Effect of ellagitannins on HSV replication.*
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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For thousands of years throughout the world, tannins have been used in traditional medicines for the treatment of various health problems. They are used in the form of tea, coffee, and various extracts and in the daily intake of tannin-rich foods. They are also purposefully included as a component of many diets. Tannins are found in all parts of the plant—roots, stems, leaves, fruits, and seeds—which contribute to the existence of numerous natural sources of these substances.
\nDue to tannins’ astringent effects, herbs containing tannins are used to treat injured and inflamed tissues, including burns, and to stop bleeding and prevent infection. Herbs contain tannins. They are also used in the treatment of mouth and throat inflammation, gastritis, enteritis, irritating bowel disorders, and other conditions [1, 2, 3], due to their ability to bind very tightly to proteins by forming multiple hydrogen bonds between their phenolic groups and the -NH groups of the peptides. Precipitation or the shrinking of proteins—the so-called tanning effect—then occurs, forming a protective layer on the surface of tissues.
\nTannins have the ability to bind to metal ions in the body to form stable compounds called tannates. This property may have both positive and negative significance for human health. On the one hand, tannins can be used as an antidote for heavy metal poisoning. On the other hand, taking tannins daily, for example, in tea or coffee, can cause calcium and iron deficiencies in the body and may cause osteoporosis and anemia [4].
\nTannins are also effective inhibitors of certain enzymes. For example, woodfruticosin (woodfordin C) shows anti-topoisomerase II activity; and eugeniflorin D1 and D2, isolated from Eugenia uniflora L., and oenothein B effectively inhibit Epstein-Barr virus (EBV) DNA polymerase. Oenothein A and B, isolated from Epilobium species, appear to be potential inhibitors of the enzymes 5α-reductase and aromatase, which play important roles in the development of benign prostatic hyperplasia. Researchers have suggested that the enzyme poly(ADP-ribose) glycohydrolase, an important factor in gene expression, DNA replication, and cell differentiation, can be inhibited by the oligomeric ellagitannins oenothein B and nobotanins B, E, and K. In addition, enzyme α-glucosidase (maltase), which may be important in the development of type-2 diabetes, is inhibited by chebulagic acid (isolated from Terminalia chebula), tellimagrandin I, and eugeniin (casuarictin) [5].
\nResearch results indicate that the crude extract of Terminalia bellerica fruit (Tb.Cr), which is rich in tannin content, induced a dose-dependent fall in the arterial blood pressure of rats. Tb.Cr inhibited the force and rate of atrial contractions, and this effect was due to a calcium antagonistic mechanism [6]. Tannins also exhibit antihypertensive activity in the body by inhibiting the effect of angiotensin I-converting enzyme (ACE) [7]. Hydrolysable tannins with pronounced antihypertensive activity are castalagin and chebulinic acid as well as corilagin isolated from the leaves of Lumnitzera racemosa [8].
\nImportant for human health is the antitumor activity different tannins show toward various tumors such as cervical and prostate cancer and malignant cells in the skin, breast, stomach, lung, esophagus, liver, and so on [9, 10], with several possible mechanisms of action. Ellagitannins possess the ability to bind to proteins located on the surface of the cell membrane, thus preventing the proliferation of metastatic cells. They can induce also apoptosis in tumor cells by inhibiting factors responsible for the formation of metastases. Another mechanism suggests that during DNA replication, ellagitannins bind carcinogens into a complex, so they cannot cause mutation [11]. There is also evidence that ellagitannins reduce the negative effects of chemotherapy and radiation in cancer treatment [12].
\nTannins also show antimicrobial activity, in both plants and animals. In plants, the effect is due to the inhibition of microbial enzymes that degrade the plant cell wall [13]. Inhibition also occurs with other microbial enzymes such as pectinase, xylanase, peroxidase, laccase, and glycosyl transferase. Two possible mechanisms of this antimicrobial activity are tannins binding to the proteins of microbial membranes, damaging their structure and function, and tannins binding with essential metal ions [14]. Due to their antimicrobial activity, tannins can be used in the production and storage of certain foods to increase the shelf life of products [15].
\nThe immunomodulatory activity of tannins has also been demonstrated, with different substances showing different mechanisms of action that enhance the functionality of macrophages [16, 17, 18] or stimulate the secretion of cytokines IL-1, IL-β2, and αTNF [18, 19].
\nThe overproduction of free radicals and the subsequent development of oxidative stress are implicated as pathogenic factors in a number of viral infections. Oxidative stress is a complex multifaceted biochemical condition, which occurs when there is an increase in oxidative damage to biomolecules and oxidation of nonprotein and protein thiols that regulate a cell’s oxidative balance [20]. The cellular injury due to viral diseases caused by over generation of free radicals has been linked to over 200 clinical disorders [21].
\nIt has been clearly established that many of viral infections trigger the production of reactive oxygen (ROS) and nitrogen (RNS) species. This is particularly true for infections caused by the blood-borne hepatitis viruses (B, C and D), human immunodeficiency virus (HIV), influenza virus, herpes simplex virus, Epstein-Barr virus, respiratory syncytial virus, coxsackievirus B3 (CVB3), and others. For acute respiratory viral infections, ROS/RNS have been implicated in lung tissue injury and epithelial barrier dysfunction, which in turn increased susceptibility to secondary infections [22].
\nA variety of DNA viruses are associated with the increased oxidative stress that promotes DNA damage, high mutagenicity, and initiation and/or progression of neoplasia [23].
\nPhenolic compounds such as phenolic acids, flavonoids, tannins, and proanthocyanidins are widely distributed in plants and are a protective mechanism against OS. Several studies, including in vivo (in experimental animals) and epidemiological investigations, have demonstrated that phenolic compounds in foods possess positive attributes such as antioxidant potential, which is the basis of antiviral, antimicrobial, and antimutagenic activities. Compounds present in food that have potential antioxidant activity include vitamins C, E, and K, phenols (phenolic acids, flavonoids, thymol, carvacrol, and tannins), and carotenoids [24, 25]. Thus, antioxidants, mainly those originating from natural products, are of great importance for human health.
\nAntioxidant therapy is becoming an attractive and effective alternative approach for the treatment of viral diseases. The antioxidant properties of apple polyphenol extract, which is rich in tannins, are effective against the development of influenza virus infection in mice—they improve survival rates and also significantly decrease lipid peroxidation and increase oxygen radical absorbance capacity (ORAC) in splenocytes [26].
\nAvian influenza is usually accompanied by virus invasion followed by the occurrence of oxidative stress and serious inflammation. The anti-inflammatory and antioxidant properties of tannin-rich extracts of Chaenomeles speciosa showed that the multiple effects of the isolates might play a cocktail-like role in the treatment of avian influenza, and C. speciosa components might be a potent source for antiviral and anti-inflammatory agents [27].
\nPomegranate juice consumption reduces oxidative stress during influenza infection [28].
\nGreen tea is an important source of polyphenol antioxidants, which are also rich in tannins. Tea polyphenols possess antiviral properties believed to help protect against influenza virus. Oxidative stress and inflammation in the oral cavity, due to cigarette smoking and cigarettes’ deleterious compounds nicotine and acrolein, can be reduced by green tea polyphenols. Generally, green tea defends healthy cells from malignant transformation, and locally, it has the ability to induce apoptosis in oral cancer cells [29].
\nFinally, oxidative stress and the stress-mediated complications of viral infections successfully respond to antioxidant prevention. However, it should be kept in mind that antioxidants are not antivirals. Their function is more auxiliary, and they are particularly beneficial when used in combination therapy with specific viral inhibitors.
\nFor a small fraction of today’s known viral diseases, there are vaccines that can be successfully applied. Medicaments that are used are also limited in number, and in most cases, their use is accompanied by the appearance of side effects or the formation of resistant viral mutants, making therapy ineffective. Therefore, turning to nature to find effective therapies is a good solution to this problem. As mentioned earlier, tannins are a component of many plants. They are found in relatively high concentrations and exhibit significant biological activities. Tannin attack targets can carry out different stages of viral replication, including the extracellular virions themselves, their attachment to the cell, their penetration into the cell and the replication process in the host cell, as well as the assembling of new viral particles, transport proteins, polysaccharides, and viral enzymes [30, 31]. In almost all of the abovementioned stages, the tannin activity is due to their ability to bind permanently to the proteins of the capsid or supercapside, either to specific viral enzymes required for viral replication or to newly synthesized viral proteins involved in the composition of the new viral particles.
\nNumerous plant extracts have been studied, in which tannins are the main component, and they have shown good results against the replication of different viruses. The resulting effects have been on both coated viruses (influenza viruses A/H3N2 and A/H5N3, herpes simplex virus type 1 (HSV-1), vesicular stomatitis virus, Sendai virus and Newcastle disease viruses) [32, 33] and non-enveloped viruses (poliovirus, coxsackievirus, adenovirus, rotavirus, feline calicivirus, and mouse norovirus) [34].
\nThe antiretroviral activity of Euphorbia hirta extracts with high tannin content has indicated a dose-dependent inhibition of reverse transcriptase activity in vitro [35].
\nExtracts of Hamamelis virginiana L. bark, with differing concentrations of tannins and individual tannins of defined structures, including pseudotannins, have been tested for effect against influenza A virus (IAV) and human papillomavirus (HPV) type 16 infections. The study demonstrated that the IAV life cycle is inhibited in the early and, to a minor extent, later steps and that HPV attachment is tannin-dependently inhibited. Of the investigated substances high molecular weight tannin inhibited both IAV receptor binding and neuraminidase activity. However, those with low molecular weight tannin inhibited neuraminidase but not hemagglutination [36].
\nMany tannins showing antiviral activity have been isolated and characterized. The hydrolyzable tannins chebulagic acid and punicalagin were identified as potent inhibitors of HCV entry [37]. The replication of human, porcine, and duck influenza A virus in vitro was prevented by the hydrolyzable tannin strictinin [38].
\nFinally, many studies have been conducted on tannins’ effects against the replication of human immunodeficiency virus (HIV), and the results of the various teams indicate that tannins have several targets of action in the HIV replicative cycle. Ellagitannins isolated from Tuberaria lignosa inhibited HIV’s entry into MT-2 cells [39]. There is evidence that ellagitannins suppressed HIV replication by inhibiting reverse transcriptase [40, 41, 42, 43, 44]. Other authors have reported on ellagitannins (geraniin and corilagin) that reduced HIV replication by inhibiting the HIV-1 protease and HIV-1 integrase enzymes [43].
\nVarious tannins have been tested for antiherpesviral activity. Ellagitannin geraniin possesses a virucidal effect against herpesviruses [45], and it inhibits the adsorption of HSV and HTLV-IIIB [46, 47, 48, 49]. The hydrolyzable tannin casuarinin isolated from Terminalia arjuna Linn prevents the attachment of HSV-2 and its penetration into the cell, and it also disturbs the late stages of infection [1]. Chebulagic acid and punicalagin—two hydrolysable tannins isolated from Terminalia chebulaRetz.—inactivate HSV-1 entry and the cell-to-cell spread of the virus by targeting HSV-1 glycoproteins [50]. Putranjivain A isolated from Euphorbia jolkini inhibits the entry of the virus and the late stages of HSV-2 replication in vitro [51].
\nSeven ellagitannins isolated from Phyllanthus myrtifolius and Phyllanthus urinary, and eugeniflorin D (1) and D (2) isolated from Eugenia uniflora L., are active against the DNA polymerase of EBV [52, 53]. Eucalyptus grandis extract containing euglobal-G1 and euglobal-G3 shows antiviral activity against EBV, as do quassinoids (ailantinol B, ailantinol C, and ailanthone). Eugenol and eugenin isolated from Geum japonicum or Syzygium aromaticum show inactivating activity on viral DNA polymerase and thus inhibit acyclovir-resistant TK-deficient HSV-1 virus, wild HSV-2, and EBV [52, 54, 55, 56]. The EBV DNA polymerase is also inhibited by ellagitannins contained in Phyllanthus myrtifolius extracts and Phyllanthus urinaria (Euphorbiaceae), probably due to the corilagin moiety of these tannins. The tannin samarangenin B contained in the alcoholic extract of Limonium sinensis significantly suppresses HSV-1 multiplication [57]. And cowaniin isolated from Cowania mexicana (Rosaceae) exhibits an inhibitory effect on the activation of EBV early antigens [58].
\nOur studies on the antiviral activity of tannins have been mainly related to substances that belong to the group of nonahydroxyterphenoil-bearing C-glucosidic ellagitannins. We investigated the activity of three compounds—castalagin, vescalagin, and grandin isolated from powdered pedunculate oak (i.e., Quercus robur)—against the replication of two strains of HSV-1 (DA and Victoria) susceptible to acyclovir (ACV), one HSV-1 strain resistant to ACV (R-100), two HSV-2 strains susceptible to ACV (XA and Bja), and one HSV-2 strain resistant to ACV (PU) (Table 1) [59, 60].
\nCompounds | \nSI = CC50/IC50 | \n|||||
---|---|---|---|---|---|---|
HSV-1 | \nHSV-2 | \n|||||
Strains sensitive to ACV | \nStrain resistant to ACV | \nStrains sensitive to ACV | \nStrain resistant to ACV | \n|||
DA | \nVictoria | \nR-100 | \nXA | \nBja | \nPU | \n|
Castalagin | \n5390.0 | \n4498.0 | \n1047.5 | \n336.9 | \n89.9 | \n97.4 | \n
Vescalagin | \n4546.0 | \n909.0 | \n900.0 | \n378.9 | \n123.9 | \n117.4 | \n
Grandinin | \n1183.0 | \n88.7 | \n650.0 | \n208.8 | \n71.0 | \n103.1 | \n
ACV | \n1270.5 | \n972.8 | \n25.3 | \n790.2 | \n810.5 | \n29.0 | \n
Currently existing therapy against HSV infections is based on the administration of nucleoside analogues, among which ACV has had the broadest application. A disadvantage of this therapy is the rapid formation of resistant mutants [61].
\nAll three investigated ellagitannins showed remarkable antiviral activity against all strains of HSV-1, the strongest being castalagin’s action against the DA strain (SI = 5390.0) followed by vescalagin’s action against that strain (SI = 4546.0), and these effects were greater than that of ACV. The effects on the replication of HSV-2 strains, although less pronounced than those on HSV-1, were significant. The strongest effects were seen on strain XA, with the following SI values: vescalagin = 378.9, castalagin = 336.9, and grandinin = 208.8.
\nThe activity of the three ellagitannins was also determined in relation to the replication of three of the most common and important HSV-1 strains of economic importance, namely, pseudorabies virus or Suid herpesvirus 1 (SuHV-1), bovine herpesvirus-1 (BoHV-1), and caprine herpesvirus-1 (CapHV-1). The effect of the three ellagitannins was strongest against SuHV-1, with the activity of castalagin (SI = 336.8) and vescalagin (SI = 309) being on the order of ACV, while grandinin exhibited a moderate effect (SI = 40.8). The activity of the three ellagitannins against BoHV-1 was comparatively weaker but still significant (castalagin SI = 45, vescalagin SI = 42.5, grandinin SI = 32.3). Activity against the CapHV-1 strain had limited values.
\nAntiviral activity against HSV-1 (Victoria strain) was also determined for nine ellagitannins, of which six are natural compounds (castalin, vescalin, acutissimin A, epiacutissimins (EPI) A and B, mongolicain) and three are vescalagin synthetic derivatives (VgSBuSH, VgSOctSH, VgOMe). Thirteen gallotannin-type compounds [Gal-01A, Gal-01B, Gal-02A, Gal-02B, Gal-03 M, Gal-04A, Gal-04B, Gal-05 M, Gal-07, Gal-08, Gal-09, Gal-11 M (tannic acid), Gal-12 (gallic acid)] as well as Gal-13 and Gal-14 (ellagic acid)] were also tested. Generally, the group of ellagitannins exhibited greater activity, with only castalin and vescalin, from the natural products, and one of the synthetic derivatives (VgSOctSH) showing no activity. The remaining four natural components exhibited more pronounced activity than did the synthetic products, with the strongest effect showing for Epi B and Epi A (Table 2). Only three of the gallotannins—Gal-04A, Gal-04B, and Gal-11 M—showed activity against HSV-1 replication (Table 2) [62].
\nCompound | \nMM (g/mol) | \nCC50 (μM) | \nIC50 (μM) | \nSI =CC50/IC50 | \n
---|---|---|---|---|
Epi A | \n1207 | \n>1000*** | \n18.0 ± 0.77*** | \n>55.5 | \n
Epi B | \n1207 | \n>1000*** | \n16.5 ± 0.14*** | \n>60.6 | \n
Acutissimin | \n1207 | \n>640*** | \n18.4 ± 1.2*** | \n>34.78 | \n
Mongolicain | \n1177 | \n>640*** | \n19.7 ± 0.84*** | \n>32.5 | \n
VgSBuSH | \n1039 | \n>640*** | \n26.0 ± 1.76*** | \n>24.6 | \n
VgOMe | \n949 | \n>640*** | \n29.0 ± 2.89*** | \n>22.0 | \n
Gal-04A | \n1701 | \n>200*** | \n7.0 ± 1.2** | \n>28.5 | \n
Gal-04B | \n1701 | \n>100*** | \n2.8 ± 0.53* | \n>35.7 | \n
Gal-11 M(TA) | \n1701 | \n>100*** | \n4.0 ± 0.07* | \n>25.0 | \n
In order to control HSV infections, especially in immunosuppressed patients, it is necessary to treat them with antiherpetic preparations. However, their systemic use leads to the selection and/or formation of resistant strains. Given the heterogeneity of the viral population, naturally resistant variants are present. Therefore, the use of new approaches to the treatment of HSV infections [63, 64], namely, by combination therapy with two or more chemotherapeutics with synergistic action, is being sought. In these new approaches, synergistic combinations of two and more preparations are used to attack multiple viral targets simultaneously. This reduces the possibility of the formation and/or selection of resistant mutants. Even more, the therapeutic doses are abruptly reduced, eliminating any side effects. Data have been reported for combinations of antiviral agents showing a synergistic or additive effect on HSV [65, 66, 67, 68].
\nEach of the three ellagitannins—castalagin, vescalagin, and grandinin—was administered in combination with ACV, and their effects against the replication of HSV-1 and HSV-2 strains sensitive and resistant to ACV’s effect were markedly synergistic [59, 60]. To evaluate the effect of the combinations, we employed the three-dimensional model system developed by Prichard and Shipman [69] using the computer program MacSynergy ™ II [70]. The program calculates the volume of synergy in μM2%, where values between 50 and 100 μM2% indicate moderate synergy (this interaction may be important in vivo) and values over 100 μM2% indicate strong synergy (these are more likely to be important in vivo). The strongest synergistic effect was seen in the combinations administered against the ACV-resistant HSV-1 strain, and the effect was also pronounced in the ACV-sensitive HSV-1 strain. The combined effect on the HSV-2 strains was weaker but also significant: in both the resistant and sensitive strains, the effect was on the same order of magnitude (Table 3).
\nCompound | \nHSV-1 | \nHSV-2 | \n||
---|---|---|---|---|
Victoria | \nR-100 | \nBja | \nPU | \n|
Castalagin | \n222.06 | \n222.13 | \n71.62 | \n97.78 | \n
Vescalagin | \n205.09 | \n324.44 | \n87.56 | \n79.11 | \n
Grandinin | \n106.0 | \n314.53 | \n132.78 | \n106.12 | \n
The telling synergistic effect of all three ellagitannins shows that they have a different mechanism of action against HSV reproduction compared to that of ACV. The exact mechanism of antiviral activity of tannins has not been studied in detail.
\nTo elucidate the mechanism of anti-herpes activity of tannins, we used a substance that showed activity similar to that of acyclovir, namely, castalagin.
\nWhen monitoring castalagin’s effect on extracellular virions, we found that it was markedly time dependent. At the first time interval—15 min—the effect was negligible, but at 30 min, the effect was already significant, and as time increased, the virucidal effect intensified. This effect was also influenced by the temperature at which it occurred, with the effect at 37°C being stronger than that at room temperature [71].
\nCastalagin’s effect on the attachment of HSV-1 virions to MDBK cells was time dependent, and it was also dependent on the concentration of castalagin and the number of infectious viral particles. The inhibitory effect was reported at 30 min (Δlog 1.7), and it increased with the time of impact, reaching a value of Δlog 3.2 at 60 min. The most remarkable effect was observed when using castalagin at a maximum non-toxic concentration of 10 μM and then reducing its effect with a decrease in its concentration [71].
\nUsing a one-staged viral replicative cycle in a timing-of-addition study, we tested castalagin’s effect on the production of infectious virions during the replication cycle of ACV-sensitive HSV-1, Victoria strain. The effect of adding castalagin at 0 hours was most pronounced, and the effect remained significant when adding the ellagitannin at up to 4 hours. After this period of time, the addition of the substance had no particular effect, and after 15 hours, a statistically significant effect was not observed. From these results, it can be concluded that castalagin affects earlier stages of the viral replicative cycle [71].
\nThese results demonstrate a very high activity of the ellagitannin derivative castalagin toward human herpes simplex viruses 1 and 2. Its effect is on the order of the most efficient anti-HSV compound, acyclovir, which is widely used in clinical practice. In addition, castalagin manifested a marked activity against ACV-resistant HSV strains, and its combination effects with ACV could be characterized as synergistic. Another advantage of this substance is its non-nucleoside chemical structure.
\nCastalagin could be considered as a candidate for in vivo testing on experimental HSV infections in laboratory animals, such as HSV-1-induced skin infection in mice, encephalitis in newborn mice, eye infection in rabbits, as well as HSV-2 genital infection in mice. A very important step in the characterization of the anti-HSV effect of castalagin is the determination of its target in the herpesvirus replication cycle via molecular genetic analysis.
\nMicrobial biofilms that are sticky exopolymeric substances (EPS) causing adherence of microorganism to biotic surfaces such as host cells or abiotic surfaces such as medical devices cause antimicrobial resistance, due to its molecular contents such as eDNA and exoenzymes (β-lactamase, toxins, etc.), limited diffusion of antimicrobials through the biofilm matrix, persister cell content, and limited nutrient and oxygen. Surface proteins and polysaccharide intercellular adhesions (PIA) play a role in the biofilm production and development. It is hard to treat biofilm-embedded bacteria than planktonic forms. Biofilm producer microorganism causes biofilm-related infections such as indwelling and medical device-related infections such as endocarditis, urinary tract infections, septic arthritis, chronic rhinosinusitis, ocular infections, wound infections, etc. The results of biofilm produced on indwelling medical devices are recurrent, untreatable infections and failure of medical device. To overcome chronic and recurrent infections, it is important to detect biofilms of microorganisms, maturation and dispersion, and determine antibiofilm and antibacterial activity of agents against biofilm and bacteria within biofilm, respectively [1]. Identification of genes involved in biofilm formation and measurement of gene expression as a result of antibiofilm and antibacterial activity of agents can be advantageous with carrying out high-throughput screens using microtiter plate assay system.
The standard antimicrobial susceptibility tests such as broth macrodilution and microdilution methods that are routinely used in laboratories and published by Clinical Laboratory Standards Institute (CLSI), National Committee for Clinical Laboratory Standards (NCCLS), and European Committee on Antimicrobial Susceptibility Testing (EUCAST) could never yield accurate results in biofilm producer microorganisms, due to being appropriate for the detection of antimicrobial activity of agents against planktonic microorganism [2].
There are several methods which have been used by clinical microbiologist for detection and measurement of microbial biofilms in response to agents (Tables 1–3). Several instruments as model system have been improved such as modified Robbins device, Calgary biofilm device, disk reactor, Centers for Disease Control (CDC) biofilm reactor, perfused biofilm fermenter, and model bladder. Model systems help to define susceptibility of antimicrobial agents against biofilm producer microorganisms by providing information about biofilm mechanisms. Substratums of modified Robbins device, Calgary biofilm device, disk reactor, CDC biofilm reactor, and perfused biofilm fermenter are silastic disks, plastic pegs, Teflon coupons, plastic needleless connectors, and cellulose acetate filters, respectively, whereas substratum of model bladder is urinary catheters (UCs). Medical devices of which dimensions are adjusted to appropriate sizes can also be used as a substratum (abiotic surfaces) for biofilm production by adapting and modifying to related methods by some biofilm researchers. The methods of modified Robbins device and Calgary biofilm device are based on viable counting. In Calgary biofilm device, pegs are sonicated before counting. The methods of disk reactor and CDC biofilm reactor based on direct and viable counting, after substratums, are sonicated, vortexed, and homogenized. In perfused biofilm fermenter, viable counting is done, after filters are shaken in sterile distilled water, whereas in model bladder, UCs are examined directly by scanning electron microscopy (SEM) or transmission electron microscopy (TEM) or by chemical analysis [2]. Rate of biofilm formed on model system can be adjusted by parameters such as composition of medium that can contain glucose, iron, antimicrobial agents, multivalent cations such as Ca2+ and Mg2+ supporting adhesion of bacteria by cross-linking anionic groups on bacteria and substratum, shear force, retention time, flow rate, roughness, and chemistry of substratum and species of organisms (Table 4) [2, 3].
Method | Action of application | Aim |
---|---|---|
Roll plate | Extraluminal biofilm detection | Growth of biofilm-embedded bacteria |
Sonication, vortex, and plate counting | Intraluminal and extraluminal biofilm detection | Growth of biofilm-embedded bacteria |
Acridine orange staining | Extraluminal biofilm detection | Direct investigation of biofilm produced on catheter by microscopy |
Streak plating of alginate swab | Investigation of biofilm produced on indwelling catheter | Growth of biofilm-embedded bacteria |
The methods used for detection and measurement of biofilms produced on medical devices.
Method | Aim |
---|---|
Tube method (TM) | Qualitative detection by observing biofilm lined on bottom and walls of tube |
Congo red agar (CRA) | Qualitative detection by observing colony color change |
Microtiter plate (MtP) | Quantitative detection of biofilm by microplate reader (microELISA) |
Real-time PCR | Detection of biofilm genes |
Conventional PCR | |
Multiplex PCR |
The methods used for detection of biofilm.
Method | Application | Target |
---|---|---|
Microtiter plate (MtP) | Measurement of biofilm produced on walls of wells in response to agent | Measures the effect of agents against biofilm production |
Microtiter plate (MtP) (MBEC) | Measurement of biofilm remained on walls of wells in response to agent and detecting MBEC of agents | Measures the effect of agents against mature biofilm formed on walls of wells |
Vortex and plate counting | Plate counting of biofilm-embedded bacteria and detecting bMBC of agents | Screens antimicrobial activity of agents against biofilm-embedded bacteria |
Checkerboard assay | Plate counting of biofilm-embedded bacteria and FIC indexes are calculated | Screens antimicrobial activity of combination of agents |
Sonication, vortex, and plate counting | Plate counting of biofilm-embedded bacteria and detecting bMBC of agents | Screens antimicrobial activity of agents against biofilm-embedded bacteria |
Quantitative PCR | Measurement of specific biofilm gene expression | Monitors expression of biofilm genes in response to agents |
Mass spectrometry (MS) | Measurement of exoenzymes located in biofilm matrix | Monitors expression of bacterial proteins in response to agents |
The screening methods for antibiofilm and antimicrobial activity of agents against biofilm producer bacteria.
Instruments | Culture dynamics | Substratum | Method |
---|---|---|---|
Modified Robbins device | Batch culture | Silastic disks | Viable counting |
Calgary biofilm device | Batch culture | Plastic polycarbonate pegs | Viable counting, after pegs are sonicated |
Disk reactor | Batch culture | Teflon coupons | Direct or viable counting, after coupons are sonicated, vortexed, and homogenized |
CDC biofilm reactor | Continuous culture | Plastic connectors | |
Perfused biofilm fermenter | Continuous culture | Cellulose-acetate filters | Viable counting, after filters are shaken in sterile distilled water |
Model bladder | Continuous culture | Urinary catheters | Examining directly by SEM or TEM or analyzing chemically |
Flow cell | Continuous culture | Chambers with transparent surfaces | Examining by confocal laser scanning microscopy |
Instruments used to produce biofilm and examine biofilm process.
CDC biofilm reactor, Centers for Disease Control biofilm reactor; SEM, scanning electron microscopy; TEM, transmission electron microscopy.
The aim of this chapter is to overview certain methods used by biofilm detection and antibacterial and antibiofilm researches such as tube method (TM), Congo red agar (CRA) method, microtiter plate (MtP) assay, plate counting of biofilm-embedded bacteria (sessile bacteria), PCR, mass spectrometry (MS), confocal laser scanning microscopy (CLSM), etc.
Complexity and dynamics of biofilms can be observed by biofilm imagining optical technology including light microscopy, SEM, TEM, and CLSM. These techniques are used to visualize 3D structure and check the existence of biofilm [4].
Light microscopy is the easiest, cheapest, most simple, convenient and fastest method to quantitatively observe the morphology of microorganisms adhered to surfaces and to semiquantitatively estimate the amount of microorganism attached on surface (exist, absent, abundant, rare, etc.). Microorganisms including Candida albicans, E. coli, Pseudomonas, and Staphylococcus epidermidis adhered on acrylic sheets of polymethacrylate films, glass cover slips, and polystyrene petri dishes have been observed by light microscope, respectively. Observation with light microscopy that requires clear, transparent, and planar surfaces on which microorganisms attach does not create 3D vision of biofilm. Dyes can be used such as epifluorescence and fluorescent to enhance image clarity of microorganisms. The observation with the light microscope enables researchers to compare morphologies of sessile form and planktonic form of microorganism required by making smear and centrifuging of sample, respectively [3].
Images of cells and cell structures such as protein and nucleic acid are obtained by electrons at high magnification and resolution. Monitoring of components of cell can be done directly in TEM by negative staining. Due to photons and electrons penetrating cells poorly, thin section of cell cut is stabilized and stained by certain chemicals with the treatment of osmic acid, permanganate, uranium, lanthanum, or lead salts. These stains contain high atomic weight. Due to stains having high atomic weight, contrast is accelerated by electron dispersion from sample. If observation of outer structure of cells will be done, it is not important whether the section of cell is thin or thick.
Due to inadequate stabilization of polysaccharides is done by the conventional fixatives such as aldehydes, glutaraldehyde, paraformaldehyde, and osmium tetroxide, water content of biofilm is eliminated by graded dehydration with alcohol after this postfixation step. After sample is infiltrated with resin, sample is embedded in gelatin capsule and headed for polymerization. Then, thin section taken is poststained with uranyl acetate and lead citrate.
Exopolysaccharide constituents are not observed with its own electron dense and staining poststains such as uranyl acetate and lead citrate with TEM, due to not only having high electron translucent, but also contrast is not developed by conventional poststains. According to the studies, glycocalyx of Staphylococcus hominis and Staphylococcus epidermidis can be stabilized by the usage of certain cationic reagent combinations including ruthenium red, alcian blue, lysine, lysine monohydrochloride, or lysine acetate and paraformaldehyde [5]. After all these steps are done, sample is observed in TEM (Figure 1).
The SEM image of S. aureus embedded in biofilm colonized on intravenous catheter [6].
To visualize 3D images of cell sample is coated with heavy metals such as gold. Electrons released from metal coating of sample are caught by SEM for image production. The procedure of SEM is similar to TEM except for some additional chemicals (gold), lacking infiltration, embedment in resin, polymerization, and thin section staining with lead citrate and uranyl acetate [5]. As in the steps of TEM method, postfixation and dehydration steps of SEM are similar to TEM. The step is applied after dehydration step is drying and coating sample with gold in the processing for SEM, rather than infiltration with resin, embedment in gelatin capsule, and staining with lead citrate and uranyl acetate in the processing for TEM. After dehydration process with graded alcohol, sample is dried and coated with gold palladium [5]. After all these steps are done, sample is observed in SEM (Figure 2).
The TEM image of Staphylococcus spp. surrounded by glycocalyx [6].
Biofilms formed on flow cells of which surface are transparent can be observed by confocal laser screening microscopy (CLSM). Three-dimensional (3D) morphology and physiology of biofilms can be screened by CLSM [2]. Thick samples such as biofilms and microorganisms localized in the depth such as biofilm-embedded microorganisms need to be observed by CLSM (Figure 3).
Bacterial community embedded in a biofilm matrix visualized by CLSM. Each bacterium observed with a distinct color located at different depths of biofilm [11].
For observation of biofilm with confocal microscopy and related methods, biofilm must be fluorescent as a result of fluorescent molecules such as green fluorescent protein (GFP) that is fluorescent protein expressed by biofilm producer microorganism within biofilm (gene of cell interested is tagged by gene cassette encoding GFP) or staining components of heterogeneous mass of biofilm with fluorescence or fluorescence-labeled dyes [2]. Stains such as lectins target extracellular matrix, whereas certain fluorophores target extracellular DNA (eDNA) to visualize eDNA content of biofilm matrix [2, 7].
By scanning laser light across the sample, deep penetration of excitated energy is provided. As a result of fluorescence of biomolecules such as GFP or chlorophyll that are intrinsic fluorophores or molecules signed by exogenous probes such as fluorescent-labeled antibodies detected by photomultiplier, 3D digital image is formed. Observation of biofilms that are multilayered and have complex 3D structures requires additional resolution [2]. Images of each layers of biofilm obtained are combined by computer for construction of digital 3D images of whole biofilm.
Biofilm producer microorganisms can be manipulated genetically by tagging of microbial gene of interest by gene cassette encoding GFP as a reporter gene (gfp genes) to monitor gene expression and metabolic physiology activity in biofilms and determine location of microorganism within biofilm [2, 8, 9].
Idea about gene activity in biofilms is given by confocal microscopy applied to 3D localization of nonenzyme reporter systems such as GFP. Growth phase and activity of bacteria embedded in biofilms can be defined by promoter-reporter systems that is designed and fluoresced just in living dividing cells. In situ cellular growth activity of bacteria embedded in biofilms is determined by measuring ribosome-hybridization-signal intensity, due to synthesis rate and content of ribosome correlated with the growth rate (especially in exponential phase). Expression cassette that is active only in growing cells, labeled by GFP and controlled by rRNA promoter, can be constructed to monitor growth phase and activity of bacteria within biofilm [2, 10].
Specific microorganisms present in a heterogeneous biofilm community can be identified by the probes of fluorescent in situ hybridization (FISH) method. GFP that is translated enables procedure not to require fixation or staining. Fluorescent-labeled microorganism within biofilm can also be examined by FISH. DNA probes designed to hybridize 16S rRNA of microorganism integrated to either fluorescent dye such as FITC or Rhodamine or enzyme such as horseradish peroxidase. The advantage of probes conjugated with horseradish peroxidase is not to destroy microorganism within biofilm. The growth rate of microorganism within biofilm can be determined by FISH method, due to the amounts of ribosomes existing in a microorganism that is directly proportional to growth activity of microorganism. Probe must be designed to label conserved region of only a single species (Figure 4) [2, 12].
Fluorescence image of 28 distinct E. coli strains labeled by fluorophore-conjugated oligonucleotides complementary to 16S rRNA of E. coli [11].
Roll plate method is applied for the detection of possible microbial colonization having a potential to develop indwelling device-associated infection on the outer surface of cylindrical materials such as catheters and vascular grafts. Microorganism colonize on external surface of catheter is detected by roll plate method, instead of microorganism colonize on intraluminal site of catheter. Material is touched and rolled on the surface of medium [3].
Congo red agar (CRA) method that is a qualitative assay for detection of biofilm producer microorganism, as a result of color change of colonies inoculated on CRA medium, is described by Freeman et al. The CRA medium is constructed by mixing 0.8 g of Congo red and 36 g of sucrose to 37 g/L of Brain heart infusion (BHI) agar. After incubation period that was 24 h at 37°C, morphology of colonies that undergone to different colors is differentiated as biofilm producers or not. Black colonies with a dry crystalline consistency indicate biofilm producers, whereas colonies retained pink are non-biofilm producers (Figure 5) [13].
CRA method applied on CRA medium. Black crystalline colonies of biofilm producer cell and pinkish-red colonies of biofilm nonproducer cell.
Tube method (TM) that is a qualitative assay for detection of biofilm producer microorganism, as a result of the occurrence of visible film, is described by Christensen et al. [14]. Isolates are inoculated in polystyrene test tube which contained TSB and incubated at 24 h at 37°C. The sessile isolates of which biofilms formed on the walls of polystyrene test tube are stained with safranine for 1 h, after planktonic cells are discharged by rinsing twice with phosphate-buffered saline (PBS). Then, safranine-stained polystyrene test tube is rinsed twice with PBS to discharge stain. After air drying of test tube process, the occurrence of visible film lined the walls, and the bottom of the tube indicates biofilm production (Figure 6) [14].
Tube method. The first two polystyrene test tubes from the left indicate biofilm production. Other test tubes rather than the first two polystyrene test tubes from the left indicate lacking of biofilm production.
Microtiter plate (MtP) assay is a quantitative method to determine biofilm production by microplate reader. Bacterial suspension is prepared in MHB supplemented with 1% glucose and adjusted to 0.5 McFarland (1.108 cfu/ml). This bacterial suspension is 20-fold (1/20) diluted to reach 5.106 cfu/ml. Then 180 μl of Mueller-Hinton Broth (MHB) supplemented with 1% glucose [15] and 20 μl of bacterial suspensions are inoculated into 96-well flat-bottomed sterile polystyrene microplate to obtain 5.105 cfu/ml as a final concentration (tenfold dilution (1/10)). Microplates are incubated at 24 h at 37°C. The sessile isolates of which biofilms formed on the walls of wells of microplate are stained with only 150 μl of safranine for 15 min, after planktonic cells in wells of microplate are discharged by washing twice with phosphate-buffered saline (PBS) (pH 7.2) and wells are dried at 60°C for 1 h [14]. Before staining with safranine, fixation of biofilms can be done by either subjecting to 150 μl of methanol for 20 min or drying at 60°C for 1 h. Then safranine-stained wells of microplates are washed twice with PBS to discharge safranine stain. After air drying process of wells of microplate, dye of biofilms that lined the walls of the microplate is resolubilized by 150 μl of 95% ethanol or 33% glacial acetic acid or methanol. Then microplate is measured spectrophotometrically at 570 nm by a microplate reader [15, 16]. The studies are repeated in triplicates. Uninoculated wells containing sterile MHB supplemented with 1% glucose that are considered to be the negative controls are used as blanks. The blank absorbance values are used to identify whether biofilm formation of isolates exists or not. The wells of isolates of which OD values are higher than blank well are considered to be biofilm producers. Cut off value (ODc) can provide categorization of isolates as biofilm producer or not.
Negative value obtained from this formula and represented as zero indicates lack of biofilm production, whereas positive value indicates biofilm production (Figure 7).
Microtiter plate assay indicating biofilm production.
To interpret results, categorization can be done as no biofilm production (0), weak (+ or 1), moderate (++ or 2), and strong biofilm production (+++ or 3) by the calculation of cutoff value (ODc) shown below [15]:
OD ≤ ODc no biofilm production
ODc< OD ≤ 2 × ODc weak biofilm production
2 × ODc< OD ≤ 4 × ODc moderate biofilm production
4 × ODc< OD strong biofilm production.
PCR techniques is used for not only identification of pathogens by amplifying species-specific nucleic acid sequences but also detection of virulence factors by amplifying target virulence genes such as biofilm genes with the usage of gene-specific primers, even in the uncultured pathogen present in the sample.
Forward and reverse primers of biofilm-associated gene are designed. Firstly, multiple alignments were done in the NCBI to find oligonucleotide sequences specific to the species. Then primer pair of biofilm-associated gene is designed by using Primer3Plus verified by FASTA analysis checking specificity of primers for microbial sequences in the database [17, 18].
Genomic DNA of microorganism is extracted by extraction kits of which protocols can vary according to species and Gram-positivity or Gram-negativity of microorganisms. DNA of microorganism is measured spectrophotometrically by microplate spectrophotometry reader to determine the amount of DNA extracted as microgram per microliter.
Biofilm-associated gene is amplified by PCR such as qualitative real-time PCR, multiplex and conventional PCR that is used to detect whether biofilm-associated gene is present or not in microorganism. If conventional and multiplex PCR protocols are applied to detect biofilm gene, rather than qualitative real-time PCR, PCR product isolated is visualized on an agarose gel containing a DNA-intercalating dye such as ethidium bromide to confirm the presence of amplified gene (Figure 8). Only in qualitative real-time PCR, the amplicon is detected by fluorescence using a pair of specific hybridization probes labeled with fluorescence dye [11].
Image of mecA gene on agarose gel. First sample is DNA size marker (ranging from 250 to 10,000 kb), second sample is ATCC 43300 methicillin-resistant Staphylococcus aureus (MRSA) positive control, third and fourth samples are mecA gene-positive isolates, and fifth sample is ATCC 29213 methicillin-sensitive Staphylococcus aureus (MSSA) as a negative control.
Microtiter plate (MtP) assay is a qualitative assay to detect efficacy of agent against biofilm production by microplate reader.
Bacterial suspension is prepared in MHB supplemented with 1% glucose and adjusted to 0.5 McFarland (1.108 cfu/ml). This bacterial suspension is 20-fold (1/20) diluted to reach 5.106 cfu/ml.
A 180 μl of agent doses and 20 μl of bacterial suspension are dispersed to each well of microplate to obtain 5.105 cfu/ml as a final concentration (tenfold dilution (1/10)). After incubation at 37°C for 24 h, ongoing processes are done according to MtP assay as mentioned previously for the determination of effect of agent against biofilm production [14, 16].
Biofilms remained after eradication by agent are measured by this technique. Biofilms of bacteria that line the walls of wells are formed according to MtP method.
After the content of microplate is discharged, 200 μl of each dose of agents is dispersed to each well of microplate of which the walls are lined with biofilm. A 200 μl of distilled water is added into a well of microplate of which the walls are lined with biofilm as a control. Then the effect of agent against mature biofilm is determined according to MtP assay as mentioned previously. Minimum concentration of agent eradicating mature biofilm that is named as minimum biofilm eradication concentration (MBEC) can be determined by this modified plate assay. MBEC50 and MBEC90 indicate the minimum concentrations of agents inhibiting 50 and 90% of mature biofilm formed.
In summary, biofilm formation process on abiotic surfaces by bacteria is done. Quantification of sessile biofilm-embedded bacteria lined on abiotic surface and sessile biofilm-embedded bacteria remained on abiotic surface after addition of agent on abiotic surface on which mature biofilms formed is determined by plate counting. Bacterial suspension is prepared and adjusted to 0.5 McFarland (1.108 cfu/mL) in Mueller-Hinton Broth (MHB) supplemented with 1% glucose [15]. This bacterial suspension is 200-fold (1/200) diluted to gain 5.105 cfu/mL. Kirschner wire orthopedic implants are placed into each test tube containing 5.105 cfu/mL isolate and incubated at 37°C for 24 h to lead bacteria to produce biofilm on Kirschner wire. After incubation, Kirschner wires on which biofilms are produced are discharged and rinsed with PBS (pH 7.2) and then transferred into each test tubes containing agent concentrations. After incubation at 37°C for 24 h, Kirschner wires are discharged and placed into test tubes containing 1 mL of sterile MHB and sonicated at 42 kHz for 2 min after vortexed for 5 min. Then 100 μl samples of each test tube sonicated and vortexed are inoculated on Mueller-Hinton agar (MHA) and incubated at 37°C for 24 h [19].
The lowest concentration of agent in which bacterial growth is below or equal to control is determined as biofilm minimum inhibitory concentration (bMIC) for biofilm. bMIC50 and bMIC90 indicate the minimum concentrations of agent inhibiting 50 and 90% of biofilm-embedded bacteria. After incubation, the lowest concentration of agent in which colonies of biofilm-embedded bacteria are not grown is determined as biofilm minimum bactericidal concentration (bMBC) of agent for biofilm [19].
Checkerboard assay is used for the determination of combination effects of two different agents. A 250 μl twofold dilutions of each agent from the stock solutions are dispersed to each row and column to obtain final varying concentrations by starting at fourfold of zero MIC for each isolate. So each well contains distinct combination of concentrations of two agents. First wells of rows and columns are left behind for sole treatments of each dose of agents. One well is used for bacterial control (Figure 9). Kirschner wires on which bacterial biofilm is produced are dispersed to each well. This microplate is incubated at 37°C for 24 h. After incubation, Kirschner wires are discharged and sonicated at 42 kHz for 2 min after vortexed for 5 min. The lowest concentration of agent in which bacterial growth that is not observed is determined as biofilm minimum inhibitory concentration (bMIC) of agent for biofilm. Then 100 μl samples of each test tube sonicated and vortexed are inoculated on MHA and incubated at 37°C for 24 h. After incubation, the lowest concentration of agent in which colonies of biofilm-embedded bacteria are not grown is determined as biofilm minimum bactericidal concentration (bMBC) of agent for biofilm. For the determination of whether the synergism is present between agents or not, fractional inhibitory concentrations (FICs) index that are calculated for each agent are summed up according to formula written below:
The schematization of checkerboard assay.
When ∑FIC is equal and lesser than 0.5, between 0.5 and 1, equal to 1, higher than 1 and equal and lesser than 4, and higher than 4, it is interpreted that the effect between agents in combination is synergistic, partial synergistic, additive, indifferent, and antagonistic, respectively [20].
The wells having the highest synergy rates of two agents that constitute the combinations are determined by taking the average and standard deviation of FIC indexes calculated of the wells with the lowest drug combination without bacterial growth in each row and column (Figure 9).
Measurements of biofilm genes repressed or induced by agent are done by quantitative real-time PCR (qPCR). So efficacy of agent against biofilm-associated genes can be detected by qPCR.
Complementary DNA (cDNA) is copied from RNA by enzyme reverse transcriptase. Gene expression in pathogen is monitored by qPCR copying cDNA from RNA of target gene. Amplified cDNA probed for identification. Fluorescent probes such as dye SYBR Green are used to indicate double-stranded DNA, consequently amplification. Accumulation of PCR amplicons labeled fluorescently is monitored through the qPCR processes (Figure 10). Visualization of amplicon on agarose gel is not needed to confirm amplification in qPCR [11].
Quantitative real-time polymerase chain reaction (qPCR) of atl (light blue), 16S RNA (red), mecA (purple), and nuc (light pink) genes of sample; icaA (gray), icaD (plato), atl (pink), mecA (blue), and nuc (green) genes of ATCC 43300 methicillin-resistant Staphylococcus aureus (MRSA); and icaA (orange), 16S RNA (yellow), and nuc (grayish blue) genes of ATCC 29213 methicillin-sensitive Staphylococcus aureus (MSSA). Expressions of all these genes are monitored by qPCR except nuc (light pink) gene sample. Lines below threshold monitored by qPCR indicate the negativity of genes such as icaA and icaD genes samples and icaD (turquoise), atl (plato), and mecA (light pink) genes of ATCC 29213 MSSA. RFI, relative fluorescence intensity.
Total RNA of microorganism is isolated according to protocols of RNA isolation kits. Kit protocols can vary according to the species of microorganism. Total RNA of microorganism is measured spectrophotometrically by microplate spectrophotometry reader to determine the amount of total RNA isolated as microgram per microliter. Then cDNA is synthesized from total RNA with qPCR using primer pair of the biofilm-associated gene, which is designed using Primer3 and verified by FASTA analysis, which controls the specificity of the primers for microbial sequences in the data system, after multiple alignments were done in the NCBI to find oligonucleotide sequences specific to the species [17, 18].
Extracellular polymeric substances (EPS) not only contain polysaccharides but also contain proteins such as extracellular enzymes. These expressed proteins located in the matrix of EPS can be detected and characterized by mass spectrometry (MS) [1]. Large biologic molecules can be also detected and characterized in complex biologic structures such as EPS by MS. Chemicals involved in biofilm process are examined in detail by MS. Electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) are the types of MS [2]. In time-of-flight (TOF) mass spectrometer, mass is analyzed by ions desorbed in vacuum chamber. These two technics are combined and called MALDI-TOF.
Sample is ionized and vaporized by laser. Ions generated from sample by laser pass through the column of MALDI-TOF device toward TOF detector by an electric field. Depending on the mass/charge ratio of molecule, measurements are done by TOF. If this ratio is smaller, ions move faster (Figure 11).
MALDI-TOF mass spectrometry device [11].
Bacteria are identified, expression of bacterial proteins such as surface proteins and exoenzymes like β-lactamase in response to antimicrobials can be monitored, and growth of bacteria is measured by applications of MALDI. MS has high sensitivity and requires minimum amount of sample [2].
Biofilm-embedded bacteria can be estimated by biologic assays that is an indirect assay. Biological assays that measure production of microbial product give an opinion about estimation of the number of microorganism within biofilm. Amount of biologic product is correlated with biofilm-embedded microorganism producing the product by standardization of planktonic microorganism. Biologic products produced by planktonic microorganism are similar to biologic products produced by biofilm-embedded bacteria. Standardization curves of each microorganism tested need to be formed. Measurement of total protein at the absorbance is 550 or 950 nm; tryptophan fluorescence, endotoxin [2], ATP production via bioluminescence caused by luciferin and luciferase, urease production to estimate number of attached microorganism, and electron transport via the production of formazan are done by biological assays [3].
Biofilms cause resistance to many antimicrobial agents. The results of biofilm produced on indwelling medical devices are recurrent, untreatable infections and failure of medical device. To overcome chronic and recurrent infections, it is important to detect biofilms of microorganisms, determine antibiofilm activity of agents against biofilm, and determine antibacterial activity of agents against biofilm-embedded microorganism with the appropriate methods by clinical microbiologist and biofilm researcher microbiologist. Identification of genes involved in biofilm formation and measurement of gene expression as a result of antibiofilm and antibacterial activity of agents can be advantageous in biofilm studies.
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She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. 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