HPV and Abnormal Pap Smear Results

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Human Papilloma Virus

The presence of human papilloma virus (HPV) is associated with female genital tract diseases such as condyloma, Bowenoid papulosis, and cervical, vaginal, and vulvar intraepithelial neoplasia and carcinoma. A general concern is the association of HPV with cervical cancer (Gl). The HPV consists of an icosahedral viral particle (virion) containing 8000 base pairs, a circular, double-stranded piece of DNA surrounded by a protein capsid. Viral replication takes place within the nuclei of infected squamous epithelial cells (H5). Following infection of epithelial cells, the viral DNA penetrates throughout the entire thickness of the epithelium, but intact viruses are found only in the upper layers of tissue. More than 20 types of HPV have been reported in genital infections. Complete genome sequences are known for nine types. These types are defined based on percent homology observed between HPV-DNA samples when assayed in a liquid phase hybridization. Indirect detection of HPV infection...

Nuclear inclusions formed during polyomavirus and papillomavirus infection

Polyoma- and papillomaviruses are small double-stranded tumorigenic DNA viruses with genomes of 5 and 8 kbp, respectively. Replication and assembly of these two viruses follow similar strategies, and both involve ND10 bodies. The VP1 capsid protein of human polyomavirus JC is targeted to ND10 domains by VP2, VP3, and agnoprotein where they are assembled into virions (Shishido-Hara et al., 2004). A similar process occurs during papillomavirus infection where the minor capsid protein, L2, is responsible for targeting capsomeres of the major capsid protein, Ll, to ND10 domains (Florin et al., 2002a). This process involves L2-induced redistribution of ND10 bodies by targeting SP100 for proteasomal degradation. At this point the cellular Daxx protein is recruited (Florin et al., 2002b). Daax has multiple functions in the nucleus including transcriptional activation and modulating Fas-mediated apoptosis reviewed by Salomoni and Khelifi (2006) . Its role in virus replication is at present...

Molecular Differential Diagnostic System for Human Papillomavirus Typing

Human papillomavirus (HPV) is known to cause cervical cancer, the second most common cancer among women worldwide. In the United States, HPV is responsible for approximately 13,000 new cases of cancer and 4500 deaths each year. A Pap test only indicates the possibility of cervical cancer. For more direct disease diagnosis, the MDD system for HPV Typing I accurately detects different HPV subtypes. When detected early, cervical cancer is one of the most successfully treated cancers. Type-specific DNA diagnosis is important for disease prevention, prognosis, and treatment. Until now, an efficient method for HPV typing was not available. The FDA-approved Digene HPV DNA diagnostic product can only identify HPV infections as high-risk or low-risk groups. Coinfection by multiple HPV types is likely to occur in more than 30 of HPV patients (Swan et al., 2005, personal communication). Certain combinations of these co-infections may be more prone to cause cancer than others. Information...

Inhibitors Of West Nile Virus And Papilloma Virus

Inhibitors of Papilloma Virus - The contribution of HPV-16 and HPV-18 to the etiology of cervical cancer was discussed as part of a broader review of the role of viruses in the development of cancer (173). ORI-1001 (56), a 20-mer phosphorothioate hybrid oligonucleotide, is being developed as a topical agent for the treatment of genital warts (174). ORI-1001, which complements the E1 mRNA start codon of HPV and has demonstrated efficacy in two animal models, is currently undergoing P1 2 clinical evaluation. The fused tetracyclic amide 57 is claimed to inhibit the E2-dependent binding of papilloma virus E1 to DNA, a critical step in viral replication, with an IC5o of < 500 nM (175). A vaccine derived from an HPV-16 virus-like particle, completely prevented the incidence of cervical neoplasias in HPV-16-na'ive young women (176). This impressive result provides strong encouragement to the development of a vaccine with a spectrum that, in addition, encompasses the broader range of HPVs...

Replication of papillomaviruses

By contrast, a related group of viruses, papillomaviruses, follow a natural replication scheme in their host that requires the formation of tumors, usually benign tumors, in their replication cycle. In this strategy of virus replication, persistence is a consequence of the continued replication of cells bearing viral genomes Papillomavirus replication combines some aspects of both the abortive and productive schemes just discussed. These viruses cause warts or papillomas, and there are many different types, with most showing no antigenic cross-reactivity with each other. Infections with most papillomavirus types are completely benign (although irritating or occasionally painful), but some can be spread by sexual intercourse, leading to persistent genital infections, especially in females. Statistical analyses comparing the incidence of cervical carcinoma and the patterns of persistent infection by some of these papillomaviruses including human papillomaviruses 16 and 18 (HPV-16 and...

Genital Warts

Genital warts, which are caused by the human papillomavirus (HPV), are one of the most common STDs. Some people who have been infected with HPV never get genital warts, but they can still spread the infection. As with other kinds of warts elsewhere on the body, genital warts start small and soft and become hard and rough-surfaced, often developing stalks. Multiple warts often grow in the same area, creating a cauliflowerlike effect. The growth is rapid, especially in men with weakened immune systems for example, men who have AIDS (acquired immunodeficiency syndrome). The good news is that the warts usually disappear on their own after a few months. The bad news is that they tend to return, even if they have been removed. Genital warts can be treated (but not cured) with prescription creams or gels such as imiquimod or podofilox. These medications are applied directly to the affected area. The warts also can be removed with surgery, which is done using a local anesthetic, cryotherapy...

Clinical Applications

Although unpopular in the clinical setting, RIA is still available for research settings. One example is the Human Papilloma Virus (HPV) type-specific competitive RIA (cRIA) used to evaluate HPV type-specific antibody titers. Briefly, HPV L1 virus-like particle (VLP) antigens (HPV-6 and HPV-11) are coated onto solidphase polystyrene beads and incubated with equal volumes of sera and diluted Mab, as well as the 125I-labeled secondary antibody (Opalka et al., 2003). Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles (VLPs) for human papillomavirus (HPV) types 6,11,16, and 18 in 50 L of serum was achieved by a multiplexed Luminex assay (Opalka et al., 2003). The HPV competitive immunoassay measures titers of polyclonal antibodies and was found to be as sensitive and precise as the currently used cRIAs.

Reducing Infectious Disease Burden

The lack of a vaccine for sexually transmitted diseases (with the exception of human papilloma virus) is also a concern, as Neisseria gonorrhea remains both an important public health problem and an organism for which resistance has been an ongoing problem (Rupp et al., 2005).

Persistent viral infections

Papilloma andpolyomavirus infections and differentiation of keratinized tissue in a wart caused by a papillomavirus. In such infections, virus replication closely correlates with the cell's differentiation state, and the virus can express genes that delay the normal programmed death (apoptosis) of such cells in order to lengthen the time available for replication. Persistent infections caused by some viruses can (rarely) lead to a neoplasm (a cancerous growth) due to continual tissue damage and resulting in mutation of cellular genes controlling cell division (oncogenes or tumor suppressor genes). Examples include infections with slow-transforming retroviruses such as human T-cell leukemia virus (HTLV), chronic hepatitis B and hepatitis C infections of the liver, certain genital papilloma virus infections, and EBV infections. The latter require the additional action of auxiliary cancer-causing factors (co-carcinogens).

Export of FGF1 and FGF2

Several reports provide evidence that export of FGF-1 and FGF-2 may involve a novel secretory pathway. Stably transfected NIH 3T3 cells, which expressed high levels of FGF-1, released inactive homodimers of FGF-1 on heat shock, in a process that required de novo synthesis of protein. This export was not prevented by Brefeldin A and methyl amine, inhibitors of ER-Golgi transport and exocytosis, respectively (130). Active export of FGF-2 in unusual high mol wt forms has been reported in cell lines derived from different stages of fibrosarcoma development in transgenic mice carrying the bovine papilloma virus genome (131). Cell lines established from the P-cell tumors of Rip1Tag2 transgenic mice (PTC) constitutively secreted FGF-1 into the culture medium (131a). Treatment of this medium with high salt recovered FGF-1 as high mol wt (HMW) forms with reduced heparin-affinity and a molecular mass of approx 40 kDa. Brefeldin A, an inhibitor of conventional secretion, did not interfere with...

Recent Sexual History

'Was this person male or female ' This will guide your questioning and assist you in the risk assessment. Please remember that if the client is female and having sex with another woman this doesn't necessarily mean that they are not at risk that other woman may have had male relationships in the past and may have acquired chlamydia, genital warts or HIV. The use of shared sex toys may also be a risk factor.

How is a diagnosis of MS made

In between the start and end of the day, I drove to the university to pick up my students' exams for grading and then to the doctor for him to examine my ears and give me my annual pap test. My father took me to the neurologist, who said I had either a large brain tumor or MS and scheduled an MRI for that day as well as a spinal tap for the next day. The MRI center was having a holiday party, and while we waited for the results to take back to the neurologist, the office administrator offered us Santa party hats and snacks to keep us distracted. My husband who was in New Jersey, kept saying, I thought you were having a pap test and had a problem with your ears. What are you doing at the neurologist ' We were all a bit in shock as the surreal nature of the day continued. With MRI results and party favors in hand, we went back to the neurologist who had waited after hours for our return. He looked at the MRI and said, You have MS.'

Acyclic Nucleoside Phosphonates

Cidofovir (Fig. 2) has been formally approved for the treatment of CMV retinitis in AIDS patients, where it is administered intravenously at a dose not exceeding 5 mg kg once weekly during the first two weeks (and every other week thereafter). Cidofovir is also used off label for the treatment of human papilloma virus (HPV) infections (i.e., cutaneous warts, anogenital warts, laryngeal and pharyngeal papilloma), polyomavirus i.e., progressive (i.e., multifocal leukoencephalopathy (PML) , adenovirus, herpesvirus, and poxvirus (i.e., molluscum contagiosum) infections, where it can be administered intravenously (at a dose of < 5mg kg once weekly or every other week) or topically as a 1 gel or cream (De Clercq and Holy 2005). Especially in immunosuppressed patients (i.e., transplant recipients), local treatment of HPV-associated lesions has often yielded spectacular results (Bonatti et al. 2007).

Signal Amplification Systems

Currently, two diagnostic companies have their signal amplification products available for diagnostic microbiology purposes. The Digene hybrid capture system is widely used to determine human papillomavirus (HPV) infection and viral types in cervical swabs or fresh cervical biopsy specimens as well as other diagnostic targets (Brown et al., 1993). Persistent high-risk human papillomavirus infection detected by the System represents a reliable tool to select populations at risk for the development of high-grade cervical lesions (Brown et al., 1993 Schiffman et al.,

Friend murine leukemia virus FrMLV A

Fringilla papillomavirus A probable species in the genus Papillomavirus. Isolated from papillomas excised from the leg of a chaffinch, Fringilla coelebs. Virion diameter 52nm sedimentation coefficient 300S and density in CsCl 1.34g ml. Composed of 72 morphological units arranged in a skew T 7d icosahedral lattice. The circular double-stranded genome measured 2.6 im. Protein composition similar to Human papillomavirus. Papillomas have only been found in two species of Fringilla the chaffinch and the brambling, F. montif-ringilla. Synonyms avian papillomavirus bird papillomavirus chaffinch papillo-mavirus.

Patients complaining of rectal bleeding consider

Blood spotting after anal sex and or blood spotting on the toilet paper is a common compliant in the GU clinic, and is usually the symptom of minor conditions such as haemorrhoids, anal fissures, genital trauma, or genital warts -which can be associated with pruritus (Rhodes & Hsin, 1995).

E1B 55kDa Gene Deletion Mutant dl 1520

Hypothesized that an adenovirus with deletion of a gene encoding a p53-hinding protein, E1B 55-kDa, would be selective for tumors that already had inhibited or lost p53 function. p53 function is lost in the majority of human cancers through mechanisms including gene mutation, overexpression of p53-binding inhibitors (e.g., mdm2, human papillomavirus E6), and loss of the p53-inhibitory pathway modulated by pl4ARF 33-35 . However, the precise role of p53 in the inhibition of adenoviral replication has not been defined to date. In addition, other adenoviral proteins also have direct or indirect effects on p53 function (e.g., E4orf6, E1B 19-kDa, E1A) 36 . Finally, E1B 55-kDa itself has important viral functions that are unrelated to p53 inhibition (e.g., viral mRNA transport, host cell protein synthesis shut-off) 37 (Fig. 3).

Broadspectrum versus HIVspecific

While the major focus of microbicide development has been HIV since HIV AIDS is a lethal and incurable disease, other sexually transmitted infections (STIs) are also significant causes of morbidity and mortality 22 . In fact, the spread of these diseases are also facilitated by the same factors driving the worldwide spread of HIV - such as lack of woman-controlled prevention methods and a lack of widespread use of condoms. Non-HIV STIs include curable infections such as trichomoniasis, Chlamydia, gonorrhea, syphilis, and chancroid, as well as non-curable infections caused by Herpes virus and human papillomavirus 22 . Since STIs are important co-factors for HIV transmission, candidate microbicides have been developed with overlapping mechanisms of action and potential activity against other sexually transmitted pathogens. Overall, women at risk for HIV

The replication of viral DNA

The replication of viral DNA generally follows the same basic rules as for cellular DNA, and the replication of small DNA-containing viruses such as the parvoviruses, polyomaviruses, and papilloma viruses use cellular DNA replication enzymes, although in the case of the latter two, the virus encodes a specific ori-binding protein. Herpesviruses, such as HSV, encode a number of the proteins required in DNA replication with the process being virtually identical to the cellular patterns outlined here as shown in Fig. 13.2. The same is true with the poxviruses. These DNA replication proteins have clear genetic relationships, with cellular enzymes having the same function. Adenoviruses also encode their own DNA polymerase, but as outlined in Chapter 16, Part IV use a protein primer for initiation of replication and carry out only leading strand synthesis.

Traditional Detection Methods

As HPV cannot be grown in cell cultures, clinical, cytological, and histologi-cal methods have traditionally been used to provide indirect evidence of HPV infection by demonstration of cellular dysplasia, which is one of the results of HPV infection. Colposcopic examination by visual inspection to detect abnormalities in the exterior parts of the genital tract is convenient and easily done at the bedside. However, this method is very insensitive, and hidden lesions in the cervix often remain undetected (Feng and Kiviat, 2003). Microscopic examination of exfoliated cell samples (Pap smears) or tissue biopsy specimens have long been used in cytological and histological methods for revealing HPV infections. Changes in HPV-infected cells can be rather subtle and there are nonspecific manifestations, such as koilocytosis or dyskeratosis of the squamous cells. These changes, however, are not always clearly presented and detectable by microscopy (Hippelainen et al., 1994). Poor intra- and...

Molecular Detection Methods

The sensitivity of PCR-based amplification tests are higher than other non-amplification-based laboratory techniques and have been commonly used in prevalence studies of HPV infection (Giuliano et al., 2001). Several hybridization techniques, mentioned in the previous section, have been modified by including PCR amplification steps to improve their sensitivities, such as PCR-dot blot and PCR-RFLP (Gravitt and Manos, 1992 Kay et al., 2002).

RING finger motif See RING finger proteins

RING finger proteins Proteins having a sequence related to the zinc finger but containing additional cysteine and histi-dine residues that help the molecule to form a ring. Play a critical role in mediating the transfer of ubiquitin both to heterologous substrates and to the RING finger proteins themselves. Ubiquitina-tion is a first step in protein degradation, and some viruses, notably Human papillomavirus, express ring finger proteins that cause ubiquitination leading to degradation of cellular proteins, such as p53.

Simian enterovirus N203 SEVN203 A

Simian papillomavirus A possible species in the genus Papillomavirus. A natural infection of cebus monkeys causing papillomas. Papillomas can be transmitted experimentally to both New and Old World monkeys. After injection of tissue extract, hyperemic patches appear within 2 weeks and then the epidermis becomes thickened to form a papilloma. No evidence of invasion of normal tissue, and regression occurs in 4-6 months. Synonym monkey papillomavirus.

Vaccines Against Viral Infections and Their Cost Effectiveness

Infections with signs that do not clearly point to bacterial origin are often thought to be viral. Since specific anti-viral treatments are often not available, vaccines that mimic closely to the natural infections are the principal means for control. Vaccines have been proved to be effective against acute, self-limiting infections and can confer long-lasting immunity. The same may not be true for chronic viral infections but with the advent of molecular biology there is a strong possibility of developing vaccines against chronic viral infections like hepatitis C virus (HCV), human papilloma virus (HPV) and HIV (Berzofsky et al. 2004). The major viral vaccination success story is the eradication of smallpox by the year 1977. The WHO spent more than 300 million in 11 years, an amount that has been repaid many times over - probably each year - in human lives saved (Ehreth 2003).

Regulation Of The Microbiology Laboratory

Cameras recorded a laboratorian pouring a patient's urine down the sink and then fabricating the results of the urine culture and susceptibility. The public outcry that followed this broadcast led Congress to enact the Clinical Laboratory Improvement Act of 1967, now known as CLIA '67. The Centers for Medicare and Medicaid Services (CMS), formerly known as The Health Care Financing Administration (HCFA), was created to oversee the enforcement of the guidelines published in CIIA '67 CMS is part of the United States Department of Health and Human Services (DHHS). CMS is also responsible for overseeing the Medicare and Medicaid programs, which were instituted to provide health care for elderly and poor persons under the Social Security Act. CIIA '67 mandated the first quality control, personnel, and proficiency testing standards for clinical laboratories but applied only to laboratories engaged in interstate commerce this represented less than 10 of all clinical laboratories. Therefore,...

Symptoms And Signs

Common skin warts mostly affect children and young adults, with multiple lesions on hands and fingers. Flat skin warts tend to localize to arms, knees and the face. Deep plantar warts are usually single and are seen in children and adults. Warts may occur on the vocal cords (laryngeal papillomas). Genital warts (condylomas), localized to cervix, vagina, vulva, penis and perineum, are transmitted by sexual contact, and appear as flat (condyloma planum) or exophytic (condyloma acuminatum) warts. In epidermodysplasia verruciformis, a rare inherited immunological disease, the warts may turn into invasive or in situ squamous-cell carcinomas upon exposure to sunlight. Juvenile laryngeal papillomas usually result from infection contracted at birth from genital warts in the mother.

Oncogenicity And Role Of Hpv In Human Cancers

Common warts and plantar warts never become malignant. Direct conversion of condylomas to carcinomas has been described anecdotally but is extremely rare. In addition to experimental evidence, large-scale epidemiological studies performed during recent years have established HPV infections as the major risk factor for cervical cancer. Skin cancers arising in immunosuppressed patients are also increasingly found to contain HPV DNA. Since the matter of causality is being elucidated, the focus is at present, and in the years to come, being shifted towards the mechanisms by which the interplay between certain HPV genotypes, the infected host cells, their environment and other factors may initiate, establish and maintain oncogenic processes in the cervix as well as other locations. HPVs associated with anogenital lesions have been divided into 'low-risk' types (6, 11, 34, 40, 42, 43) or 'high-risk' types (16, 18, 31, 33, 35, Figure 38.1 HUMAN PAPILLOMAVIRUS. Bar, 50 nm (Electron micrograph...

Laboratory Diagnosis

Papillomavirus particles are easily demonstrated by electron microscopy of skin wart scrapings, while there may be too few particles in condylomas to be detected by direct electron microscopy. HPV cannot be cultivated. There are two clinical uses of HPV testing where the predictive values may be high enough to justify general use as an adjunct to cervical cytological screening the clarification of equivocal and low-grade Pap smears, and the general screening in older women. HPV testing has generally been conducted by Southern blotting, PCR methods or commercially available dot-blot kits. Typing of high-risk and low-risk HPV strains is tedious with the two former methods, while the latter has so far been very selective and picks up only a few strains of each category. In addition to simpler typing procedures, quantitative data reflecting viral concentration have been warranted, since the viral load

Culture Confirmation and Tissue Pathogen Detection by Direct In Situ Hybridization

Though in situ hybridization (ISH) is typically performed in histology rather than clinical microbiology laboratories, it can provide extremely useful information to clinical microbiologists. Several pathogen targets have been used for direct hybridization to nucleic acid probes in situ. Bacterial targets include Helicobacter pylori (Makristathis et al., 2004), and Legionella spp. (Hayden et al., 2001b). Yeast forms of the dimorphic fungi (Hayden et al., 2001a), and molds such as Aspergillus spp., Fusarium spp., and Pseudoallesheria spp. (Hayden et al., 2002, 2003) have also proven to be useful as ISH targets. Typically, in situ hybridization is chosen when it is useful for the pathogen to be identified in association with intact cells or tissue, but branched DNA probes have been used to identify the presence of human papilloma virus (HPV) and the gene expression signal from HPV mRNA (Kenny et al., 2002). As a method for culture confirmation, PNA FISH (peptide nucleic acid fluorescent...

G cmyc as Target for Anticancer Therapy

In general, c-Myc inactivation in c-Myc-induced tumors results in proliferative arrest, re-differentiation, apoptosis, or and vascular degeneration. Nevertheless, the outcome of c-Myc inactivation varies in different c-Myc-induced tumors depending on cell type, context, genetic, and epigenetic features. Thus, even brief c-Myc inactivation resulted in sustained tumor regression in osteogenic sarcoma (Jain et al., 2002), whereas prolonged c-Myc inactivation failed to cause tumor regression in the majority of mammary adenocarcinomas (Boxer et al., 2004 D'Cruz et al., 2001). Generally, four different outcomes of c-Myc inactivation can be distinguished in c-Myc-induced tumors. (1) Tumor regression with initial differentiation of tumor cells followed by their complete permanent elimination through apoptosis (lymphoma, leukemia Felsher and Bishop, 1999a Karlsson et al., 2003a). (2) Tumor regression with differentiation into normal mature quiescent tissue (osteogenic sarcoma Jain et al., 2002...

Painted turtle herpesvirus Synonym for chelonid herpesvirus

Papilloma of chamois A parapox virus infection. See chamois contagious ecthyma virus. Papillomaviridae A family of viruses containing only one genus, Papillomavirus. The family description follows the genus description. Papillomavirus A genus of the family Papillomaviridae. Virions are 55nm in diameter, nonenveloped. The capsid is icosahedral composed of 72 capsomeres in a skewed (T 7) arrangement. The DNA genome is a single molecule of double-stranded DNA between 6.8 and 8.4 kb in length, G+C content 40-60 . Proteins are encoded on one DNA strand only, with 9-10 open reading frames called E1 to E8 and L1 to L2. Cause papil-lomas of the skin and mucous membranes in various species (cattle, deer, elk, reindeer, dog, humans, rabbit, horse, monkey, sheep, goat, elephant and birds) and are species-specific. Rarely cause transformation in cell cultures or CPE. Type species Cottontail rabbit papillomavirus. Chan S-Y et al (1992) J Virol 66, 5714 Myers G et al (1997) In Human...

Topical Microbicides Under Development 51 Preclinical

Human papillomavirus, human papillomavirus, Haemophilus ducreyi, HIV-1, Herpes simplex, human papillomavirus, Candida albicans HIV-1 Phase 1 (Vaginal Defense Enhancer) Phase 1 HIV-1, Treponema pallidum, Phase 1 Herpes simplex, Chlamydia trachomatis, Haemophilus ducreyi, Neisseria gonorrheae, Trichomonas vaginalis, BV-associated bacteria, Staphylococcus aureus, human papillomavirus HIV-1 Phase 1 human papillomavirus, Chlamydia trachomatis, HIV-1, Neisseria gonorrheae HIV-1, Chlamydia Phase 1

Clinical Manifestations

Syphilis Penis

Lesions of the Skin and Mucous Membranes. Numerous organisms can cause genital lesions that are diverse in both their appearance and their associated symptoms (Figure 58-2). The agents and their features of infection are summarized in Table 58-2. Some of these infections, such as genital herpes (caused by HSV) or genital warts (caused by HPVs and discussed in Chapter 51), are common, whereas others, such as lymphogranuloma venereum and granuloma inguinale, are uncommon in the United States. Of note, specific HPVs, referred to as genotypes, infect mucosal cells in the cervix and can cause a progressive spectrum of abnormalities classified as low-grade and high-grade squamous intra- Human papillomavirus

Orf subgroup viruses Synonym for parapoxvirus

Orf virus (ORFV) The type species of the genus Parapoxvirus. Virions are ovoid, 252 x 158nm, with a characteristic surface structure that appears in the electron microscope as a spiral coil or 'ball of yarn'. DNA genome 130-150kb, G+C is 64 . Virus is inactivated by chloroform, but ether may not inactivate. Causes disease predominantly in lambs and kids. There are vesicles on the lips and nose, progressing to pustules, ulcers and warty scabs. Malignant aphtha is a severe form of the disease which may be fatal. Papilloma of chamois is caused by Orf virus, and there is evidence of natural infection in dogs, goats, Himalayan tahr, musk-ox, reindeer, steenbok and alpaca. Man may be infected from animals but human-to-human infection is very rare. Does not naturally infect cattle but they can be infected experimentally as can rabbits, horses, dogs and monkeys. Dried scabs retain infectivity at room temperature for years. Virus does not replicate on the CAM but multiplies in ovine and bovine...

Hybrid Capture Technology

The hybrid capture 2 (HC2) technology is the platform for signal-amplified, nucleic acid tests (for review, seeLorincz and Anthony, 2001). HC2 systems areavail-able to detect human papillomavirus (HPV), cytomegalovirus (CMV), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), and hepatitis B virus (HBV). An assay for herpes simplex virus (HSV) is in development. Cervical cancer is one of the few malignancies for which the cause has been identified the human papillomavirus, a small DNA tumor virus that belongs to the family Papovaviridae and is sexually transmitted (Schiffman, 2000 Munoz, 2003). There are more than 100 types of HPV. Low-risk types of HPV may cause genital warts. High-risk types have been shown to cause most cases of cervical cancer. The HC2 HPV test uses two RNA probe cocktails to differentiate between carcinogenic and low-risk HPV types. Thirteen types are implicated in the pathogenesis of High-Grade squamous intraepithelial lesion (HSIL) and invasive cancer...

Degeneration And Aggregation Of Vzv

A readily available technique for the detection of virus is cytologic or histologic examination for the presence of characteristic viral inclusions. This involves the morphologic study of cells or tissue, respectively. Viral inclusions are intracellular structures formed by aggregates of virus or viral components within an infected cell or abnormal accumulations of cellular materials resulting from viral-induced metabolic disruption. Inclusions occur in single or syncytial cells. Syncytial cells are aggregates of cells fused to form one large cell with multiple nuclei. Pap- or Giemsa-stained cytologic smears are examined for inclusions or syncytia. Cytology is most frequently used to detect infections with VZV and HSV (see Figure 51-14, A). A stained smear of cells from the base of a skin vesicle used to detect VZV or HSV inclusions is called a Tzanck test. Inclusions resulting from infection with CMV, adenovirus, parvovirus, papilloma virus, and molluscum contagiosum virus are...

Papovavirus Replication

The term papovavirus stands for papilloma, polyoma, vacuolating viruses. Actually, members of the group fall into two distinct families the papillomaviruses and polyomaviruses. These two groups are similar regarding icosahedral capsids, circular genomes, and the ability to remain associated with the host for long periods, as well as their requirement to specifically alter cell growth in the host cell's response to neighboring cells for virus replication. They differ in genome size and in many details of host cell specificity.

In Situ Hybridization ISH Probes for Virus Detection Identification

ISH is an important technique for identifying and localizing viral nucleic acids associated with infectious disease and cancer. ISH has been used to determine the intracellular localization of the hepatitis viruses, human papillomaviruses, and herpes simplex viruses, and to detect these viruses. ISH has also been used to detect adenovirus, cytomegalovirus (Wu et al., 1992), JC virus, Epstein-Barr virus (Prange et al., 1992), and HHV-8 (Li et al., 1996). Human papilloma virus (HPV) is accepted as the primary causative agent in the development of cervical cancer. Although there have been approximately 100 HPV genomic types identified, most of these are not oncogenic and therefore do not lead to the development of cervical cancer. Those HPV genotypes that have been identified as types that contribute to the development of cervical cancer are categorized into intermediate and high risk HPV. ISH has been widely used to detect and differentiate HPV in cervical specimens. Dako Corporation...

Clinical Presentation

Ing along with diarrhea include Salmonella, Shigella, Campylobacter, enterohemorrhagic E. coli, enterinvasive E. coli, Clostridium difficile, Entamoeba histolytica, and Yersinia. Bleeding can also occur from viral agents, most commonly cytomegalovirus (CMV), which causes discrete ulcerations, herpes simplex virus (HSV), and human papillomavirus (HPV), which result in mass lesions that may bleed secondary to friability and trauma (Table 1).

Routes of Transmission

Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, human immunodeficiency virus (HIV), Treponema pallidum, Ureaplasma urealyticum, Mycoplasma hominis, other mycoplasmas, herpes simplex virus (HSV), and others may be acquired as people engage in sexual activity. In addition, other agents that cause genital tract disease and may be sexually transmitted include adenovirus, coxsackievirus, molluscum contagiosum virus (a member of the poxvirus group), the human papillomaviruses (HFVs) of genital warts (condylomata acuminata types 6, 11, and others) and those associated with cervical carcinoma (predominandy types 16 and 18, but numerous others are also implicated), Calymmatobacterium granulomatis, and ectoparasites such as scabies and lice. Some of these Genital and anal warts (condyloma) cervical dysplasia cancer Vaginitis Human papillomavirus

Herpes And Related Viruses

Pseudorabies Virus Herpes Virus

A series of anti-herpes agents were initially found to be immunomodulators via potent induction of interferon-alpha and other cytokines in rodents (65). The topical antiviral activity of the imidazo-quinolines imiquimod (39) and resiquimod (40) has since been realized, with the latter being launched as a topical product for genital warts and lesions related to human papilloma virus.

Chronic Myelogenous Leukemia and Acute Leukemias Current Diagnostics

Human Papilloma Virus Current Diagnostics In situ hybridization techniques are used to subtype the papilloma virus that may be found in premalignant lesions in uterine cervix. Most of the techniques use nonradioactively labeled avidin-biotin probes. A number of specific biotinlabeled probe cocktails are available for HPV subtype identification (e.g., HPV 6-11, 16-18, 31-33-35). Some of these techniques use chemiluminescent components to enhance the sensitivity of HPV subtype detection (H5).

Preanalytic Component

This has become the standard sample for analysis in the clinical molecular genetics laboratory, and it is fast becoming the sample of choice in pharmacogenetic studies. Cells derived from these samples can be archived or immortalized (although this is not done in clinical genetics laboratories) moreover, large amounts of DNA, sufficient for Southern blot analysis and many hundreds or even thousands of genotypes, can be secured. Collection specifications still include a prohibition on heparinized blood (largely for historical reasons) as well as clotted or hemolyzed blood samples (owing to their well-documented low DNA yields). An exception is viral load testing, in which plasma, rather than cells, is the subject of nucleic acid purification and testing. In HIV, HCV, hepatitis B virus (HBV), and human cytomegalovirus (HCMV) viral load testing, plasma alone is often subjected to extraction and analysis. In the case of HCMV and human papilloma virus (HPV), cells are often desirable test...

Cervical Cancer

Approximately 12000 women were newly diagnosed with cervical cancer in the USA in 2003.1 Although cervical cancer remains a leading killer of women worldwide, the incidence in the USA represents a significant decrease, mainly attributable to the widespread implementation of Pap test screening. The Pap smear is designed for detecting pre-invasive disease of the cervix. This allows treatment to be initiated prior to the development of cancer.2 Human papillomavirus (HPV) is a sexually transmitted virus associated with cervical dysplasia and invasive cancer. Low-risk HPV types, such as 6 and 11, are associated with cervical intraepithelial neoplasia (CIN) I and condyloma. High-risk types of HPV, such as types 16, 18, 31, 33 and 35, are observed in association with high-grade dysplasia or cervical cancer. HPV DNA can be detected in close to 100 of patients with invasive cervical cancer. Although the prevalence of HPV in some populations approaches 30-90 , only a small number of these women...

The Target Viruses

Papilloma against rare viral diseases. Front-line target viruses are therefore HIV-1, herpes, influenza and common cold viruses, with more recent attention on hepatitis B, hepatitis C and papilloma viruses. There is a further important fact which will encourage chemists to produce even more antivirals. A quasi-species RNA virus such as HIV existing as a 'swarm' of countless genetic variants will easily, by mutation and selection, evade the blocking effects of a single inhibitor. Therefore, as with tuberculosis, the practical answer is to find inhibitors of a wide range of virus-specific enzymes or proteins and to use them in a patient simultaneously. This search for new drugs will be a continuing need as it is with antibacterials. Similarly, inhibitors of pandemic and epidemic influenza A viruses will need the continuing attention of antiviral chemotherapists. The human herpes viruses (HHV1-8) cause a remarkably diverse range of important diseases and will continue to remain important...


The number of tetramers available for the study of CD8+ T-cell populations specific for various viruses is increasing e.g. influenza (26), HIV (19), EBV (27), CMV (28), hepatitis B virus (HBV) (29), hepatitis C virus HCV (30), human papillomavirus (HPV) (31), human T-cell lymphotrophic virus type 1 (HTLV-1) (32), RSV (33) and dengue virus (34) , covering a large range of HLA types. Together with these technological advances, a better identification of individuals in early stages of viral infections have facilitated more detailed studies of virus specific CD8+ T-cells found in human peripheral blood from primary infection to the establishment of viral latency. During primary infection, most viruses induce a substantial antigen-driven activation and expansion of CD8+ T-cells, referred to as the effector phase (35). The use of tetramers has revealed that T-cell frequencies in diverse viral infection are much higher than estimated previously. The expansion during the primary infection is...


P., In-situ hybridization for the diagnosis and typing of human papillomavirus. Clin. Biochem. 23, 301-306 (1990). C4. Coutlee, F., Provencher, D., and Voyer, H., Detection of human papillomavirus DNA in cervical lavage specimens by a nonisotopic consensus PCR assay. J. Clin. Microbiol. 33, 1973-1978 (1995). XI. Xi, F. L., Demers, G. W., Koutsky, L. A., Kiviat, N. B., Kuypers, J. et al., Analysis of human papillomavirus type 16 variants indicates establishment of persistent infection. J. Infect. Dis. 172, 747-755 (1995).

Tinea cruris

GENITAL WARTS Genital warts are caused by human papillomavirus (HPV). Those with genital warts usually report the appearance of lumps or growths on their genitalia. Occasionally other symptoms such as itchiness are reported. A diagnosis of genital warts is made by visualisation of the lesions. Genital warts usually appear in women at the introitus, vulva, perineum and perianal area, and in men on the penis, scrotum, urethral meatus and perianal area. It is less common to find them on the vaginal walls or cervix in women. Areas of friction during sex are more commonly associated with warts. Different morphologies exist condylomata acuminata are cauliflower-like peduculated warts that are skin-coloured warts may also be flat or dome-shaped. However, despite differing appearances most genital warts are caused by HPV type 6 or 11. Differential diagnoses include the condylomata lata of secondary syphilis and tumours either malignant or benign.

HC Technology

Amplification technology has made HPV DNA testing possible to reduce the incidence of cervical carcinoma substantially, especially in patients diagnosed with ambiguous low-grade lesions, such as ASCUS, or on Pap smears. Reflex HPV DNA testing of thin-layer preparations diagnosed as ASCUS will play a major role in the management of abnormal cervical cytology. Other applications, such as primary screening, in the future may play a substantial role in cervical cancer screening. In addition, a new way of processing liquid-based cervical cytology specimens by filtration-based processing method (NPM) exists for HPV DNA testing by HC2 (Castle, 2005). NPM reduces specimen handling and decreases total testing time by approximately 33 without significant losses in HC2 test performance.

Pegylated IFNa

In a prospective pilot study involving nine patients coinfected by HIV and HCV genotype 1, HIV replication showed a slow continuous decline during the first week of pegylated IFN-a administration, and there was no rebound when pegylated IFN-a was withdrawn (Neumann et al. 2007). Pegylated IFN-a was also reported to display antiretroviral activity in two patients with refractory HIV-related Kaposi's sarcoma (van der Ende et al. 2007) and in HIV-infected patients with condylomata acuminata (Brockmeyer et al. 2006). Finally, pegylated IFN-a has been shown to participate in early control of viral replication during primary HIV-1 infection when combined with antiretroviral drugs (Emilie et al. 2001). However, there was no control group in this study, and further investigations are therefore needed.


Gissman, L., Identification of human papilloma virus in genital tumors. Cancer Surv. 3, 161181 (1984). H5. Howley, P. M., Papilloma virinae and their replication. In Fundamental Virology (B. N. Fields and D. M. Knipe, eds), 2nd ed., pp. 743-768. Raven Press, New York, 1991. LI. Lorinez, A. T., Reid, R., Jenson, A. B., Green, M. D., Lancaster, W., and Kurman, R. J., Human papillomavirus infection of the cervix Relative risk associations of 15 common anogenital types. Obstet. Gynecol. 79, 328-337 (1992). Ml. Margall, N., Matias-Guiu, X., Chillon, M., Coll, P., Alejo, M., Nunes, V., Quilez, M., Rabella, N., Prats, G., and Prat, J., Detection of human papilloma virus 16 and 18 DNA in epithelial lesions of the lower genital tract by in situ hybridization and polymerase chain reaction. J. Clin. Microbiol. 31, 924-930 (1993).

Treatment Of Warts

Condylomata acuminata (genital warts) are benign proliferative tumours, and are caused by human papilloma viruses (HPV). These are double-stranded DNA viruses that infect squamous epithelial cells. There are different types of HPV, which can be either low-risk (can cause genital warts) or high-risk (can cause cancers). Most patients that are infected with HPV will remain unsymp- tomatic however, a small minority of patients will develop genital warts. Immunocompromised patients are more likely to develop systemic infections due to HPV. Disease symptoms can be physically painful and can cause considerable psychological distress. Podophyllotoxin is the purified form of podophyllin, an antimitotic agent, and it is a chemical, topical treatment that is used to remove genital warts.


Transillumination of the breast began in 1929 with the real-time viewing (diaphanoscopy) of the breast by a dark-adapted examiner (Cutler, 1929). The technique was found somewhat helpful in distinguishing cystic from solid lesions and, specifically, in suggesting the diagnosis of hematoma and retroareolar intraductal papilloma. After a period of initial interest, the technique lapsed into relative obscurity, only to be revived in France in the 1950s with the recording of hard-copy images (diaphanography) on photographic film. Subsequent modifications in technique resulted in improved diagnostic performance, but transillumination still was considered useful only as an adjunct to other breast diagnostic procedures, especially, for identifying hematomas and some benign breast cysts (Gros et al., 1972). Specifically, the technique was not able to distinguish reliably between benign and malignant breast masses. For this reason, and particularly because dramatic advances in mammography were...

Immune Response

Cell-mediated immunity (CMI) seems to play the major role in combating HPV infection. Genetic, acquired or iatrogenic CMI deficiencies are accompanied by high frequencies of cutaneous or genital warts as well as anogenital neoplasias. Cytotoxic T-lymphocytes, mainly directed against the E6 and E7 proteins, seem to play a crucial role. Natural cytotoxicity may also be important for immunosurveillance. HPV-transformed cells have been lysed by NK cells and activated macrophages, and their proliferation is inhibited by TNF-a. HLA DQW3 is associated with a higher risk of developing cervical carcinoma, suggesting an immunogenetically controlled susceptibility.

Groin And Pubic Area

In order to undertake a thorough examination of skin in the genital area it is essential to use a good light with magnification (Fuller & Schaller-Ayers, 2000). The pubic area needs to be checked for infestations, molluscum contagiosum, genital warts, ulceration, dermatosis etc. It is possible to see Phthirus pubis (pubic lice) on pubic hairs or attached to the skin. These can be easily removed and placed on a microscopy slide for microscopic observation. The eggs of the pubic lice can also be seen adhering to the pubic hairs. Infestation with Sarcoptes scabiei (scabies) mites can commonly be seen in the pubic region, where papular skin eruptions emerge over burrows made by the egg-laying female mites. Both pubic lice and scabies infestation can cause intense pruritus, and evidence of scratching may be visible on the skin. Molluscum contagiosum and genital warts are commonly diagnosed by visual examination of the genital and pubic skin. Small white or skin-coloured dome-shaped...

Rectal pain

Sexually transmitted infections need to be considered in anal lesions ulceration. Herpetic ulcers lesions can cause tenesmus and severe pain (BASHH, 2001b Morse et al., 2003), whereas the syphilitic ulcers lesions known as chancres are painless in nature (BASHH, 2002b Holmes et al., 1990). Herpetic lesions ulcers may look like clusters of blisters or healing sores, but often their appearance can be atypical. With syphilitic lesions in primary syphilis there is often one solitary circular sore but again this is not always the case. Swabs for Herpes simplex virus, microscopy and culture should be obtained, and dark-ground microscopy should be performed on wet mounts of serum and saline for Treponema pallidum as well as syphilis serology, which may have to be repeated in early suspected syphilis. Condylomata lata are mucosal lesions in secondary syphilis and tend to have a flatter appearance than anal warts, which are more papilliferous by nature (Holmes et al., 1990 Morse et al., 2003)....


Papillomaviruses The Papillomaviridae family (Table 51-14) includes the human papilloma viruses (HPVs). HPVs cause human warts. They have not been cultivated in cell culture, thus preventing the production of type-specific antigens and corresponding typing antisera. HPVs have been divided into more than 200 genotypes based on DNA sequences, approximately 80 of which have been well characterized. Genotypes have differing cellular tro- 730 PartVI VIROLOGY Table 51 -14 Papillomaviruses Family Papovaviridae Common Name Papillomavirus _ Characteristics Double-stranded DNA genome icosahedral capsid, no envelope includes papilloma viruses Virus Human papilloma virus (HPV) Characteristics Contains more than 200 DNA types Transmission Direct contact, sexual contact for genital warts Site of latency Epithelial tissue Disease Skin and genital warts, benign head and neck tumors, anogenital warts Diagnosis Cytology, DNA probes pisms, resulting in associations of HPV types with specific clinical...

Viral Esophagitis

Other rare viral causes of bleeding esophageal lesions include varicella zoster virus, human papillomavirus, and human immunodeficiency virus (HIV) (Fig. 3) (54,55). There are reports of isolation of HIV from esophageal ulcers in infected patients (56), suggesting a pathologic role of the virus. However, the role of HIV in the development of esophageal ulceration is still unclear, as the presence of HIV in the esophageal mucosa is common and often is independent of esophageal pathology (55,57).