutraceutical, antioxidant, and healthy levels. The content of secondary metabolites in olive at harvest may be affected by different water regimes, with significant effects on olive oil composition and quality and, consequently, on its healthy and nutritional features. In this work, a summary of several research studies dealing with the biosynthesis of healthy and nutraceutical metabolites of the secondary metabolism in olive fruit will be reported. The phytochemical findings have been correlated with the expression of key genes involved in polyphenol, terpenoid, and carotenoid biosynthesis and metabolism in response to different development stages and water regimes. Flavonoids were highest in immature fruits, while anthocyanins increased at ripening. In epicarp tissue, this was clearly associated with an up-regulation of the UFGT gene. Olive fruits cultivated under different water regimes were analyzed by metabolomics. This method identified several hundred metabolites in the ripe mesocarp. Among them, 46 were differentially accumulated in the comparison between rain-fed and irrigated conditions. Well-known healthy metabolites were more abundant at a higher level of water regimes. Increased content of polyphenols was observed in the rain-fed fruit; particularly, anthocyanin concentration was higher at ripening. Several secondary metabolites were differentially accumulated between different irrigation conditions. These results showed that these metabolic approaches could be efficiently used to determine the effects of agronomic treatments on olive fruit physiology and, consequently, on nutritional and healthy properties of the obtained extra-virgin olive oil.

Keywords: olea europea, anthocyanins, polyphenols, water regimes

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Authors: Monthon Tangjitmungman

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Numerous diseases have been linked to oxidative stress, in which a disproportion of free radicals in the body leads to tissue or cell damage. Polyphenols are the most abundant antioxidants found in plants, and they are highly effective at scavenging oxidative free radicals. Due to the presence of phenolic compounds in Caesalpinia sappan has been discovered to have antioxidant activity. It has several health benefits, the most important of which is preventing cardiovascular and cancer diseases. This study aimed to determine the phenolic content and antioxidant activity of C. sappan extract using a variety of antioxidant assays. The extract of C. sappan was made using a mixture of solvents (ethyl alcohol: water in ratio 8:2). The total phenolic content of C. sappan extract was determined and expressed as gallic acid equivalents using the Folin-Cioucalteu method (GAE). The antioxidant activity of C. sappan extract was assessed using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay and the ABTS radical scavenging capacity assay. An association was found between antioxidant activity and total phenol content. The antioxidant activity of C. sappan extract was also determined by DPPH and ABTS assays. The IC50 values for C. sappan extract from DPPH and ABTS assays were 54.48 μg/mL ± 0.545 and 25.46 μg/mL ± 0.790, respectively, in the DPPH assay. In the DPPH assay, vitamin C was used as a positive control, whereas Trolox was used as a positive control in the ABTS assay. In conclusion, C. sappan extract contains a high level of total phenolics and exhibits significant antioxidant activity. Nevertheless, more research should be done on the antioxidant activity, such as SOD and ROS scavenging assays and in vivo experiments, to determine whether the compound has antioxidant activity.

Keywords: ABTS assay, antioxidant activity, Caesalpinia sappan, DPPH assays, total phenolic content

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Authors: Abdullah Abdu Qaseem Shamsan

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Background: Gliomas represent the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy is an established procedure for tumor cell sampling that aids diagnosis, tumor grading, and prediction of prognosis. We studied and compared the levels of liquid biopsy markers in patients with different grades of glioma. Also, it tried to establish the potential association between glioma and specific blood groups antigen. Result: 78 patients were identified, among whom maximum percentage with glioblastoma possessed blood group O+ (53.8%). The second highest frequency had blood group A+ (20.4%), followed by B+ (9.0%) and A- (5.1%), and least with O-. Liquid biopsy biomarkers comprised of ALT, LDH, lymphocytes, Urea, Alkaline phosphatase, AST Neutrophils, and CRP. The levels of all the components increased significantly with the severity of glioma, with maximum levels seen in glioblastoma (grade IV), followed by grade III and grade II respectively. Conclusion: Gliomas possess significant clinical challenges due to their progression with heterogeneous nature and aggressive behavior. Liquid biopsy is a non-invasive approach which aids to establish the status of the patient and determine the tumor grade, therefore may show diagnostic and prognostic utility. Additionally, our study provides evidence to demonstrate the role of ABO blood group antigens in the development of glioma. However, future clinical research on liquid biopsy will improve the sensitivity and specificity of these tests and validate their clinical usefulness to guide treatment approaches.

Keywords: GBM: glioblastoma multiforme, CT: computed tomography, MRI: magnetic resonance imaging, ctRNA: circulating tumor RNA

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Authors: Aisling Eves, Andrew Pieri, Ross McLean, Nerys Forester

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Background: The breast unit local guideline recommends that 12 cores should be used in a stereotactic-guided biopsy to diagnose DCIS. Twelve cores are regarded to provide good diagnostic value without removing more breast tissue than necessary. This study aimed to determine compliance with guidelines and investigated how the number of cores impacted upon the re-excision rate and size discrepancies. Methods: This single-centre retrospective cohort study of 72 consecutive breast screened patients with <15mm DCIS on radiological report underwent stereotactic-guided core biopsy and subsequent surgical excision. Clinical, radiological, and histological data were collected over 5 years, and ASCO guidelines for margin involvement of <2mm was used to guide the need for re-excision. Results: Forty-six (63.9%) patients had <12 cores taken, and 26 (36.1%) patients had ≥12 cores taken. Only six (8.3%) patients had 12 cores taken in their stereotactic biopsy. Incomplete surgical excision was seen in 17 patients overall (23.6%), and of these patients, twelve (70.6%) had fewer than 12 cores taken (p=0.55 for the difference between groups). Mammogram and biopsy underestimated the size of the DCIS in this subgroup by a median of 15mm (range: 6-135mm). Re-excision was required in 9 patients (12.5%), and five patients (6.9%) were found to have invasive ductal carcinoma on excision (80% had <12 cores, p=0.43). Discussion: There is poor compliance with the breast unit local guidelines and higher rates of re-excision in patients who did not have ≥12 cores taken. Taking ≥12 cores resulted in fewer missed invasive cancers lower incomplete excision and re-excision rates.

Keywords: stereotactic core biopsy, DCIS, breast screening, Re-excision rates, core biopsy

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Authors: Nuralam Sam, Irawan Yusuf, Irfan Idris, Endi Adnan

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The most case in the shoulder in the the adult is the frozen shoulder. It make an uncomfortable sensation which disturbance daily activity. The studies of frozen shoulder are still limited. This study used a true experimental pre and post test design with a group design. The participant underwent dextrose prolotherapy injection in the rotator cuff, intraarticular glenohumeral joint, long head tendon biceps, and acromioclavicular joint injections with 15% dextrose, respectively, at week 2, week 4, and week 6. Participants were followed for 12 weeks. The specific biomarker MMP and TIMP, ROM, DASH score were measured at baseline, at week 6, and week 12. The data were analyzed by multivariate analysis (repeated measurement ANOVA, Paired T-Test, and Wilcoxon) to determine the effect of the intervention. The result showed a significant decrease in The Disability of the Arm, Shoulder, and Hand (DASH) score in prolo injection patients in each measurement week (p < 0.05). While the measurement of Range of Motion (ROM), each direction of shoulder motion showed a significant difference in average each week, from week 0 to week 6 (p <0.05).Dextrose prolotherapy injection results give a significant improvement in functional outcome of the shoulder joint, and ROMand did not show significant results in assessing the specific biomarker, MMP-1, and TIMP-1 in tissue repair. This study suggestion an alternative to the use of injection prolotherapy in Frozen shoulder patients, which has fewer side effects and better effectiveness than the use of corticosteroid injections.

Keywords: frozen shoulder, ROM, DASH score, prolotherapy, MMP-1, TIMP-1

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Authors: Hamzeh Alipour, Masoumeh Bagheri, Abbasali Raz, Javad Dadgar Pakdel, Kourosh Azizi, Aboozar Soltani, Mohammad Djaefar Moemenbellah-Fard

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Background: Maggot debridement therapy is an appropriate, effective, and controlled method using sterilized larvae of Luciliasericata (L.sericata) to treat wounds. Netrin-A is an enzyme in the Laminins family which secreted from salivary gland of L.sericata with a central role in neural regeneration and angiogenesis. This study aimed to production of new recombinant Netrin-A protein of Luciliasericata larvae by baculovirus expression vector system (BEVS) in SF9. Material and methods: In the first step, gene structure was subjected to the in silico studies, which were include determination of Antibacterial activity, Prion formation risk, homology modeling, Molecular docking analysis, and Optimization of recombinant protein. In the second step, the Netrin-A gene was cloned and amplified in pTG19 vector. After digestion with BamH1 and EcoR1 restriction enzymes, it was cloned in pFastBac HTA vector. It was then transformed into DH10Bac competent cells, and the recombinant Bacmid was subsequently transfected into insect Sf9 cells. The expressed recombinant Netrin-A was thus purified in the Ni-NTA agarose. This protein evaluation was done using SDS-PAGE and western blot, respectively. Finally, its concentration was calculated with the Bradford assay method. Results: The Bacmid vector structure with Netrin-A was successfully constructed and then expressed as Netrin-A protein in the Sf9 cell lane. The molecular weight of this protein was 52 kDa with 404 amino acids. In the in silico studies, fortunately, we predicted that recombinant LSNetrin-A have Antibacterial activity and without any prion formation risk.This molecule hasa high binding affinity to the Neogenin and a lower affinity to the DCC-specific receptors. Signal peptide located between amino acids 24 and 25. The concentration of Netrin-A recombinant protein was calculated to be 48.8 μg/ml. it was confirmed that the characterized gene in our previous study codes L. sericata Netrin-A enzyme. Conclusions: Successful generation of the recombinant Netrin-A, a secreted protein in L.sericata salivary glands, and because Luciliasericata larvae are used in larval therapy. Therefore, the findings of the present study could be useful to researchers in future studies on wound healing.

Keywords: blowfly, BEVS, gene, immature insect, recombinant protein, Sf9

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Authors: Sadam Elayah

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Background: One of the most critical competencies in advanced dentistry is alveolar ridge preservation after exodontia. The aim of this clinical trial was to assess the impact of autologous concentrated growth factor (CGF) as a socket-filling material and its ridge preservation properties following the lower third molar extraction. Materials and Methods: A total of 60 sides of 30 participants who had completely symmetrical bilateral impacted lower third molars were enrolled. The short-term outcome variables were wound healing, swelling and pain, clinically assessed at different time intervals (1st, 3rd & 7th days). While the long-term outcome variables were bone height & width, bone density and socket surface area in the coronal section. Cone beam computed tomography images were obtained immediately after surgery and three months after surgery as a temporal measure. Randomization was achieved by opaque, sealed envelopes. Follow-up data were compared to baseline using Paired & Unpaired t-tests. Results: The wound healing index was significantly better in the test sides (P =0.001). Regarding the facial swelling, the test sides had significantly fewer values than the control sides, particularly on the 1st (1.01±.57 vs 1.55 ±.56) and 3rd days (1.42±0.8 vs 2.63±1.2) postoperatively. Nonetheless, the swelling disappeared within the 7th day on both sides. The pain scores of the visual analog scale were not a statistically significant difference between both sides on the 1st day; meanwhile, the pain scores were significantly lower on the test sides compared with the control sides, especially on the 3rd (P=0.001) and 7th days (P˂0.001) postoperatively. Regarding long-term outcomes, CGF sites had higher values in height and width when compared to Control sites (Buccal wall 32.9±3.5 vs 29.4±4.3 mm, Lingual wall 25.4±3.5 vs 23.1±4 mm, and Alveolar bone width 21.07±1.55vs19.53±1.90 mm) respectively. Bone density showed significantly higher values in CGF sites than in control sites (Coronal half 200±127.3 vs -84.1±121.3, Apical half 406.5±103 vs 64.2±158.6) respectively. There was a significant difference between both sites in reducing periodontal pockets. Conclusion: CGF application following surgical extraction provides an easy, low-cost, and efficient option for alveolar ridge preservation. Thus, dentists may encourage using CGF during dental extractions, particularly when alveolar ridge preservation is required.

Keywords: platelet, extraction, impacted teeth, alveolar ridge, regeneration, CGF

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Authors: Abraham Dayan

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Remediation of soil containing volatile contaminants is often conducted by vapor extraction (SVE) technique. The operation is based on injection of air at ambient temperatures with or without thermal soil warming. Thermal enhancements of soil vapor extraction (TESVE) processes are usually conducted by soil heating, sometimes assisted by added steam injections. The current study addresses a technique which has not received adequate attention and is based on using exclusively hot air as an alternative to the common TESVE practices. To demonstrate the merit of the hot air TESVE technique, a sandy soil containing contaminated water is studied. Numerical and analytical tools were used to evaluate the rate of decontamination processes for various geometries and operating conditions. The governing equations are based on the Darcy law and are applied to an expanding compressible flow within a sandy soil. The equations were solved to determine the minimal time required for complete soil remediation. An approximate closed form solution was developed based on the assumption of local thermodynamic equilibrium and on a linearized representation of temperature dependence of the vapor to air density ratio. The solution is general in nature and offers insight into the governing processes of the soil remediation operation, where self-similar temperature profiles under certain conditions may exist, and the noticeable role of the contaminants evaporation and recondensation processes in affecting the remediation time. Based on analyses of the hot air TESVE technique, it is shown that it is sufficient to heat the air during a certain period of the decontamination process without compromising its full advantage, and thereby, entailing a minimization of the air-heating-energy requirements. This in effect is achieved by regeneration, leaving the energy stored in the soil during the early period of the remediation process to heat the subsequently injected ambient air, which infiltrates through it for the decontamination of the remaining untreated soil zone. The characteristic time required to complete SVE operations are calculated as a function of, both, the injected air temperature and humidity. For a specific set of conditions, it is demonstrated that elevating the injected air temperature by 20oC, the hot air injection technique reduces the soil remediation time by 50%, while requiring 30% of additional energy consumption. Those evaluations clearly unveil the advantage of the hot air SVE process, which for insignificant cost of added air heating energy, the substantial cost expenditures for manpower and equipment utilization are reduced.

Keywords: Porous Media, Soil Decontamination, Hot Air, Vapor Extraction

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Authors: Cherifi Katia, Al-Hawat Marie-Lynn, Tricou Leo-Paul, Lamontagne Stephanie, Tran Minh, Ngu Amy Ching Yie, Manrique Gabriela, Guirguis Natalie, Machuca Parra Arturo Israel, Matoori Simon

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Diabetic foot ulcers (DFUs) are a serious and prevalent complication of diabetes. Current diagnostic options are limited to macroscopic wound analysis such as wound size, depth, and infection. Molecular diagnostics promise to improve DFU diagnosis, staging, and assessment of treatment response. Here, we developed a rapid and easy-to-use fluorescent pH-sensing bandage for wound diagnostics. In a fluorescent dye screen, we identified pyranine as the lead compound due to its suitable pH-sensing properties in the clinically relevant pH range of 6 to 9. To minimize the release of this dye into the wound bed, we screened a library of ionic microparticles and found a strong adhesion of the anionic dye to a cationic polymeric microparticle. These dye-loaded microparticles showed a strong fluorescence response in the clinically relevant pH range of 6 to 9 and a dye release below 1% after one day in biological media. The dye-loaded microparticles were subsequently encapsulated in a calcium alginate hydrogel to minimize the interaction of the microparticles with the wound tissue. This pH-sensing diagnostic wound dressing was tested on full-thickness dorsal wounds of mice, and a linear fluorescence response (R2 = 0.9909) to clinically relevant pH values was observed. These findings encourage further development of this pH-sensing system for molecular diagnostics in DFUs.

Keywords: wound ph, fluorescence, diagnostics, diabetic foot ulcer, wound healing, chronic wounds, diabetes

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Authors: Kanchan Yadav, Ai-Chuan Chou, Rajesh Kumar Ulaganathan, Hua-De Gao, Hsien-Ming Lee, Chien-Yuan Pan, Yit-Tsong Chen

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Optogenetics is an innovative technology now widely adopted by researchers in different fields of the biological sciences. However, due to the weak tissue penetration capability of the short wavelengths used to activate light-sensitive proteins, an invasive light guide has been used in animal studies for photoexcitation of target tissues. Upconverting nanoparticles (UCNPs), which transform near-infrared (NIR) light to short-wavelength emissions, can help address this issue. To improve optogenetic performance, we enhance the target selectivity for optogenetic controls by specifically conjugating the UCNPs with light-sensitive proteins at a molecular level, which shortens the distance as well as enhances the efficiency of energy transfer. We tagged V5 and Lumio epitopes to the extracellular N-terminal of channelrhodopsin-2 with an mCherry conjugated at the intracellular C-terminal (VL-ChR2m) and then bound NeutrAvidin-functionalized UCNPs (NAv-UCNPs) to the VL-ChR2m via a biotinylated antibody against V5 (bV5-Ab). We observed an apparent energy transfer from the excited UCNP (donor) to the bound VL-ChR2m (receptor) by measuring emission-intensity changes at the donor-receptor complex. The successful patch-clamp electrophysiological test and an intracellular Ca2+ elevation observed in the designed UCNP-ChR2 system under optogenetic manipulation confirmed the practical employment of UCNP-assisted NIR-optogenetic functionality. This work represents a significant step toward improving therapeutic optogenetics.

Keywords: Channelrhodopsin-2, near infrared, optogenetics, upconverting nanoparticles

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Authors: R. Tajau, R. Rohani, M. S. Alias, N. H. Mudri, K. A. Abdul Halim, M. H. Harun, N. Mat Isa, R. Che Ismail, S. Muhammad Faisal, M. Talib, M. R. Mohamed Zin

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Bio-based polymeric materials are increasingly used for a variety of applications, including surface coating, drug delivery systems, and tissue engineering. These polymeric materials are ideal for the aforementioned applications because they are derived from natural resources, non-toxic, low-cost, biocompatible, and biodegradable, and have promising thermal and mechanical properties. The nature of hydrocarbon chains, carbon double bonds, and ester bonds allows various sources of oil (edible), such as soy, sunflower, olive, and oil palm, to fine-tune their particular structures in the development of innovative materials. Palm oil can be the most eminent raw material used for manufacturing new and advanced natural polymeric materials involving radiation techniques, such as coating resins, nanoparticles, scaffold, nanotubes, nanocomposites, and lithography for different branches of the industry in countries where oil palm is abundant. The radiation technique is among the most versatile, cost-effective, simple, and effective methods. Crosslinking, reversible addition-fragmentation chain transfer (RAFT), polymerisation, grafting, and degradation are among the radiation mechanisms. Exposure to gamma, EB, UV, or laser irradiation, which are commonly used in the development of polymeric materials, is used in these mechanisms. Therefore, this review focuses on current radiation processing technologies for the development of various radiation-curable bio-based polymeric materials with a promising future in biomedical and industrial applications. The key focus of this review is on radiation curable palm oil-based products, which have been published frequently in recent studies.

Keywords: palm oil, radiation processing, surface coatings, VOC

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Authors: Ayda Youssef, Mohammed Ali Khalaf, Tarek Rafaat

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Background: Langerhans cell histiocytosis (LCH) is a rare multi-systemic disease that shows an abnormal proliferation of these kinds of cells associated with a granular infiltration that affects different structures of the human body, including the lung, liver, spleen, lymph nodes, brain, mucocutaneous, soft tissue (head and neck), and salivary glands. Evaluation of the extent of disease is one of the major predictors of patient outcome. Objectives: To recognize the pathogenesis of Langerhans cell histiocytosis (LCH), describe the radiologic criteria that are suggestive of LCH in different organs rather than the bones and to illustrate the appropriate differential diagnoses for LCH in each of the common extra-osseous sites. Material and methods: A retrospective study was done on 150 biopsy-proven LCH patients from 2007 to 2012. All patients underwent imaging studies, mostly US, CT, and MRI. These patients were reviewed to assess the extra-skeletal manifestations of LCH. Results: In 150 patients with biopsy-proven LCH, There were 33 patients with liver affection, 5 patients with splenic lesions, 55 patients with enlarged lymph nodes, 9 patient with CNS disease and 11 patients with lung involvement. Conclusions: Because of the frequent LCH children and evaluation of the extent of disease is one of the major predictors of patient outcome. Radiologist need to be familiar with its presentation in different organs and regions of body outside the commonest site of affection (bones). A high-index suspicion should be raised a biopsy is recommended in the presence of radiological suspicion. Chemotherapy is the preferred therapeutic modality.

Keywords: langerhans cell histiocytosis, extra-skeletal, pediatrics, radiology

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Authors: Nashwa A. Mohamed

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Introduction: Omeprazole is a proton pump inhibitor used commonly in the treatment of acid-peptic disorders. Although omeprazole is generally well tolerated, serious adverse effects such as renal failure have been reported. Ginger is an antioxidant that could play a protective role in models of experimentally induced nephropathies. Aim of the work: The aim of this work was to study the possible histological changes induced by omeprazole on renal cortex and evaluate the possible protective effect of ginger on omeprazole-induced renal damage in adult male albino rats. Materials and methods: Twenty-four adult male albino rats divided into four groups (six rats each) were used in this study. Group I served as the control group. Rats of group II received only an aqueous extract of ginger daily for 3 months through a gastric tube. Rats of group III were received omeprazole orally through a gastric tube for 3 months. Rats of group IV were given both ginger and omeprazole at the same doses and through the same routes as the previous two groups. At the end of the experiment, the rats were sacrificed. Renal tissue samples were processed for light, immunohistochemical and electron microscopic examination. The obtained results were analysed morphometrically and statistically. Results: Omeprazole caused several histological changes in the form of loss of normal appearance of renal cortex with degenerative changes in the renal corpuscle and tubules. Cellular infilteration was also observed. The filteration barrier was markedly affected. Ginger ameliorated the omeprazole-induced histological changes. Conclusion: Omeprazole induced injurious effects on renal cortex. Coadministration of ginger can ameliorate the histological changes induced by omeprazole.

Keywords: ginger, kidney, omeprazole, rat

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Authors: Alaa Hamed Habib

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The Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated with systemic inflammation. Inflammation is an important process that follows infection and facilitates the repair of damaged tissue. Polyunsaturated fatty acids play an important role in the inflammatory process. These lipids can target transcription factors to modulate gene expression and protein function. Here, we evaluated whether differences in basal levels of different types of biomarkers can be detected in freshly frozen plasma samples from patients with and without COVID19. Fatty acid methyl ester (FAME) analysis showed a decrease in arachidic acid and myristic acid, but an increase in caprylic acid, palmitic acid, and eicosenoic acid in the plasma of COVID-19 patients compared to non-COVID19 patients. Multiple chemokines, including IP-10, MCP-1, and MIP-1 beta, were increased in the COVID-19 group compared to the non-COVID-19 group. Similarly, cytokines including IL-1 alpha and IL-8, and cell adhesion and inflammatory response markers including ICAM-1 and E-selectin were greater in the plasma of COVID-19 patients compared to non-COVID-19 patients. A baseline signature of specific polyunsaturated fatty acids, cytokines, and chemokines present in the plasma after COVID-19 viral infection may serve as biomarkers that can be useful in various applications, including determination of the severity of infection, an indication of disease prognosis and consideration for therapeutic options.

Keywords: MARKS, COVID 19, UEVS NON COVIDS, kidneys, nanoparticles

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Authors: Evangelos Koumparoudis

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The definition of death is a deep philosophical question, and no single meaning can be ascribed to it. This essay focuses on the ontological, epistemological, and ethical aspects of death and dying in view of technological progress in information technology and biomedicine. It starts with the ad hoc 1968 Harvard committee that proposed that the criterion for the definition of death be irreversible coma and then refers to the debate over the whole brain death formula, emphasizing the integrated function of the organism and higher brain formula, taking consciousness and personality as essential human characteristics. It follows with the contribution of information technology in personalized and precision medicine and anti-aging measures aimed at life prolongation. It also touches on the possibility of the creation of human-machine hybrids and how this raises ontological and ethical issues that concern the “cyborgization” of human beings and the conception of the organism and personhood based on a post/transhumanist essence, and, furthermore, if sentient AI capable of autonomous decision-making that might even surpass human intelligence (singularity, superintelligence) deserves moral or legal personhood. Finally, there is the question as to whether death and dying should be redefined at a transcendent level, which is reinforced by already-existing technologies of “virtual after-” life and the possibility of uploading human minds. In the last section, I refer to the current (and future) applications of nanomedicine in diagnostics, therapeutics, implants, and tissue engineering as well as the aspiration to “immortality” by cryonics. The definition of death is reformulated since age and disease elimination may be realized, and the criterion of irreversibility may be challenged.

Keywords: death, posthumanism, infomedicine, nanomedicine, cryonics

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Authors: Y. Kumru, K. Enhos, H. Köymen

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In this paper, we report the experimental results on using complementary Golay coded signals at 7.5 MHz to detect breast microcalcifications of 50 µm size. Simulations using complementary Golay coded signals show perfect consistence with the experimental results, confirming the improved signal to noise ratio for complementary Golay coded signals. For improving the success on detecting the microcalcifications, orthogonal complementary Golay sequences having cross-correlation for minimum interference are used as coded signals and compared to tone burst pulse of equal energy in terms of resolution under weak signal conditions. The measurements are conducted using an experimental ultrasound research scanner, Digital Phased Array System (DiPhAS) having 256 channels, a phased array transducer with 7.5 MHz center frequency and the results obtained through experiments are validated by Field-II simulation software. In addition, to investigate the superiority of coded signals in terms of resolution, multipurpose tissue equivalent phantom containing series of monofilament nylon targets, 240 µm in diameter, and cyst-like objects with attenuation of 0.5 dB/[MHz x cm] is used in the experiments. We obtained ultrasound images of monofilament nylon targets for the evaluation of resolution. Simulation and experimental results show that it is possible to differentiate closely positioned small targets with increased success by using coded excitation in very weak signal conditions.

Keywords: coded excitation, complementary golay codes, DiPhAS, medical ultrasound

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Authors: Shukla Ila, Azmi Lubna, S. S. Gupta, Ch. V. Rao

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Oxidative stress has been increasingly associated with the induction and progression of liver damage. The current study was conducted to record the effect of combination of Lactobacillus and Lichen rangiferinus extract (LRE + Lac) on the severity of injury in experimental alcoholic liver disease and how it affects plasma levels of prostaglandin E2, endotoxin, thromboxane B2, and leukotriene B4. Male Wistar rats were grouped into five comprising six animals in each group. Group 1 served as negative control. Groups 2-5 were administered 10% ethanol for six weeks. Group 3 was administered with extract (200 mg/kg), group 4 received the diet containing 10% ethanol plus a bolus of lactobacilli GG (1010 CFU), and group 5 animals were given silymarin along with alcohol and it served as positive control. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein content, γ-glutamyltransferase, glutathione S-transferase, oxidative stress markers, glutathione, malondialdehyde and glutathione reductase were determined using standard diagnostic kits. Histopathological analysis of liver tissue was also made. A positive relation was found between plasma endotoxin levels and degree of liver injury. The pathology records were also related positively with leukotriene B4 and thromboxane B2. But a negative correlation was obtained with PgE2 levels. This study led us to hypothesize that the increased endotoxin levels modulate liver metabolism of eicosanoid, which gradually leads to liver injury. Endotoxemia increases leukotriene and thromboxane levels in plasma.

Keywords: lactobacillus, Lichen rangiferinus, endotoxemia, silymarin

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Authors: Bhuwan C. Joshi, Atish Prakash, Ajudhia N. Kalia

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Ethnopharmacological relevance: The plant Urtica dioica L. (Urticaceae) is used in various diseases including hepatic ailments. Traditionally, the leaves and roots of the plant are used in jaundice. Objective: The aim of the present work was to evaluate hepatoprotective potential of potent antioxidant from Urtica dioica L. against CCl4 induced hepatotoxicity in-vitro and in-vivo model. Materials and methods: Antioxidant activity of hydro alcoholic extract and its fractions petroleum ether fraction (PEF), ethyl acetate fraction (EAF), n-butanol fraction (NBF) and aqueous fraction (AF) were determined by DPPH radicals scavenging assay. Fractions were subjected to in-vitro cell line study. Further, the most potent fraction (EAF) was subjected to in-vivo study. The in-vivo hepatoprotective active fraction was chromatographed on silica column to isolate the bioactive constituent(s). Structure elucidation was done by using various spectrophotometric techniques like UV, IR, 1H NMR, 13C NMR and MS spectroscopy. Results and conclusion: The ethyl acetate fraction (EAF) of Urtica. dioica L. possessed the potent antioxidant activity viz. DPPH (IC50 78.99 ± 0.17 µg/ml). The in-vitro cell line study showed EAF prevented the cell damage. The EAF significantly attenuated the increased liver enzymes activities in serum and tissue. Column chromatography of most potent antioxidant fraction (EAF) leads to the isolation of 4-hydroxy-3-methoxy cinnamic acid which is responsible for its hepatoprotective potential. Hence, the present study suggests that EAF has significant antioxidant and hepatoprotective potential on CCl4 induced hepatotoxicity in-vitro and in-vivo.

Keywords: Urtica dioica L., antioxidant, HepG2 cell line, hepatoprotective

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Authors: Salina Saddick, Mohamed Afifi, Osama Abuznadah

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This study was carried out to determine the median lethal concentrations (LC50) of Zinc nanoparticles (ZnNPs) on Oreochromis niloticus and Tilapia zillii. The biochemical and molecular potential effects of ZnNPs (500 and 2000 μg L−1) on the antioxidant system in the brain tissue of O. niloticus and T. zillii were investigated. Four hundred fish were used for acute and sub-acute studies. ZnNP LC50 concentrations were investigated in O. niloticus and T. zillii. The effect of 500 and 2000 μg L−1 ZnNPs on brain antioxidants of O. niloticus and T. zillii was investigated. The result indicated that 69 h LC50 was 5.5 ± 0.6 and 5.6 ± 0.4 for O. nilotica and T. zillii, respectively. Fish exposed to 500 μg L−1 ZnNPs showed a significant increase in reduced glutathione (GSH), total glutathione (tGSH) levels, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activity and gene expression. On the contrary, malondialdehyde (MDA) levels significantly decreased. Meanwhile, fish exposed to 2000 μg L−1 ZnNPs showed a significant decrease of GSH, tGSH levels, SOD, CAT, GR, GPx and GST activity and gene expression. On the contrary, MDA levels significantly increased. It was concluded that, the 96 h LC50 of ZnNPs was 5.5 ± 0.6 and 5.6 ± 0.4 for O. nilotica and T. zillii, respectively. ZnNPs in exposure concentrations of 2000 μg/L induced a deleterious effect on the brain antioxidant system of O. nilotica and T. zillii. In contrast, ZnNPs in exposure concentrations of 500 μg L−1 produced an inductive effect on the brain antioxidant system of O. nilotica and T. zillii.

Keywords: ZnNPs, LC50, antioxidants, O. nilotica

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Authors: Mehrnaz Aminitabar, Moghan Amirhosseinian, Morteza Elsa

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Bioactive glasses (BGs) are a group of surface-reactive biomaterials used in clinical applications as implants or filler materials in the human body to repair and replace diseased or damaged bone. Sol-gel technique was employed to prepare a SiO₂-CaO-P₂O₅ glass with nominal composition of 58S BG with the addition of Sr and Li modifiers which imparts special properties to the BG. The effect of simultaneous addition of Sr and Li on bioactivity and biocompatibility, proliferation, alkaline phosphatase (ALP) activity of osteoblast cell line MC3T3-E1 and antibacterial property against methicillin-resistant Staphylococcus aureus (MRSA) bacteria were examined. BGs were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy before and after soaking the samples in the simulated body fluid (SBF) for different time intervals to characterize the formation of hydroxyapatite (HA) formed on the surface of BGs. Structural characterization indicated that the simultaneous presence of 5% Sr and 5% Li in 58S-BG composition not only did not retard HA formation because of opposite effect of Sr and Li of the dissolution of BG in the SBF but also, stimulated the differentiation and proliferation of MC3T3-E1s. Moreover, the presence of Sr and Li on dissolution of the ions resulted in an increase in the mean number of DAPI-labeled nuclei which was in good agreement with live/dead assay. The result of antibacterial tests revealed that Sr and Li-substituted 58S BG exhibited a potential antibacterial effect against MRSA bacteria. Because of optimal proliferation and ALP activity of MC3T3-E1cells, proper bioactivity and high antibacterial potential against MRSA, BG-5/5 is suggested as a multifunctional candidate for bone tissue engineering.

Keywords: antibacterial activity, bioactive glass, sol-gel, strontium

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Authors: Hansraj Riteesh Bookun, Emily Maree Stevens, Jarryd Leigh Solomon, Anthony Chan

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Objective: This was a retrospective cross-sectional study evaluating the safety and efficacy of femoral endarterectomy using the eversion technique with transection as opposed to the conventional endarterectomy technique with either vein or synthetic patch arterioplasty. Methods: Between 2010 to mid 2017, 19 patients with mean age of 75.4 years, underwent eversion femoral endarterectomy with transection by a single surgeon. There were 13 males (68.4%), and the comorbid burden was as follows: ischaemic heart disease (53.3%), diabetes (43.8%), stage 4 kidney impairment (13.3%) and current or ex-smoking (73.3%). The indications were claudication (45.5%), rest pain (18.2%) and tissue loss (36.3%). Results: The technical success rate was 100%. One patient required a blood transfusion following bleeding from intraoperative losses. Two patients required blood transfusions from low post operative haemogloblin concentrations – one of them in the context of myelodysplastic syndrome. There were no unexpected returns to theatre. The mean length of stay was 11.5 days with two patients having inpatient stays of 36 and 50 days respectively due to the need for rehabilitation. There was one death unrelated to the operation. Conclusion: The eversion technique with transection is safe and effective with low complication rates and a normally expected length of stay. It poses the advantage of not requiring a synthetic patch. This technique features minimal extraneous dissection as there is no need to harvest vein for a patch. Additionally, future endovascular interventions can be performed by puncturing the native vessel. There is no change to the femoral bifurcation anatomy after this technique. We posit that this is a useful adjunct to the surgeon’s panoply of vascular surgical techniques.

Keywords: endarterectomy, eversion, femoral, vascular

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Authors: P. Dey, S. K. Pal

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Ceramics or glass ceramics with the property of bone bonding at the nearby tissues and producing possible bone in growth are known to be bioactive. The most extensively used glass in this context is 45S5 which is a silica based bioglass mostly explored in the field of tissue engineering as scaffolds for bone repair. Nowadays, the borate based bioglass are being utilized in orthopedic area largely due to its superior bioactivity with the formation of bone bonding. An attempt has been made, in the present study, to observe the effect of B2O3 addition in 45S5 glass and perceive its consequences on the thermal, mechanical and biological properties. The B2O3 was added in 1, 2.5, and 5 wt% with simultaneous reduction in the silica content of the 45S5 composition. The borate based bioglass has been synthesized by the means of sol-gel route. The synthesized powders were then thermally analyzed by DSC-TG. The as synthesized powders were then calcined at 600ºC for 2hrs. The calcined powders were then pressed into pellets followed by sintering at 850ºC with a holding time of 2hrs. The phase analysis and the microstructural analysis of the as synthesized and calcined powder glass samples and the sintered glass samples were being carried out using XRD and FESEM respectively. The formation of hydroxyapatite layer was performed by immersing the sintered samples in the simulated body fluid (SBF) and mechanical property has been tested for the sintered samples by universal testing machine (UTM). The sintered samples showed the presence of sodium calcium silicate phase while the formation of hydroxyapaptite takes place for SBF immersed samples. The formation of hydroxyapatite is more pronounced in case of borated based glass samples instead of 45S5.

Keywords: 45S5 bioglass, bioactive, borate, hydroxyapatite, sol-gel synthesis

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Authors: Maurice Mbah

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Entomological survey of mosquitoes responsible for the transmission of lymphatic filariasis in Biase Local Government area of Cross River State, Nigeria within March and June 2017. Lymphatic filariasis is a mosquito-borne parasitic disease that is caused by three species of tissue dwelling filaroids (Wuchereria bancrofti; Brugia malayi; Brugia timori): Wuchereria bancrofti is responsible for 90% of cases and is found throughout the tropics and in some sub-tropical areas worldwide. The mosquitoes were caught using human landing catches, and pyrethrum spray catches method. The entomological analysis of mosquitoes which include speciating into genus and dissecting them to unveil any microfilaria in the thoracic region, abdomen, and mouth parts of the mosquitoes. Entomological analysis shows that, from the 1296 mosquitoes caught 795 (61.3%) were Culex species, 342 (26.4%) Anopheles species, 102 (7.9%) Aedes species, and 57 (4.4%) of other Genera. There was a statistically significant difference in the number of mosquitoes caught in the dry and rainy season (X²=0.62, P < 0.05). Out of 1213 mosquitoes dissected, 24(0.02%) contained developed stages (L₁ – L₃) of W. bancrofti larvae. 13 (0.01%) of the infected mosquitoes were of Culex species, and Anopheles species accounted for the other 11 (0.009%). There was a statistically significant difference in the infection rate between the two seasons (X²=0.87, P < 0.05). The correlation analysis showed a positive correlation between the infection rate among mosquitoes in the dry and rainy season (r=0.85, P < 0.05). The entomological studies showed that Anopheles species and the Culex species are the vectors of lymphatic filariasis in the study area.

Keywords: entomological survey, mosquitoes, lymphatic filariasis, biase

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Authors: Kolja Them, Johannes Salamon, Harald Ittrich, Michael Kaul, Tobias Knopp

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Superparamagnetic iron oxide nanoparticles (SPIONs) are nanoscale magnets which can be biologically functionalized for biomedical applications. Stem cell therapies to repair damaged tissue, magnetic fluid hyperthermia for cancer therapy and targeted drug delivery based on SPIONs are prominent examples where the visualization of a preferably low concentrated SPION distribution is essential. In 2005 a new method for tomographic SPION imaging has been introduced. The method named magnetic particle imaging (MPI) takes advantage of the nanoparticles magnetization change caused by an oscillating, external magnetic field and allows to directly image the time-dependent nanoparticle distribution. The SPION magnetization can be changed by the electron spin dynamics as well as by a mechanical rotation of the nanoparticle. In this work different calibration methods in MPI are investigated for image reconstruction of magnetically labeled stem cells. It is shown that a calibration using rotationally immobilized SPIONs provides a higher quality of stem cell images with fewer artifacts than a calibration using mobile SPIONs. The enhancement of the image quality and the reduction of artifacts enables the localization and identification of a smaller number of magnetically labeled stem cells. This is important for future medical applications where low concentrations of functionalized SPIONs interacting with biological matter have to be localized.

Keywords: biomedical imaging, iron oxide nanoparticles, magnetic particle imaging, stem cell imaging

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Authors: Mi Kyeong Yu, Seon Jeong Lee, So Young Kim, Bora Choi, Young Mi Lee, Su-Jung Cho, Je Tae Woo, Myung-Sook Choi

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A high-fat diet (HFD) induces excessive fat accumulation in white adipose tissue (WAT), which increases metabolic disorders such as obesity, dyslipidemia and type 2 diabetes. Many plants are known to have effects that improve metabolic disorders. Therefore, the aim of this present study is to investigate the effect of nepodin-enrich plant extract on dyslipidemia, hyperglycemia in high fat diet-induced C57BL/6J mice. Male C57BL/6J mice were randomly divided into two groups, and fed HFD (20% fat, w/w) or HFD supplemented with nepodin-enrich plant extract (NPE 0.005%, w/w) for 16 weeks. Body weight and food intake were measured every week. And we also analysed metabolic rates (respiratory quotient), blood glucose level, and plasma high-density lipoprotein (HDL)-cholesterol, free fatty acid, apolipoprotein (apo) A-1 and apo B levels. Food intakes and body weights were not different between NPE group and HFD group, while plasma apo B, free fatty acid levels, and blood glucose concentration were significantly decreased in NPE group than in HFD group. Furthermore, plasma apo A and HDL-cholesterol levels in NPE group were remarkably increased than in HFD group. Metabolic rates (respiratory quotient) were significantly increased in NPE group than in HFD group. These results indicate that NPE can alleviate dyslipidemia, hyperglycemia. Further studies are required to identify the effects of NPE on metabolic disorders.

Keywords: dyslipidemia, hyperglycemia, metabolic disorders, nepodin enrich plant extract

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Authors: Zonglin Yang, Tatsuya Akiyama, Kerry S. Williamson, Michael J. Franklin, Thiruvarangan Ramaraj

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Pseudomonas aeruginosa is an opportunistic pathogen that forms surface-associated microbial communities (biofilms) on artificial implant devices and on human tissue. Biofilm infections are difficult to treat with antibiotics, in part, because the bacteria in biofilms are physiologically heterogeneous. One measure of biological heterogeneity in a population of cells is to quantify the cellular concentrations of ribosomes, which can be probed with fluorescently labeled nucleic acids. The fluorescent signal intensity following fluorescence in situ hybridization (FISH) analysis correlates to the cellular level of ribosomes. The goals here are to provide computationally and statistically robust approaches to automatically quantify cellular heterogeneity in biofilms from a large library of epifluorescent microscopy FISH images. In this work, the initial steps were developed toward these goals by developing an automated biofilm detection approach for use with FISH images. The approach allows rapid identification of biofilm regions from FISH images that are counterstained with fluorescent dyes. This methodology provides advances over other computational methods, allowing subtraction of spurious signals and non-biological fluorescent substrata. This method will be a robust and user-friendly approach which will enable users to semi-automatically detect biofilm boundaries and extract intensity values from fluorescent images for quantitative analysis of biofilm heterogeneity.

Keywords: image informatics, Pseudomonas aeruginosa, biofilm, FISH, computer vision, data visualization

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Authors: Mustafa Al-Yaseen, Haider Mohammed Mahdi, Haider Ali Al–Zahid, Nazar S. Haddad

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Background: Early diagnosis of musculoskeletal infections is of vital importance to avoid devastating complications. There is no single laboratory marker which is sensitive and specific in diagnosing these infections accurately. White blood cell count, erythrocyte sedimentation rate, and C-reactive protein are not specific as they can also be elevated in conditions other than bacterial infections. Materials Culture and sensitivity is not a true gold standard due to its varied positivity rates. Serum Procalcitonin is one of the new laboratory markers for pyogenic infections. The objective of this study is to assess the value of PCT in the diagnosis of soft tissue, bone, and joint infections. Patients and Methods: Patients of all age groups (seventy-four patients) with a diagnosis of musculoskeletal infection are prospectively included in this study. All patients were subjected to White blood cell count, erythrocyte sedimentation rate, C-reactive protein, and serum Procalcitonin measurements. A healthy non infected outpatient group (twenty-two patients) taken as a control group and underwent the same evaluation steps as the study group. Results: The study group showed mean Procalcitonin levels of 1.3 ng/ml. Procalcitonin, at 0.5 ng/ml, was (42.6%) sensitive and (95.5%) specific in diagnosing of musculoskeletal infections with (positive predictive value of 87.5% and negative predictive value of 48.3%) and (positive likelihood ratio of 9.3 and negative likelihood ratio of 0.6). Conclusion: Serum Procalcitonin, at a cut – off of 0.5 ng/ml, is a specific but not sensitive marker in the diagnosis of musculoskeletal infections, and it can be used effectively to rule in the diagnosis of infection but not to rule out it.

Keywords: procalcitonin, infection, labratory markers, musculoskeletal

Procedia PDF Downloads 162

Authors: Seung Ju Yeon, Seul Ki Min, Jun Sang Park, Yeo Seon Kwon, Hoo Cheol Lee, Hyun Jung Shim, Il-Doo Kim, Ja Kyeong Lee, Hwa Sung Shin

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In brain injury, depleting oxidative stress is the most effective way to reduce the brain infarct size. C-phycocyanin (C-Pc) is a well-known antioxidant protein that has neuroprotective effects obtained from green microalgae. Astrocyte is glial cell that supports the nerve cell such as neuron, which account for a large portion of the brain. In brain injury, such as ischemia and reperfusion, astrocyte has an important rule that overcomes the oxidative stress and protect from brain reactive oxygen species (ROS) injury. However little is known about how C-Pc regulates the anti-oxidants effects of astrocyte. In this study, when the C-Pc was treated in oxidized astrocyte, we confirmed that inflammatory factors Interleukin-6 and Interleukin-3 were increased and antioxidants enzyme, Superoxide dismutase (SOD) and catalase was upregulated, and neurotrophic factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) was alleviated. Also, it was confirmed to reduce infarct size of the brain in ischemia and reperfusion because C-Pc has anti-oxidant effects in middle cerebral artery occlusion (MCAO) animal model. These results show that C-Pc can help astrocytes lead neuroprotective activities in the oxidative stressed environment of the brain. In summary, the C-PC protects astrocytes from oxidative stress and has anti-oxidative, anti-inflammatory, neurotrophic effects under ischemic situations.

Keywords: c-phycocyanin, astrocyte, reactive oxygen species, ischemia and reperfusion, neuroprotective effect

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Authors: Joana Mourão

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Transition to a low carbon economy requires changes in consumption and production patterns, including the improvement of existing buildings’ environmental performance. Urban rehabilitation is a top policy priority in Europe, creating an opportunity to increase this performance. However, urban rehabilitation comprises different typologies of interventions with distinct levels of consideration for cultural urban heritage values and for environmental values, thus with different impacts. Cities rely on both material and non-material forms of heritage that are deep-rooted and resilient. One of the most relevant parts of that urban heritage is the historical pre-industrial housing stock, with an extensive presence in many European cities, as Lisbon. This stock is rehabilitated and transformed at the framework of urban management and local governance traditions, as well as the framework of the global economy, and in that context, faces opportunities and threats that need evaluation and control. The scope of this article is to define methodological bases and research lines for the assessment of impacts that urban rehabilitation initiatives set on the vulnerable and historical pre-industrial urban housing stock, considering it as an environmental and cultural unreplaceable material value and resource. As a framework, this article reviews the concepts of urban regeneration, urban renewal, current buildings conservation and refurbishment, and energy refurbishment of buildings, seeking to define key typologies of urban rehabilitation that represent different approaches to the urban fabric, in terms of scope, actors, and priorities. Moreover, main types of interventions - basing on a case-study in a XVIII century neighborhood in Lisbon - are defined and analyzed in terms of the elements lost in each type of intervention, and relating those to urbanistic, architectonic and constructive values of urban heritage, as well as to environmental and energy efficiency. Further, the article overviews environmental cultural heritage assessment and life-cycle assessment tools, selecting relevant and feasible impact assessment criteria for urban buildings rehabilitation regulation, focusing on multi-level urban heritage integrity. Urbanistic, architectonic, constructive and energetic integrity are studied as criteria for impact assessment and specific indicators are proposed. The role of these criteria in sustainable urban management is discussed. Throughout this article, the key challenges for urban rehabilitation planning and management, concerning urban built heritage as a resource for sustainability, are discussed and clarified.

Keywords: urban rehabilitation, impact assessment criteria, buildings integrity, embodied energy

Procedia PDF Downloads 195

Authors: Emily Schlebes, Christian Hundhausen, Jens W. Fischer

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The glycosaminoglycan hyaluronan (HA) is a major component of the extracellular matrix, typically produced by fibroblasts of the connective tissue but also by immune cells. Here, we investigated the capacity of human peripheral blood CD8 T cells from healthy donors to produce HA and to express HA receptors as well as HA degrading enzymes. Further, we evaluated the effect of pharmacological HA inhibition on CD8 T cell function. Using immunocytochemistry together with quantitative PCR analysis, we found that HA synthesis is rapidly induced upon antibody-induced T cell receptor (TCR) activation and almost exclusively mediated by HA synthase 3 (HAS3). TCR activation also resulted in the upregulation of HA receptors CD44, hyaluronan-mediated motility receptor (HMMR), and layilin (LAYN), although kinetics and strength of expression varied greatly between subjects. The HA-degrading enzymes HYAL1 and HYAL2 were detected at low levels and induced by cell activation in some individuals. Interestingly, expression of HAS3, HA receptors, and hyaluronidases were modulated by the proinflammatory cytokines IL-6 and IL-1bβ in most subjects. To assess the functional role of HA in CD8 T cells, we performed carboxyfluorescein succinimidyl ester (CFSE) based proliferation assays and cytokine analysis in the presence of the HA inhibitor 4- Methylumbelliferone (4-MU). Despite significant inter-individual variation with regard to the effective dose, 4-MU resulted in the inhibition of CD8 T cell proliferation and reduced release of TNF-α and IFN-γ. Collectively, these data demonstrate that human CD8 T cells respond to TCR stimulation with a synthesis of HA and expression of HA-related genes. They further suggest that HA inhibition may be helpful in interfering with pathogenic T cell activation in human disease.

Keywords: CD8 T cells, extracellular matrix, hyaluronan, hyaluronan synthase 3

Procedia PDF Downloads 98