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How To Manage And Live With Herpes

How To Manage And Live With Herpes Shows Herpes Sufferers How To Have Healthy, Happy Relationships Despite This Crippling Disease That Affects Millions Of New People Each Year. With This Simple-to-use Guide They Can Manage Herpes And Enjoy Love. Youre about to: Find out how to get rid of embarrassing sores and blisters and never suffer the embarrassment of looking like a zombie again. Discover how to keep those nasty outbreaks at bay with powerful natural remedies. Discover how to identify the 9 types of herpes and sleep better at night without fear of transmitting herpes. Understand why you have frequent herpes outbreaks. Re-invent your sex life and manage herpes simplex. Stop it from managing you! Learn about the one thing you Must know if you want to have 100% safe sex moving forward. Never feel guilty about infecting a partner again.

How To Manage And Live With Herpes Summary


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Timing Route Of Transmission And Clinical Manifestations Of Neonatal Herpes Simplex Virus

Intrauterine HSV disease occurs in approx 1 in 300,000 deliveries (1). Although rare, in utero disease is unlikely to be missed because of the degree of involvement of affected babies. Infants acquiring HSV in utero typically have a triad of clinical findings consisting of cutaneous manifestations (scarring, active lesions, hypo- and hyper-pigmentation, aplasia cutis, or an erythematous macular exanthem), ophthalmological findings (micro-opthalmia, retinal dysplasia, optic atrophy, or chorioretinitis), and neurological involvement (microcephaly, encephalomalacia, hydranencephaly, or intrac-ranial calcification) (2-5). A summary of 71 infants with intrauterine HSV infection and disease is presented in Table 1. HSV infections acquired either peripartum or postpartum can be further classified as (1) encephalitis, with or without skin, eye, or mouth (SEM) involvement (central ner- One-third of all neonates with HSV infection are categorized as having CNS disease (with or without SEM...

Laboratory Assays For The Diagnosis Of Neonatal Herpes Simplex Virus Disease

Because these methods have a sensitivity of only 60-70 , they should not be the sole diagnostic determinant for HSV infection in the newborn (39). For neonatal lesions, material from the vesicle should be obtained by scraping the periphery of the base of the lesion, smearing this on a glass slide, and promptly fixing it in cold ethanol. Following staining, the preparation should be viewed by a trained cytologist. The presence of intranuclear inclusions and multinucleated giant cells are indicative of, but not diagnostic for, HSV infection. In contrast to other congenital and neonatal infections, serologic diagnosis of HSV infection is not of great clinical value. With the licensure of reliable type-specific assays, one barrier to interpreting serologic results in babies with suspected HSV disease has been removed. However, the presence of transplacentally acquired maternal immu-noglobulin G still confounds the assessment of the neonatal antibody status during...

Herpes Zoster Ophthalmicus

This is caused by the varicella-zoster virus, the same virus that causes chickenpox. It is thought that the initial infection with the virus occurs with an attack of childhood chickenpox and that the virus remains in the body in a latent form, subsequently to manifest itself as herpes zoster in some individuals. The virus appears to lodge in the Gasserian ganglion. The onset of the condition is heralded by headache and the appearance of one or two vesicles on the forehead. Over the next three or four days the vesicles multiply and appear on the distribution of one or all of the branches of the fifth cranial nerve. The patient can develop a raised temperature and usually experiences malaise and considerable pain. Sometimes a chickenpox-like rash appears over the rest of the body. The eye itself is most at risk when the upper division of the fifth nerve is involved. There might be vesicles on the lids and conjunctiva and, when the cornea is affected,punctate-staining areas are seen,...

Diagnosis And Assays For Human Herpesvirus 8 Infection

Kaposi's sarcoma-associated herpesvirus a new DNA tumor virus. Annu Rev Med 2001 52 453-470. 2. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994 266 1865-1869. 3. Sarid R, Wiezorek JS, Moore PS, Chang Y. Characterization and cell cycle regulation of the major Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter. J Virol 1999 73 1438-1446. 4. Roizman B, Desrosiers RC, Fleckenstein B, Lopez C, Minson AC, Studdert MJ. The family Herpesviridae an update. Arch Virol 1992 123 425-449. 5. Moore PS, Gao SJ, Dominguez G, et al. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol 1996 70 549-558. 6. Renne R, Lagunoff M, Zhong W, Ganem D. The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 1996 70 8151-8154. 7. Russo JJ, Bohenzky...

Herpesvirus Infections

The family of human herpesviruses encompasses the following important DNA viruses with strong affinity for the nervous tissue Herpes simplex type 1 virus (HSV-1) Herpes simplex type-2 virus (HSV-2) Cytomegalovirus (CMV) Human herpes viruses 6 and 7 (HHV 6 and 7) Herpesviruses, distributed worldwide, may infect the fetus in utero, neonates, and individuals of all ages. The initial infection may be inapparent or mild, producing fever, adenopathy, and nonspecific respiratory symptoms. Characteristically, following an initial infection, HSV-1, HSV-2, and VZV latently reside in the neurons, and CMV and EBV in the hematopoietic cells. Malignancies, febrile illnesses, diabetes, age-related decline of the immune system, and even emotional stress are potential risks for the reactivation of a latent infection. Among immunosuppressed individuals, those with HIV infection are most vulnerable. Once the viruses are reactivated, a variety of neurologic diseases arise in both immunocom-petent and...

Herpes Simplex Virus1 Infection

Herpes simplex virus-1 infection is the major cause of sporadic and malignant encephalitis, chiefly in adults and young subjects. The infection is acquired by exposure to contaminated saliva or respiratory secretion. The virus initially causes a nasopharyngitis. By retrograde axonal transport, it reaches the trigeminal ganglia, where it becomes latent. Reactivation of the virus produces herpes vesicles on the lips (cold sore) or oral mucosa. The brain is infected by spread of the virus along the trigemi-nal nerve roots or dural nerves to the meninges and then to the frontal and basal temporal regions. Alternatively, it is suggested that a nasopharyngeal infection spreads along the olfactory nerves to the frontobasal and temporal regions, evoking an acute encephalitis. Herpes simplex virus-specific DNA is identified in the CSF using PCR. Neuroimaging adds to the diagnosis. CT scan during the early course of the disease shows bilateral, often asymmetrical, low densities in the orbital...

Cytomegalovirus Infection

Neurologic diseases associated with cytomegalovirus infection are more often encountered in immunocom-promised particularly HIV-infected patients. The infection is acquired by exposure to infected saliva or respiratory secretion, transfusion, and possibly by sexual contact. Fetuses are infected by transplacental transmission and, neonates are infected by feeding with infected breast milk.

Herpes Simplex Infection

There are two main types of herpes simplex viruses (HSV). HSV type 1 infects the tissues around the lips and mouth (and rarely the eye), while HSV type 2 causes genital infections. Herpes produces recurrent clusters of small, painful blisters containing the virus. HSV infections are common it is estimated that 20-40 of the US population have recurrent infections of one or both forms. HSV type 1, in otherwise healthy adults, is not dangerous, but genital herpes occuring during pregnancy and delivery can produce a life-threatening infection in the newborn. Although most people are exposed to herpes viruses (contact with HSV type 1 is nearly universal), not everyone develops a recurrent

Herpes Zoster

Herpes zoster (shingles) results when the viruses pass from the ganglia to the skin along the sensory nerves. It commonly occurs in adults, and the incidence increases in the elderly. Clinically, herpes zoster manifests with erythematous vesicles in the skin, associated with pain and sensory deficits in the dermatomes that correspond to the involved ganglia. Common sites are the thoracic dermatomes, the ophthalmic division of the trigeminal nerve (ophthalmic zoster), and the somatosensory branch of the facial nerve (otic zoster). Notably, painful radicular neuropathy may occur in the absence of cutaneous changes. Postherpetic neuralgia is often a protracted disabling complication with severe pain and paresthesias. The pathology of herpes zoster is a radiculogangli-onitis with mononuclear cell infiltrates. In severe cases, the ganglia are hemorrhagic and necrotic, and the inflammation extends into the spinal cord.


The hypothesis that viruses might be associated with the development and progression of atherosclerosis has been around for years, but despite substantial effort, a strong association has yet to be confirmed. The most likely candidate is cytomegalovirus (CMV), a member of the herpes virus family. Researchers discovered in the midtwentieth century that a herpes virus was the cause of a malignant disorder in chickens called Marek lymphomatosis (69). Chickens with this disease also developed significant atherosclerosis, raising the question, could other herpes viruses capable of infecting humans also induce atherosclerosis (70)

Other Herpesviruses

Although CMV has the most information regarding its potential role in the development and progression of coronary atherosclerosis, a variety of other viruses have also been implicated. Herpes simplex virus (HSV) has been associated with atherosclerosis in a variety of ways. In vitro studies of HSV-1 and HSV-2 have demonstrated the presence of similar potentially proatherogenic mechanisms similar to those found with CMV. Specifically, HSV infection leads to lipid accumulation in vascular cells, attraction of leukocytes with subsequent inflammatory damage, and induction of procoagulant changes on endothelium, with increased thrombin generation and platelet adhesion. It also has been shown that HSV causes atherosclerosis in experimental animals. From a clinical standpoint, several investigators have reported the detection ofHSV in some, but not all, atherosclerotic lesions. As with a variety of other antibody studies, serological evidence ofHSV infections is common, not only in...

Herpes Simplex Virus

Herpesviruses are promising vehicles for transferring genes into cells. Among this virus family, herpes simplex virus type 1 (HSV-1) is the most extensively studied for potential use in human We found that CLL B-cells are highly sensitive to infection with vectors derived from replication-defective (rd)HSV-l (29). CLL B-cells express high levels of herpesvirus entry mediator (Hve)A, but not HveC, the other known receptor for HSV-1. In contrast to B-cells of normal donors, CLL B-cells are relatively resistant to the cytopathic effects of infection by rdHSV-1 and can maintain high-level expression of the transgene for many days after infection, possibly because of the high-level expression of anti-apoptotic genes, e.g., BCL-2, by CLL cells. Consistent with this hypothesis, we found that transduction of HeLa cells with a retrovirus expression vector encoding BCL-2 rendered HeLa cells resistant to the cytopathic effects of rdHSV-1 (29).

The History Of Aids Psychiatry

In 1981, previously healthy young men and women were being admitted with pneumonia and severe respiratory distress to the intensive care unit of our municipal academic medical center in New York City. They were dying of respiratory failure. The reason for these deaths was not clear. At about the same time, Michael Gottlieb, an immunologist in an academic medical center in Los Angeles, California, began to investigate the reasons for the occurrence of Pneumocystis carinii pneumonia (PCP) in five previously healthy young men. On June 5, 1981, his report of these cases was published in the Morbidity and Mortality Weekly Report (CDC, 1981a). Gottlieb's first patients were also described as having cytomegalovirus and candida infections. In a more detailed article, published on December 10, 1981, in the New England Journal of Medicine, Gottlieb and colleagues (1981) linked an immune deficiency with this new cluster of infections. They presented evidence for an association ofthe illnesses...

Diagnosing Infection By Serologic Means

Agents such as cytomegalovirus (CMV) or HIV, the need to make a rapid diagnosis increased in importance. In the following sections, various strategies used to diagnose congenital infections, particularly those comprised by the TORCH (toxoplasmosis, other infections, rubella, CMV, and herpes simplex virus HSV ) agents, are explored. It should become obvious that they all have shortcomings. As a consequence, and with the development of more rapid and specific nucleic acid detection methods, assays utilizing polymerase chain reaction amplification of specific pathogen-related nucleic acid has largely supplanted serologic methods. natal or prenatal serum titer. IgM, although produced in acute infection, may also persist for long periods of time, as evidenced by detection of toxoplasma-specific IgM in 7 of pregnant women who were infected prenatally (12). IgM may persist for more than 1 year after acute infection (13). In addition, for viruses that cause chronic infection (i.e., the...

Tiziana Lazzarotto Maria Paola Landini

Human cytomegalovirus (CMV) is one of the eight viruses belonging to the Her-pesviridae family to infect humans. CMV belongs to the Betaherpesvirinae subfamily of viruses characterized by a restricted host spectrum, in vitro replication in fibroblasts of the natural host species in vivo, a slow replication cycle, the induction of intranuclear and intracytoplasmic inclusions and the ability to induce latency mainly in the myeloid cell linage.

Isolation And Identification

The selection, transport, storage, and processing of the specimen are crucial for isolation attempts to be meaningful. The ideal specimen is taken from the site of the lesion or symptoms as early in the course of the illness as possible. The risk of fetal exposure or infection is determined by the status of the mother. Herpes I or II, enterovirus, rubella, and varicella-zoster virus (VZV) are some of the viruses that may be isolated and that are clinically relevant to the fetus or newborn. Other important agents such as hepatitis B virus, HIV, and parvovirus B-19 are either extremely difficult to culture or cannot be cultured. Viral isolation attempts are initiated by inoculating specimen aliquots into tubes or bottles of cell cultures. Companion control and inoculated cells are incubated at 33 C for growth of respiratory viruses and at 36 C for optimal growth of other viruses. For some viruses, growth is enhanced by continuous slow rotation of the tubes. The cultures are examined...

Acute Chorioamnionitis

Chronic inflammation of the fetal membranes has rarely been described in conjunction with viral infections including herpes simplex virus (HSV) (53), rubella (54), and toxoplasmosis (55). Chronic chorioamnionitis tends to be most often associated with nonspecific chronic inflammation elsewhere within the placenta, such as villitis of undetermined etiology (VUE) (56). It is usually focal, rarely involves the amnion connective tissue, and does not result in necrosis of the amnion epithelium (57). Chronic chorioamnionitis is often associated with chronic inflammatory lesions elsewhere within the placental or decidual tissues but can occur as an isolated phenomenon.

Etiology and Pathogenesis 361 Etiology

In carcinoma of the thyroid in young people has been discussed elsewhere 4 . The highest incidence rates for NPC are found in parts of the Far East where it occurs in association with EBV infection. The rare cases of NPC in young people in Western developed countries may also be associated with EBV, and this should be explored, but it is likely that other cofactors are involved 67 . Carcinoma of the cervix and uterus, although typical of older age groups, is relatively frequent in young adult females and appears to be closely linked with sexually transmitted infections including herpes simplex virus type 2 and human papilloma virus 65 . Other carcinomas seen in adolescents and young adults that occur typically in later life may be strongly associated with genetic predisposition at young ages, as will be discussed below.

Lonnie Minera James F Bale

Herpes simplex virus (HSV) infection of the newborn is an important, potential source of morbidity and mortality among young children. Neonatal HSV infections can be categorized as (1) mucocutaneous (infection localized to the skin, eye, and or mouth) (2) disseminated (infection involving multiple organs or tissues, including the central nervous system (CNS)) or (3) encephalitic (infection of the CNS with or without skin lesions). In addition, 5-10 of HSV infections in the neonatal period result from intrauterine (also called, congenital) infection. The polymerase chain reaction (PCR) has greatly improved the detection of HSV infection at all ages, including the neonate. However, as many as 25 of the infants with proven CNS HSV infections have negative PCR studies of the cerebrospinal fluid. Despite impressive advances in the development of antiviral therapies and in the medical management of infants with perinatal HSV infections, many infants die or have permanent neurodevelopmental...

Pathogenesis Of Intrauterineacquired Maternal Hematogenous Infection

Villitis attributable to specific infectious agents is the exception, probably accounting for only 5 of all villitides (2). Acute villitis is seen in maternal sepsis with organisms such as Escherichia coli, group B streptococcus, and L. monocytogenes (Fig. 9B). The inflammatory infiltrates in VUE and known infectious etiologies are similar (77) and have provided circumstantial evidence that VUE is the result of chronic infection (80, p. 261). Most investigators are less convinced of an underlying pathogen in most cases of VUE. The most significant difference in VUE and the specific villitides appears to be the presence of significant numbers of plasma cells, which should be a warning to rule out infectious agents, particularly cytomegalovirus (CMV) (Fig. 9C), syphilis, and HSV. Granulomatous villitis (Fig. 9D) may be seen in infection with organisms that cause granulomatous inflammation elsewhere and include mycobacte-rium, toxoplasmosis, herpes simplex virus, and varicella.

Stress Management And Psychiatric Interventions

There were also changes in indicators of antiviral immunity over the 10-week intervention period. Men assigned to either CBSM or exercise interventions showed significant decreases in IgG antibody titers (reflecting better immunologic control) to EBV and HHV-6, which moved into the normal range for age-matched healthy men. This was in contrast to IgG antibody titer values for assessment-only controls, which remained elevated (Esterling et al., 1992). The reductions in EBV IgG antibody titers in the CBSM group appeared to be mediated by the greater social support levels maintained in this condition (Antoni et al., 1996). Finally, a 2-year follow-up of the HIVpositive men in this trial found that less distress at diagnosis, decreased HIV-specific denial coping after diagnosis, and better participant adherence to CBSM treatment protocol all predicted slower disease Similarly, reductions in anxiety during the 10-week intervention period have been observed to co-vary with decreases in...

Risk Of Maternal Infection During Pregnancy

Genital herpes occurs with a frequency of about 1 at any time during gestation (15,16). Recurrent genital herpes infections are the most common form of genital HSV during gestation (13). However, as discussed below, it is the woman with primary HSV disease who is at highest risk of transmitting the virus to her baby. About 10 of HSV-2-seronegative pregnant women have an HSV-2-seropositive sexual partner and thus are at risk of contracting a primary HSV-2 infection (17). Among such discordant couples, women who are seronegative for both HSV-1 and HSV-2 have an estimated chance of seroconversion for either virus of 3.7 those women who are already seropositive for HSV-1 have an estimated chance of HSV-2 seroconversion of 1.7 (18). Approximately two-thirds of women who acquire genital herpes during pregnancy have no symptoms to suggest a genital HSV infection (18). Several prospective studies have evaluated the frequency and nature of viral shedding throughout pregnancy in women with a...

Risk Of Neonatal Infection

Factors that influence transmission from mother to neonate include type of maternal infection (primary vs recurrent), maternal antibody status, duration of rupture of membranes, and integrity of mucocutaneous barriers (e.g., use of fetal scalp electrodes). Several studies have demonstrated that infants born to mothers who have a first episode of genital HSV infection near term are at much greater risk of developing neonatal herpes than are those whose mothers have recurrent genital herpes. In three separate studies, 3 of 6, 2 of 6, and 6 of 18 infants born to mothers with first episode (primary or initial) genital HSV infections at delivery developed neonatal infection, for an overall attack rate of 36.7 (11 of 30 infants) (16,25,30). In contrast, among infants delivered to mothers with recurrent HSV infection and documented viral shedding at the time of delivery, the rate of neonatal infection has been reported to be between 3 (25) and 4.3 (16). Last, the application of fetal scalp...

Clinical Evaluation Of The Infant

The vesicular rash that occurs with HSV infection may be confused with the cutaneous manifestations of other infectious diseases, such as varicella-zoster virus infection, postnatally acquired enteroviral disease, and disseminated cytomegalovirus infection. Such distinctions are especially difficult when HSV assumes an atypical cutaneous presentation. Definitive confirmation of HSV disease can be achieved by culture of the skin vesicles. Noninfectious cutaneous conditions such as incontinentia pigmenti, acrodermatitis enteropathica, erythema toxicum, and neonatal melanosis should also be considered. Lesions associated with these diseases can often be distinguished rapidly from those caused by HSV by the presence of eosinophils on staining of a tissue scraping, by peripheral eosinophilia, and by appropriate viral cultures.

Virus Characteristics

CMV is morphologically similar to other herpesviruses and is the largest member of the family (2). The virus consists of a 64-nm core enclosed by a 110-nm icosahedral capsid. The capsid is surrounded by a poorly defined amorphous tegument that itself is surrounded by a loosely applied, lipid-containing tegument (2). The genome of CMV consists of linear double-stranded deoxyribonucleic acid (DNA) molecule approx 240 kb (3,4). The genome of CMV is similar to that of herpes simplex virus in that it has long and short unique segments, both of which are bounded by homologous repetitive sequences. The CMV genome is approx 50 larger than herpes simplex virus and encodes for at least 35 structural proteins and an undefined number of nonstructural proteins (5). Although the replication of CMV is very similar to that described for herpes simplex virus, the replicative cycle is much slower than for herpes simplex (6).

Annexin 2 And Viral Infection

In addition to possible roles in bacterial infection, annexin 2 is also implicated as a co-receptor for a number of viruses. It was identified as a potential receptor for respiratory syncytial virus (RSV) on Hep2 cells, binding to the viral G-protein, and indeed its expression was increased following viral infection (Raynor et al., 1999 Malhotra et al., 2003). Annexin 2 has also been identified as a co-receptor for cytomegalovirus (CMV) (Adlish et al., 1990 Taylor and Cooper, 1990 Raynor et al., 1999) and was localised to the surface of the mature virion by immunofluorescence (Wright et al., 1994) where it interacts directly with the viral glycoprotein B (Pitropaolo and Compton, 1997). Annexin 2 on the surface of the virion and on the host endothelium have both been implicated in the process of infection, though the direct role of annexin 2 in this regard remains speculative. It was not found to be necessary for CMV infection of fibroblasts (Pitropaolo and Compton, 1999), which...

Infectious Vasculitis

A number of bacteria and fungi that infect the nervous system often produce an acute inflammatory, necrotizing, or chronic granulomatous vasculitis of the cerebral blood vessels. Spirochetes may infect the blood vessels Treponema pallidum in neurosyphilis and Borrelia burgdorferi in Lyme disease. HIV-associated vasculitis is prone to cause ischemic episodes in both adults and children. Vasculitis of the large cerebral arteries accounts for the hemiplegia that develops contralaterally to a facial or ocular herpes zoster infection. Post varicella vasculopathy is a potential risk for stroke in children.

Allergic Conjunctivitis

Keratoconjunctivitis have a higher risk than normal for the development of herpes simplex keratitis the condition is also associated with the corneal dystrophy known as keratoconus or conical cornea. They are likely to develop skin infections and chronic eyelid infection by staphylococcus. The recurrent itch and irritation (in the absence of infection) is relieved by applying local steroid drops, but in view of the long-term nature of the condition, these should be avoided if possible because of their side effects. (Local steroids can cause glaucoma in predisposed individuals and aggravate herpes simplex keratitis.)

Monoclonal Antibodies

Alemtuzumab has been explored as a treatment for relapsed or refractory CLL in several clinical trials. A consistent response rate of 30-40 , and PFS of approximately 1 year in responders, is reported by these studies when the drug is administered at 30 mg as an IV infusion three times a week for 3-4 months.16-20 Alemtuzumab is particularly useful in the treatment of CLL characterized by 17p deletions that are known to be chemotherapy resistant.21 The drug is associated with significant and sometimes severe infusion reactions, however. These reactions are muted, with no apparent loss of efficacy, when alemtuzumab is administered sub-cutaneously, though this administration route in no way abrogates its immunosuppressive side effects.22,23 Patients treated with alemtuzumab require antimicrobial prophylaxis against bacteria, Pneumocystis jeroveci, and Herpes viruses.24 In addition, there is a substantial risk of cytomegalovirus reactivation and infection that requires a high level of...

Asad Ansaria Adriana Weinbergb

Human herpes viruses (HHV) 6 and 7 are two of three recently identified members of the human herpes virus family. They infect most of the human population by early childhood and exhibit properties similar to other herpes viruses including lifelong infection, asymptomatic shedding and periodic reactivations during periods of immune suppression, which may or may not be clinically relevant. The asymptomatic shedding, mainly in the saliva, is the major source of transmission, and hence a formidable barrier to disruption of transmission. These viruses cause self-limited infections in immunocompetent individuals, but have been associated with serious morbidity and mortality in immunocompromised hosts, especially HHV-6B. Patients with immunosuppression may be treated with manipulation of the immune system and use of antiviral medications. No vaccine candidate is being currently studied for either of the two viruses. Salahuddin et al. (1986) first isolated the human herpes virus (HHV) 6 from...

Types of Corneal Ulcer

Examination reveals conjunctival congestion,which is often mainly localised to an area adjacent to the corneal ulcer. The ulcer is often seen as a white crescent-shaped patch near the corneal margin but there is usually, but not always, a small gap of clear cornea between it and the limbus (the corneoscleral junction). Such marginal ulcers are thought to be caused by exotoxins from S. aureus, mainly because they are often associated with S. aureus blepharitis. On the other hand, it is not possible to grow the organism from the corneal lesion, and for this reason, it is said that the infiltrated area is some form of allergic response to the infecting organism. Furthermore, these marginal ulcers respond rapidly to treatment with a steroid-antibiotic mixture. It is essential that the usual precautions before applying local steroids to the eye are taken, that is to say, the possibility of herpes simplex infection should be excluded and the intraocular pressure should be...

Alternative Tissue Sources

Another important issue is the potential of ES cells to form tetra-carcinomas, because remaining undifferentiated ES cells in grafted cell suspension can continue to divide, forming tumors. For example, Bjorklund et al. (65) grafted a mouse ES cell line into a rat model of PD and reported that five out of 25 grafts formed teratoma-like tumors, with consequential death of the animals. One method for eliminating undifferentiated cells is introducing suicide genes, such as the E. coli gpt and herpes thymidine kinase (HSVtk), into the cells prior to transplantation. Differentiated ES cells are resistant to the effects of ganciclovir. Therefore, the presence of a neo-mycin resistance gene in the plasmid vector allows selection of the undifferentiated ES cells out of the cell suspension. Undifferentiated HSVtk-positive cells that continue to proliferate can then be destroyed by the conversion of prodrug nucleoside ganciclovir to its phosphorylated form, which is then incorporated into the...

Absent Corneal Sensation

Corneal anaesthesia can result from a lesion at any point in the fifth cranial nerve from the cornea to the brainstem. In the cornea itself, herpes simplex infection can ultimately result in anaesthesia. Herpes zoster is especially liable to lead to this problem and, because this condition can often be treated at home rather than in the ward, it will be considered in more detail here.

Genetically Engineered Cells

The herpes simplex viral (HSV) vector was the first virus to be tested to introduce genes into the adult CNS (135-137). More recently, other viral vectors have been introduced, including adenovirus, the recombinant adeno-associated virus (rAAV), lentivirus, and pseudotyped vectors. The rAAV vector is more efficient than the HSV because it achieves much higher levels of expression. The use of such vectors has allowed genes to be transferred to a specific group of cells in the CNS (138) and has provided support for the efficacy of such factors as glial cell line-derived neurotrophic factor (GDNF) for PD (139-142) and ciliary neurotrophic factor (CNTF) for HD (143-146).

Longterm Complications

The initial concern for patients treated with the purine nucleosides was for an increased risk of infection and the development of second malignancies due to the profound long-term suppression of CD4 and CD8 lym-phocytes.27 28 However, a significant increase in infections is not seen in patients who have responded to treatment and have normal neutrophil counts. In our series, during the 7-year median follow-up, only herpes zoster was seen in remission patients.24

Materials and Methods

Because of duplication and paralogous sets of genes, a second level of homology detection was employed. After initial clustering, larger clusters that contained more than one gene per genome were 'pruned' using a second algorithm described in the following section. An e-value cutoff was chosen manually to minimize cluster overlap and generate the greatest number of ideally sized clusters. For Baculovirus cluster iterations, this e-value was 1e-12. This ideal value varies for different datasets, but tests with Poxviridae and Herpesviridae (data unpublished) suggest that this value works well for many large viral genomes.

Telomere Studies And Hiv Pathogenesis

The telomere shortening and the presence of CD28 T cells observed in HIV disease is a more dramatic example of events that also occur in healthy individuals, and may possibly reflect a common pattern of T-cell dynamics with respect to pathogens in general. In HIV-seonegative individuals, the proportion of T cells lacking CD28 expression increases progressively with age, from 1 in newborns to levels of 35 in centenarians (Azuma et al., 1993 Boucher et al., 1998). Interestingly, at all ages, cells with this phenotype are significantly more prevalent within the CD8 versus CD4 subset. The notion that at least some of these expanded clones were originally generated during acute antiviral responses is supported by observations in mice that secondary responses are composed of the same clonotypes dominating the primary responses (Mar-yanski et al., 1996). In humans, maintenance of specific T-cell receptor (TCR) clonotypes at high frequencies in the circulating CD8 T cells has been observed in...

Varicellazoster virus

Chickenpox (varicella) was rarely recognized until the sixteenth century. The name is thought to be derived from the Old English gican, meaning itch. While shingles (herpes zoster) has been recognized as a unique clinical entity, varicella was differentiated from smallpox by the English physician Heberden in 1767. The relationship between chickenpox and shingles was first noted in 1898 by the Hungarian pediatrician Bokay. In 1952, the American virologists Weller and Stoddard first isolated the etiologic agent of varicella and zoster, the varicella-zoster virus (VZV), The VZV is a member of the Alphaherpesvirinae subfamily within the family Herpesviridae. The spherical, 120-300 nm large particle of virus consists of a linear double-stranded DNA genome with about 125,000 base pairs and an icosahedric capsid composed of 162 capsomers. This nucleocapsid is surrounded by the tegument made up of glycoproteins as well as a trilaminar glycoprotein- and lipid-containing envelope. VZV cannot be...

Strategies To Enhance Dna Vaccine Potency

Another strategy for increasing the number of antigen-expressing DCs is to promote the spread of an encoded antigen between DCs by linking the antigen with proteins capable of intercellular transport. We have investigated the use of DNA encoding HPV-16 E7 fused to herpes simplex virus type 1 VP22 (HSV-1 VP22), a viral protein with intercellular trafficking properties, in a DNA vaccine. In vivo experiments showed that the vaccine dramatically enhanced E7-specific CD8+ T cell responses and generated greater antitumor effects than did DNA vaccines encoding E7 alone 3 . We then generated a vaccine encoding E7 linked to Marek's disease virus type 1 VP22 (MDV-1 VP22), a protein with some homology to HSV-1 VP22, and observed powerful vaccine-elicited antitumor immunity as well 4 .

Risk Of Fetalneonatal Infection

Zoster during the first year of postnatal life, which is normally exceedingly rare, is extremely common in children with the congenital varicella syndrome 18 of reported cases have manifested zoster (7). This occurrence probably also relates to an increased incidence of latent infection when varicella develops in fetal life. By analogy, in animal models of latent infection with herpes simplex virus, the incidence of viral reactivation is directly related to the extent of latent infection in ganglia (11).

Prenatal Evaluation Of Mother

Women who have varicella while pregnant bear close medical attention. They should be carefully observed for development of disseminated VZV infection. Severe varicella may be manifested by high fever, chest or abdominal pain, shortness of breath, and cough. In severe cases, there may be hundreds to thousands of skin vesicles, which may become hemorrhagic and continue to erupt for many days. For best results, treatment should be started before this stage has been reached. As has been noted, the risk is greatest in the last trimester of pregnancy. Women who appear to be developing severe varicella should receive prompt treatment with intravenous acyclovir.

Clinical Evaluation Of Infant

Babies whose mothers have the onset of rash in the high-risk period (4 days before to 2 days after delivery) do not need any particular diagnostic workup, but they should be given VZIG as soon as possible after birth. About 50 will nevertheless develop varicella, which is usually mild. A small percentage, however, may develop more severe varicella and require antiviral therapy. Treatment for these infants must be individualized carefully with close follow-up. It is preferable to overtreat in the sense of administering intravenous acyclovir to babies who may not turn out to need it rather than to withhold medication until an infant has developed full-blown disseminated varicella, which may be rapidly fatal. Infants with possible severe varicella should have a complete blood cell count, liver chemistries, and a chest x-ray at the bare minimum. A lumbar puncture is usually not indicated. Skin lesions that appear to be caused by varicella may be cultured for virus, tested for VZV antigens...

Diagnostic Assays For Evaluation Of Infant And Mother

Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy prospective study of 1739 cases. Lancet 1994 343 1548-1551. 11. Lekstrom-Himes JA, Pesnicak L, Straus SE. The quantity of latent viral DNA correlates with the relative rates at which herpes simplex virus types 1 and 2 cause recurrent genital herpes outbreaks. J Virol 1998 72 2760-2764.

Historical Perspectives

Cause the common cold in humans and induce sarcomas in newborn hamsters and rats and (4) such herpesviruses as Herpes saimiri, which is indigenous in the New World squirrel monkey and may induce lymphosarcomas and leukemias when inoculated into certain species of monkeys. Table 2-4 lists some of the different types of RNA and DNA oncogenic viruses.

Description Of Organisms

HHV-6 and HHV-7 are closely related to human cytomegalovirus (CMV). Like all herpesviruses, HHV-6 and HHV-7 possess a nucleocapsid containing deoxyribonucleic acid (DNA), surrounded by a dense tegument and a lipid envelope (6). Although HHV-6 and HHV-7 DNAs possess a high degree of homology, there are distinct antigenic differences (7). Two subtypes of HHV-6 (A and B) have been described (8). Most cases of roseola are caused by subtype B (9,10), and the few congenital HHV-6 infections evaluated thus far have also been caused by subtype B. No disease has been consistently associated with subtype A, although it may be found more frequently in African children (11). HHV-7 subtypes have not been reported. HHV-6 and HHV-7 infections occur early in life. Almost all newborns possess maternally derived antibodies, but by age 6 months, most have lost maternal antibodies and are susceptible to infection. Acquisition of HHV-6 occurs rapidly, with 50-60 of children becoming HHV-6 seropositive by...

Adoptive immune therapy

In these early studies, LAK cells were derived from peripheral blood mononuclear cells and activated ex vivo with high-dose IL-2. Ex vivo activated LAK cells were capable of lysing tumor cells in a process unrelated to major histocompatibility proteins (25). After initial preclinical success, clinical efforts focused on the use of LAK cells and IL-2 in the treatment of solid tumors such as renal cell carcinoma and melanoma. Unfortunately, no advantage has been clearly demonstrated for the administration of LAK cells and IL-2 over administration of IL-2 alone in metastatic cancer (26). Recent studies have offered an explanation for the limited therapeutic efficacy of LAK cells, given their inability to home exclusively to the tumor (27,28). A search for more potent killer cells has led to the discovery of tumor-infiltrating lymphocytes (TILs) (29). With the phenotype of cytotoxic lymphocytes, these cells kill in a major histocompatability complex (MHC)-restricted...

Viral Diagnostic Assays And Their Interpretation

Because of the rarity of congenital or perinatal HHV-6 and HHV-7 infections as well as the apparent absence of serious consequences in the majority of patients, no standards for diagnostic testing have yet been established. However, numerous tests have been developed for the diagnosis of HHV-6 and HHV-7 infection in other age categories and have been used in studies evaluating newborns for suspected congenital and acquired infections. Specific testing for HHV-6 or HHV-7 infection may include Laboratory Tests Used for Distinguishing Active From Latent HHV-6 and HHV-7 Infections In considering performance of these viral tests, one must remember the latent nature of these herpesviruses and understand that tests differ in their ability to distinguish nonreplicating, latent virus from replicating, active virus (Table 2). The presence of HHV-6 or HHV-7 DNA in PBMCs or other cellular material indicates viral infection but does not necessarily imply viral disease because these viruses persist...

Classification Of Aa Based On Etiology And Pathophysiologic Mechanisms

In many respects, clinical and pathophysiologic features of AA suggest a possible infectious etiology. Most commonly, viruses have been implicated. Over the years, many of the suggested agents have been excluded as etiologic factors. The search for AA agents has been extensive. Hepatitis B and A were proven not to be the causative agent for typical AA. Similarly, cytomegalovirus (CMV), although certainly capable of producing bone marrow suppression under certain clinical circumstances, such as following stem cell transplantation, is not responsible for idiopathic AA. Certain serologic CMV types have been implicated in transplantation-refractory AA, but these studies have not found application to explain typical AA.48-50 A series of cases clearly

Epidemiology And Routes Of Transmission

The prevalence of HHV-8 infection has not yet been firmly established, but it seems to vary among different populations and in different regions of the world. Unlike most other herpesviruses, HHV-8 infection does not seem to be widely distributed in most populations. The frequency of infection appears to be low in the general population in North America, certain Asian countries, and in northern European nations such as the United Kingdom and Germany (18,19). In these countries, the seroprevalence of HHV-8 in different risk groups mirrors the incidence of AIDS KS, with a seroprevalence rate of between 25 and 50 among homosexual men. In other countries such as Italy, Greece, and Israel, especially southern Italy, the infection rate seems to be much higher in the general population and is more variable, ranging between 5 and 35 . A likely route of nonsexual transmission is via saliva. Oral and nasal secretions have been hypothesized to be a source of HHV-8 infection, similar to other...

Neuroinflammatory Imaging

Cecil et al. (41) reviewed the newer structural or metabolic imaging tools in brain inflammation and concluded that proton MR spectroscopy is a sensitive and specific imaging tool in Creutzfeldt-Jakob disease, herpes simplex encephalitis, and AIDS, indicating its usefulness in longitudinal studies for predicting and monitoring the response to therapy (41). Likewise, Bitsch et al. (42) found that the measured increases of choline and myo-inositol corresponded to the histopathologically verified glial proliferation and the infiltration of subcortical grey

Prenatal Evaluation Of The Mother And Fetus

Although HHV-8 can be vertically transmitted, as documented in both a report (52) and the finding of KS in very young infants, the frequency of vertical transmission is as yet unknown. It probably happens only rarely, with a frequency probably no higher than that of perinatally acquired herpes simplex infection (i.e., 1 2000-1 5000). Unlike perinatally or congenitally acquired herpes simplex infection, however, the natural history of perinatally acquired HHV-8 infection has yet to be determined.

Guillain Barre syndrome

GBS etiology has a clear environmental component about two-thirds of GBS patients have antecedent gastrointestinal or respiratory infections by Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, or Mycoplasma pneumonia. The most frequently identified cause of GBS is C. jejuni infection - identified in up to 41 of patients. Patients with antecedent C. jejuni infection are more likely to require ventilation and have prolonged severe disability.10

CRP as a Marker of Widespread Inflammation

Complex interplay between inflammatory response and progression ofatherosclerosis. Inflammatory response is indeed observed in patients with ACSs. The stimuli for inflammation, however, are poorly understood. Several stimuli may be involved, including oxidized low-density lipoprotein (ox-LDL) and other sources of endothelial injury. Localized or systemic infections, in particular from Helicobacter pylori (HP), Chlamydia pneumoniae (CP), and cytomegalovirus (CMV), have been suggested as promoters of enhanced inflammatory response, but their role is controversial. The inflammatory reaction is responsible for the secondary effects of cytokine production liver synthesis of acute-phase reactants. CRP, SAA, and fibrinogen are the most widely studied acute-phase proteins. CRP itself is responsible for amplification ofthe inflammatory response by a direct effect on endothelium, platelets, coagulation, and eventually thrombosis, and the development of acute atherothrombosis further...

Expression and Presentation of Tumor Antigens

TAA may be presented to the immune system by uptake and degradation processing by APC. Processed TAA may be associated with MHCI, MHCII, or non-classical MHCI such as CD1 molecules and thus, in principle, activate T cells or NKT cells. If the TAA are normal self-structures, they may be expressed in increased amounts as a consequence of carcinogenesis e.g., Rae1 and H60 MHCI-like molecules are expressed in tumor cells, and less or not at all in normal cells (Sauter et al. 2000). The MHCI-like molecules may also be induced by cellular stress such as oncogene transformation, infection, heat shock, or DNA damage. The up-regulation of MHCI-like molecules alerts the immune system for the presence of damaged and potentially dangerous cells via NKG2D and other receptors (Diefenbach et al. 2001). Furthermore, glycolipid-loaded DC induce tumor cell immunity by NKT-DC interactions dependent on CD40-CD40L reactions (Corthay et al. 2005), and such interactions induce tumor-specific memory (Fujii...

Joseph B Muhlestein MD

Introduction Chlamydia pneumoniae Helicobacter pylori Mycoplasma pneumoniae Cytomegalovirus Other Herpesviruses Human Immunodeficiency Virus Influenza Virus Chronic infection has been found to be significantly associated with the development of atherosclerosis and the clinical complications of unstable angina, myocardial infarction, and stroke. A variety of infectious agents have been proposed to be involved in atherothrombosis, and, indeed, the number of implicated agents continues to increase each year. These include specific bacterial and viral agents, as well as a variety of agents associated with periodontal disease. However, failure to confirm initial reports of serological associations also has been common. The infectious agents with the most evidence to support an etiological role in atherosclerosis include Chlamydia pneumoniae and cytomegalovirus. In addition, evidence is mounting for a variety of other potential agents including other herpes viruses, influenza, other...

T and B Cell Activation and Costimulation

Since the recognition of CD28 as a T cell costimulatory receptor other costimulatory receptors belonging to the Ig, CD2, and TNFR superfamilies have been identified. Within the TNFR superfamily CD27, CD30, CD134 (OX40), CD137 (4-1BB), herpes virus entry mediator (HVEM), and glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) have all been shown to serve as costimulatory receptors for T cells (Watts, 2005).

Cell Biology Of

PML-NBs have been found to contain many other proteins, including, for example, the RAD50 MRE11 NBS1 complex, Daxx, hypophosphorylated Rb, and p53, implicating the PML-NBs in transcription, apoptosis, DNA-damage response, and maintenance of genomic stability (82). Certain DNA viruses, including herpes simplex virus, ctyomegalovirus, and adenovirus 5, encode proteins that disrupt the PML-NBs, and other viruses, including Epstein-Barr virus and SV40, segregate key viral proteins to the PML-NBs (83). The viral genomes themselves associate physically with the bodies early in the infection cycle where they are transcribed and viral replication is initiated.

Background Of Reporter Gene Imaging

Figure 1 Four different strategies of imaging reporter gene reporter probe. (A) Enzyme-based bioluminescence imaging. Expression of the firefly luciferase (Fluc) reporter gene leads to the firefly luciferase reporter enzyme (FL), which catalyzes the reporter probe (D-Luciferin) that results in a photochemical reaction. This yields low levels of photons that can be detected, collected, and quantified by a charge-coupled device (CCD) camera. (B) Enzyme-based PET imaging. Expression of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene leads to the thymidine kinase reporter enzyme (HSV1-tk), which phosphorylates and traps the reporter probe ( 18F -FHBG) intracellularly. Radioactive decay of 18F isotopes can be detected using PET. (C) Receptor-based PET imaging. The 18F -FESP is a reporter probe that interacts with the dopamine 2 receptor (D2R) to result in probe trapping on or in cells expressing the D2R gene. (D) Receptor-based MRI imaging. Overexpression of...

Risk Of Fetal And Neonatal Infection

Neonatal nonpoliovirus EV infections are common. In one study, 13 of infants younger than 1 month were infected by an EV during the summer and fall months 21 of infected newborns were symptomatic. Infection was associated with non-breastfeeding and lower socioeconomic status (35,80). EVs were responsible for 65 of hospital admissions of those younger than 3 months with suspected sepsis in the summer and fall in the same community (81). In another report, asymptomatic or symptomatic neonatal EV infections were detected by culture in 5 of infants and by serology in 7 during EV season (69). In a series of neonates evaluated for possible sepsis over a 13-month period, 4 were found to have EV infection by culture or antigen detection (82). Review of cases of neonatal meningitis at one institution found EVs to be the most frequently identified cause between days 8 and 29 of life, comprising at least one-third of cases (83). Overall, estimates suggest that the incidence of neonatal EV...

Magnetic Resonance Imaging

In a follow up study by the same investigators, the T R was probed for with superparamagnetic transferrin crossed linked iron oxides (Tf-CLIO) probes while using a herpes simplex virus-based amplicon vector system (25). These studies hold promise for in vivo imaging in humans because of the availability of clinical MR scanners, the super-paramagentic particles are relatively nontoxic when administered intravenously, the iron oxide core is biodegradable, and similar preparations are already in

Human Immunodeficiency Virus

Some evidence has also linked human immunodeficiency virus (HIV) with atherosclerosis. Constans et al. (82) showed that, although no clinically relevant atherosclerotic lesions were found, plaques occurred more often in patients with HIV than in control subjects. During postmortem examination of eight HIV-seropositive male patients, major atherosclerosis in coronary arteries was present in the absence of an associated cardiovascular risk factor (83). Investigators have postulated that viral infection, either HIV or coexisting herpesviruses, may play a role in the development of the coronary lesions. However, because of the complexity of the disease, it is difficult to establish whether HIV itself, or an opportunistic pathogen, or both are causally related to the process of atherosclerosis.

Pet Reporter Genes And Probes

FIAU-accumulation was observed in the other four patients, whose histology showed a significantly lower number of proliferating tumor cells. These data indicate that a certain critical number of the thymi-dine kinase-gene transduced tumor cells per voxel (threshold) have to be present for accumulation of FIAU and detection by PET. Complications of the blood-brain-barrier and clearance of tracer somewhat limited the findings of this study. Recently, a more detailed clinical trial involving PET imaging was completed (31). In this study, seven patients (age range 51-78) with hepatocellular carcinomas underwent intratumoral injection of recombinant adenovirus carrying the cytomegalovirus promoter driving herpes simplex virus type 1 thymidine kinase (Ad-CMV-tk). Successful PET imaging was visualized in patients using 9-(4-fluoro-3-hydroxymethylbutyl)g uanine ( 18F -FHBG) as the PET reporter probe with very good signal to background. Repeated imaging was also possible in this study because...

Cardiac Reporter Gene Imaging Studies

In the first proof-of-principle study involving cardiac optical bioluminescence imaging, adenovirus with a constitutive cytomegalovirus (CMV) promoter driving firefly luciferase reporter gene (Ad-CMV-Fluc 1x109 pfu) was injected into the rat myocardium via aseptic lateral thoracotomy (47). The reporter probe D-Luciferin (125 mg kg body weight) was injected intraperitoneally before imaging. Cardiac transgene expression was assessed over 2 weeks (Fig. 4). The in vivo imaging results correlated well with in vitro enzyme assays (r2 0.92), indicating that bioluminescence imaging can be used in parallel or in lieu of traditional biochemical assays. Cardiac firefly luciferase activity peaked within the first 3-5 days but declined rapidly thereafter due to host cellular immune response against the adenoviral vector (48). Leakage into the systemic circulation allowed the adenovirus to bind to cox-ackie-adenovirus receptors on hepatocytes, leading to expression at an unintended target site...

Evaluation Of The Neonate

Microbiologic evaluation should be targeted at EVs and other pathogens that can cause similar disease manifestations. The latter include herpes simplex virus, adenovirus, bacteria such as group B streptococcus and Escherichia coli, and depending on the clinical situation, congenital infections by cytomegalovirus, rubella virus, syphilis, and Toxoplasma gondii (33,37). Viral culture specimens with the highest yield for diagnosis of neonatal EV infections are rectum or stool (91-93 positive), cerebrospinal fluid (62-83 positive), and nasopharyx or throat (52-67 positive). Yields of serum and urine culture are lower (24-47 ) however, cultures of serum specimens may grow more rapidly than those of other body fluids sites (33,37,91). Positive serum cultures are more likely with echoviruses, low serum-neutralizing antibody titer, and onset of illness within the first 5 days of life (85,91).

Interpretation Of Diagnostic Evaluations

In general, positive cultures and PCR assays of mucosal sites such as throat or rectum may reflect asymptomatic infection or presence of virus that is causing symptoms. Positive culture and PCR tests of body fluids such as serum and cerebrospinal fluid more specifically suggest disease causation (35,91). Nevertheless, a positive culture or PCR from a mucosal site in the first month of life (even in the absence of positive testing of normally sterile body fluids) in the presence of an EV-compatible illness and in the absence of another viral (e.g., herpes simplex virus, cytomegalovirus, or adenovirus) or bacterial (e.g., group B Streptococcus or E. coli) pathogen or noninfectious condition (e.g., metabolic disorder or structural cardiac disease) that can produce the constellation of clinical findings likely signifies that an EV is the etiologic agent. Herpes simplex virus infection of the newborn can closely mimic findings of neonatal EV infection surface viral cultures and PCR testing...

Applications of Stability Information in Medicinal Chemistry

Another application of stability data is in the optimization of structures. Structure-stability relationships can be developed that indicate how the structure may be modified to improve stability in plasma. Figure 8 indicates the structure-stability relationships of a series from a human cytomegalovirus (HCMV) protease program.45 It was observed that increasing the steric hindrance and increasing the electron withdrawal at the lactam result in improved stability. An analog was found that balanced activity and stability.

Alemtuzumab Campath1H

Alemtuzumab is a humanized monoclonal antibody directed against the lymphocyte surface antigen CD52, which is abundantly expressed on normal and most malignant T lymphocytes.78 Alemtuzumab is currently the focus of many clinical trials in hematologic malignancies and has been used in the treatment of lymphomas and lymphoid leukemias. A published phase II trial of alemtuzumab in 22 patients with advanced MF SS demonstrated a clinical response in 55 of the cases, with 32 complete remissions, including some SS patients clearing effectively circulating Sezary cells.79 Median response duration was 12 months, and ranged from 5 to 32 months. The compound is associated with significant hematologic toxicity and infectious complications consisting of reactivation of cytomegalovirus, herpes zoster, miliary tuberculosis, and pulmonary aspergillosis.

Predictors Of Aidsrelated Lymphoma

Genetic, infectious, and immunologic factors influence the development of AIDS-related lymphoma. For example, germline chemokine and chemokine receptor gene variants have been found to influence the chance of developing these tumors.1819 Acyclovir has mild activity against Epstein-Barr in vivo, and one case-control study has shown that administration of high-dose acyclovir (> 800 mg day) for > 1 year was associated with a significant reduction in the incidence of NHL.20

Physicochemical Descriptors

Fairly simple descriptors have been shown to give good correlations to ADME properties. In 1997, Lipinski proposed the 'rule of 5,' an important, but not sufficient filter for oral drugs.22 This 'rule of 5' comprises four rules (molecular weight MW< 500, Clog P < 5, number of hydrogen bond donor atoms HBD < 5, and number of hydrogen bond acceptor atoms HBA< 10) and states that good absorption is less likely for a compound if two or more of these rules are violated. However, this can only help for a first interpretation of a molecule - a compound that fulfills all criteria is more likely to be permeable and, thus, also more likely to be orally bioavailable. Nevertheless, not all compounds that do fulfill the criteria have good bioavailability or even good absorption (e.g., acyclovir, fluvastatin, and terbutaline all have bioavailability below 30 ,23 acyclovir also has a fraction absorbed below 30 ,24 and they do not violate any of Lipinski's rules). In addition, compounds that...

Hivassociated Multicentric Castlemans Disease

Benjamin Castleman first described multicentric Castleman's disease (MCD) as a case record of the Massachusetts General Hospital, familiar to all the readers of the New England Journal of Medicine, in 1954.110 Interest in MCD has grown in recent years with the AIDS epidemic, since there has been an increased incidence of MCD in HIV-positive patients. This followed the recognition of an association between MCD and AIDS-associated KS, again following initial publication of case reports.4 5 Castleman's disease is divided into localized disease and MCD which is characterized by polylymphadenopathy and multiorgan involvement. The localized form is treated with surgery but the management of MCD is less clear and has a more aggressive course. Histologically, it is divided into the hyalinized vascular form and plasma variant, the former being more common in localized disease and the latter more common in MCD. MCD is associated with Kaposi's sarcoma herpesvirus (KSHV) infection, which is also...

Incidence And Risk Factors

The incidence of PTLD varies depending on the type of transplant, recipient age, and type of immunosuppres-sion used (Tables 62.1 and 62.2). The incidence of PTLD is 4 times higher in pediatric than in adult transplant recipients.16 In SOT recipients, the incidence of PTLD varies with the type of allograft 19 of intestinal transplants, 2-10 of heart transplants, 5-9 of heart-lung transplants, 2-8 of liver transplants, and 1-10 of renal transplants.16 Additional risk factors for PTLD in SOT patients include high levels of immunosuppression (particularly with antithymocyte globulin), EBV seronegative recipient of a seropositive donor, development of primary EBV infection after transplant, and presence of cytomegalovirus (CMV) disease. For example, PTLDs are the most common tumors in children after organ transplant and represent over 50 of all posttransplant tumors this is in contrast to adults where such tumors comprise only

Classification of Diabetes Mellitus and the Metabolic Syndrome

Cytomegalovirus Certain viruses, including congenital rubella, Coxsackie virus B, cytomegalovirus, adenovirus, and mumps, have been associated with b-cell destruction and have been implicated as an environmental trigger for the immune response in T1DM. However, no specific virus appears to be responsible for the majority of cases.

Innate and Adaptive Immune Reponses in the Skin

Skin DCs take up foreign proteins, transport them to draining lymph nodes, and present processed peptides from these proteins to T cells or pass the protein antigens to other lymph node-resident DCs. When Langerhans cells encounter microbes, they are activated by engagement of Toll-like receptors (see Chapter 6). The cells lose their adhesiveness for the epidermis, enter lymphatic vessels, begin to express the CCR7 chemokine receptor, and migrate to the T cell zones of draining lymph nodes in response to chemokines produced in that location. The Langerhans cells also mature into efficient antigen-presenting cells. What remains unclear is the relative contribution of the different skin DC subsets to the initiation of T cell responses. Mouse models have been developed in which langerin-expressing DCs can be selectively eliminated, and under the proper conditions, the mice lack Langerhans cells but have dermal DCs. Using these models, investigators have shown that some T cell responses...

Nef Signals That Stimulate Antiand Proapoptotic Pathways

Cellular death is induced, in principle, by two different routes. Internal sensors (for example, p53) activate the so-called intrinsic pathway, which initiates a process leading to the ultimate loss of mitochondrial integrity and apoptosis. Proteins of the Bcl-2 family (Figure 8.2) regulate this process. Proapoptotic members of this family (Bad, Bax, Bak, Bid, and others) form heterodimers with and thereby inactivate pro-survival members of the same family (Bcl-2, Bcl-Xl, Bcl-w, and others). In antiapoptotic signaling, the proapoptotic effectors such as Bad are phosphorylated on specific serine residues that release Bcl-2 for pro-survival activity by blocking Apaf-1-mediated activation of initiator caspase-9. The signaling pathway that leads to Bad phosphorylation usually starts with the activation of PI3 kinase, through ligation of cytokine or growth factor receptors. Downstream, PI3 kinase activates the Akt serine threonine kinase that directly phosphorylated the Bad protein. As...

The Ly49 Receptor Family

Dependent on the interaction of the positively charged arginine residue of the transmembrane domain of the Ly49 receptor and the negatively charged aspartic acid residue of DAP12. Interestingly, the specific Ly49 repertoire and the amount of each Ly49 receptor directly depend on the H-2 expression of the host (Yokoyama and Plougastel, 2003). IL-12 and IL-18 treatment enables NK cells to mediate cytotoxicity and produce IFN-y despite expression of inhibitory receptors (Ortaldo and Young, 2003). These NK cells need two activating signals (activating Ly49 receptor and IL-12 IL-18) to overcome inhibition. These observations support the notion that temporary autore-activity could occur during acute inflammation from IL12 IL18 production by dendritic cells (DCs) that can induce IFN-y expression in NK cells, ultimately leading to expansion of the immune response. Another possible explanation for this phenomenon is that the main activating ligand for the Ly49 receptors is not H-2 but some...

Integrin Expression on Osteogenic Cells

To this end, we have successfully transfected a2 integrin subunit to a2 integrin negative HOS and Saos-2 cell lines. A commonly used cytomegalovirus promoter was too weak to drive the expression of integrin subunits, so we instead used a construct carrying a spleen focus forming virus LTR promoter.46 The stable expression of an integrin was achieved by having the neomycin analogue, G418, resistance gene in the same expression construct. The increased expression of a2p1 integrin was assessed by measuring the plasmid derived mRNA with Northern blot analysis and the protein levels with immunoprecipitation. Flow cytometry was used to measure the cell surface expression.

Adaptive Immunity to Viruses

In latent infections, viral DNA persists in host cells but the virus does not replicate or kill infected cells. Latency is often a state of balance between infection and the immune response. CTLs are generated in response to the virus that can control the infection but not eradicate it. As a result, the virus persists in infected cells, sometimes for the life of the individual. Any deficiency in the host immune response can result in reactivation of the latent infection, with expression of viral genes that are responsible for cytopathic effects and for spread of the virus. These cytopathic effects may include lysis of infected cells or uncontrolled proliferation of the cells. Such latent infections are common with Epstein-Barr virus and several other DNA viruses of the herpesvirus family.

Treatment and Management

Some infective types of anterior uveitis, the diagnosis is usually made before the uveitis appears because the condition occurs as a secondary event. This is the case following herpes simplex keratitis and also in patients with herpes zoster affecting the upper division of the fifth cranial nerve. By contrast, anterior uveitis can be an important clue to the diagnosis of a venereal disease.

Synthetic Antigen Vaccines

A goal of vaccine research has been to identify the most immunogenic microbial antigens or epitopes, to synthesize these in the laboratory, and to use the synthetic antigens as vaccines. It is possible to deduce the protein sequences of microbial antigens from nucleotide sequence data and to prepare large quantities of proteins by recombinant DNA technology. Vaccines made of recombinant DNA-derived antigens are now in use for hepatitis virus, herpes simplex virus, foot-and-mouth disease virus (a major pathogen for livestock), human papillomavirus, and rotavirus. In the case of the most widely used human papillomavirus vaccine, recombinant viral proteins from four viral strains (HPV 6, 11, 16, and 18) are made in yeast and combined with an adjuvant. HPV 6 and 11 are common causes of warts, and HPV 16 and 18 are the most common HPV strains linked to cervical cancer. This antiviral vaccine is therefore also a preventive cancer vaccine.

Evaluation And Treatment

Because of routine serologic screening of pregnant women for syphilis, the pediatric health care provider is often alerted to the possibility of congenital syphilis when the maternal serologic tests are reactive. Otherwise, when a diagnosis of congenital syphilis is entertained in a newborn, one should first obtain a maternal nontreponemal test (Fig. 3). A nonreactive result excludes the diagnosis unless the maternal serum specimen is exhibiting a prozone phenomenon. If the nontreponemal test result is nonreactive even after dilution of the specimen, then the diagnosis of congenital syphilis in an infant who has clinical signs of a congenital infection is excluded, and the possibility of disease caused by other agents such as cytomegalovirus or Toxoplasma gondii should be investigated. If the maternal nontreponemal test is reactive, then the specific titer of the assay and a treponemal test are obtained. Maternal syphilis is confirmed if the treponemal test result is reactive a...

Inhibitors of Leukocyte Migration

Immunosuppressive therapy leads to increased susceptibility to various types of intracellular infections and virus-associated tumors. The major goal of immunosup-pression to treat graft rejection is to reduce the generation and function of helper T cells and CTLs, which mediate acute cellular rejection. It is therefore not surprising that defense against viruses and other intracellular pathogens, the physiologic function of T cells, is also compromised in immunosuppressed transplant recipients. Reactivation of latent herpesviruses is a frequent problem in immuno-suppressed patients, including cytomegalovirus, herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus. For this reason, transplant recipients are now given prophylactic antiviral therapy for herpesvirus infections. Immunosuppressed allograft recipients are also at greater risk for a variety of so-called opportunistic infections, which normally do not occur in immunocompetent people, including fungal infections...

Immunodeficiency After Bone Marrow Transplantation

The consequence of immunodeficiency is that bone marrow transplant recipients are susceptible to viral infections, especially cytomegalovirus infection, and to many bacterial and fungal infections. They are also susceptible to Epstein-Barr virus-provoked B cell lymphomas. The immune deficiencies of bone marrow transplant recipients can be more severe than those of conventionally immunosuppressed patients. Therefore, bone marrow transplant recipients commonly receive prophylactic antibiotics and anti-cytomegalovirus therapy and are often actively immunized against capsular bacteria such as pneumococcus before transplantation.

Neuropathic Pain Syndromes

In primary care as well as many types of specialty practice, the term neuropathic pain has been most often thought of as simply meaning painful peripheral neuropathy, as commonly occurs in severe diabetes mellitus (DM). This association may have developed based on the high incidence of diabetes, the bilateral, distal distribution of other symptoms (sensory loss), and signs (reduced temperature, circulatory compromise) commonly seen in this illness. In general clinical practice, the pains of well-known neurologic disorders, such as those created by herpes zoster and inflammatory involvement of the trigeminal nerves, are more likely to be thought of as focal neuralgias, rather than neuropathic pain. Similarly, the pain created by local compression of nerve roots is considered to represent just one aspect of a radiculopathy rather than being part of a neuropathic pain syndrome. Even when contralateral pain is created by unilateral thalamic or other deep hemispheric infarctions, the...

The Internal Tumor Environment

Besides LTa 1 2, LT R is activated by another member of the TNF family, LIGHT name derived from homologous to lymphotoxins, shows i nducible expression, and competes with herpes simplex virus glycoprotein D for h erpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes 34 . LIGHT is a ligand that signals through two receptors, LT R expressed on stromal cells and HVEM expressed on T cells 34,35 . LIGHT is expressed predominantly on lymphoid tissues, especially on the surface of activated DCs and T cells. Signaling via its receptor HVEM, LIGHT acts as a strong costimulatory molecule

The Costimulatory CD137 Signaling Pathway 21 The Expression of CD137L and CD137

CD137 (4-1BB, ILA, TNFRFS9) belongs to the tumor necrosis factor (TNF) receptor superfamily and is inducibly expressed on T cells following stimulation through the TCR complex (Pollok et al. 1993). With soluble antigens, such as superantigens or ovalbumin (OVA) delivered with lipopolysaccharide (LPS), CD137 is expressed only transiently on the T cells in vivo (Takahashi et al. 1999). However, CD137 expression can be prolonged with persistent antigen stimulation, such as cardiac allograft rejection, adenovirus delivered antigen, persistent herpes simplex virus (HSV)-1 infection, or severe influenza infection (Tan et al. 2000 Seo et al. 2003 Lin et al. 2009). Thus, the effects of CD137 on activated T cells may depend in part on its expression pattern in the particular model studied. In addition to antigen stimulation, the cytokines of interleukin 2 (IL-2) and IL-15 can induce expression of CD137 on memory but not naive CD8+ T cells in vitro, which may contribute to memory T cell...

Ophthalmia Neonatorum

It is important to realise that in the early part of this century, a large proportion of the inmates of blind institutions had suffered from ophthalmia neonatorum. The disease affects primarily the conjunctiva and cornea and is the result of infection by organisms resident in the maternal birth passage. The gonococcus was the most serious cause of blindness but a number of other bacteria have been incriminated, including staphylococci, streptococci and pneumococci. It has also been shown that chlamydial infection of the genital tract can lead to the same problem, as can infection by the herpes simplex virus. The blindness that resulted from this condition was so serious that any excessive discharge from the eyes has been a notifiable disease in this country since 1914. Ophthalmia neonatorum is caused by unhygienic conditions at birth and its relative rarity nowadays is because of the fact that midwives are trained to screen for the condition. Bacterial conjunctivitis usually occurs...

Transient Transfection of DNA in Adherent Cells

The efficiency of expression after transient transfection of plasmid DNA is dependent on the number of cells that incorporate DNA, the gene copy number, and the expression level per gene determined by the strength of the promoter in the plasmid. For several transformed cell lines (COS, HEK293, NIH3T3) it is possible to directly introduce plasmid DNA into 10 to 50 of the cells in the population. In contrast, primary fibroblasts and MEFs are extremely difficult to transfect and they require particular protocols (see following subheading). Transient expression offers a convenient means to compare different vectors and ensure that an expression plasmid is functional before using it to establish a stably transfected expressing cell line. A large variety of expression vectors for transient expression are described in the literature. Most useful vectors contain multiple elements that include (1) a simian virus 40 (SV40) origin of replication for amplification to high copy number in COS...

Adoptive Transfer ofT Cells with CD137 Costimulation

As an alternative to deliver the CD137 signal, Stephan and colleagues (Stephan et al. 2007) recently employed a genetic approach to constitutively co-express CD80 and CD137L in primary human cytomegalovirus (CMV)-specific T cells and prostate-specific membrane antigen (PSMA)-targeted T cells, substituting for the lack of these ligands on APCs. The T cells expressing CD80 and CD137L vigorously respond to tumor cells lacking costimulatory ligands and provoked potent rejection of large, systemic tumors in immunodeficient mice. These findings obtained in a very challenging tumor model, underscore the remarkable biological activity and potency of constitutive, high-level expression of costimulatory ligands on T cells.

Adenoviral delivery systems

In contrast to nonviral delivery systems, viral vectors have shown much higher transduction efficiencies both in vitro and in vivo, which allows the potential for large-scale clinical trials. Recombinant adenovirus vectors are among the most popular delivery systems because they are easy to produce in vitro and can transduce nonreplicating cells safely and efficiently. Gene transfer is accomplished by creating adenovirus recombinants. The first generation adenoviral vectors, which are the most common type currently being used in lung cancer gene therapy trials, lack the E1 region of the viral genome. Into the E1 region the wild-type p53 gene was inserted in conjunction with a cytomegalovirus (CMV) promoter to drive protein production. Because the E1 region is critical for replication, the E1-deleted adenoviral recombinants (Ad-p53 alternatively called Ad-CMVp53) are capable of infecting cells but not replicating. Even though viral replication does not occur, the transferred gene is...

Bone Marrow As A Source Of Cells For Brain Repair

Moters of the two genes necessary for the cells to synthesize l-dopa, introducing them in a self-inactivating retrovirus (pSIR) or standard retroviruses. pSIR vectors are constructed using the mouse phosphoglycerate kinase-1 promoter or the cytomegalovirus promoter to drive expression of a GFP reporter gene or a bicistronic sequence containing the genes for human tyrosine hydroxylase type I and rat GTP cyclohydrolase I. Such transduced BMSCs express GFP and are able to synthesize and secrete l-dopa (89283 pmol 106cells h). Additionally, engineered BMSCs can be cultured and expanded more than 1000-fold in 4 wk while they continue to express GFP or produce l-dopa (28). Transduced BMSCs have been transplanted into the corpus striatum of 6-hydroxydopamine-lesioned rats, where they engrafted, produced l-dopa and metabolites, and promoted functional recovery (28).

Markers Of Immune Activation

Several studies have demonstrated an increase in CD38 and HLA-DR activation antigens on CD4 and CD8 cells in HIV-infected individuals.56 CD38 antigen is broadly distributed on both immature and activated lymphocytes, and its increased expression has been linked to poor prognosis of subjects with HIV disease. The median density of CD38 molecules on CD4 and CD8 T cells is, in some studies, a more reliable measure of activated T cells than percentage of CD38 cells.20 The T cell activation in HIV is generalized, involving cells of antigen specificities other than HIV, as documented by CD38 upregulation in CD8 T cells specific for Epstein-Barr virus (EBV), cytomegalovirus, and influenza virus during primary HIV infection.34

Postherpetic Neuralgia

The prevalence is currently debatable. It is noted that approximately 10 of patients with VZV herpes zoster infection will develop PHN. The incidence rises with age, with more than 50 of cases in patients older than 60. Fifty percent of these patients are reported to have pain that is refractory to treatment (174). Another study showed that the pain can precede the eruption of the vesicular rash. It noted that 10 to 15 of patients with herpes zoster develop chronic PHN (pain lasting three months or more after the rash resolves) (175).

Causes And Mechanisms Of Immune Activation In Hiv Infection

Independently of the effect of HIV viral gene products, another important cause of immune activation stems from co-infections with non-HIV pathogens. In many regions of the world, the co-infection of HIV-infected patients with other pathogens is highly prevalent, and these co-infections often persist as chronic and recurrent acute infections. Common co-infections17,18 include protozoan parasites (e.g., Leishmania donovani, Toxoplasma gondii, Plasmodium falciparum) and bacteria (e.g., Mycobacterium sp. and Neisseria gonorrhea). Co-infections with viruses such as human herpesvirus (HHV)-6, human simplex virus (HSV)-1, cytomegalovirus, and hepatitis B and C viruses are also prevalent worldwide. Certain co-infections, in particular, parasitic infections, are believed to contribute significantly to HIV-associated morbidity and mortality by a mechanism of microbial-induced immune activation and its consequences. The mechanism of immune activation in these situations has been attributed to...

Deficiencies in Humoral Immunity

Most patients are deficient in at least one IgG subclass, even some with early-stage disease (22). The most significant deficiencies are in IgG3 and IgG4 (23). IgG3 is a major component of the humoral response to herpes simplex, which is a common cause of viral infection in CLL patients. IgG4 is an important humoral response to parasitic infections. It has been suggested that selective deficiencies in these two IgG subclasses could be caused by abnormal cytokine production by altered T-cells.

Infections in Untreated Patients

Herpesvirus infections, predominantly dermatomal herpes zoster and oral herpes simplex, accounted for about 10 of infections (42,43). Other infections associated with CLL were generally identified from studies of specific infections and included tuberculosis, salmonellosis, cryptococcosis, and, rarely, pneumocystosis and progressive multifocal leukoencephalopathy. All of these infections are associated with impaired cellular immunity, indicating that hypo GG was not the sole deficiency in host defenses in nontreated and minimally treated patients.

Infections Associated With Purine Analog Therapy

The therapy of CLL has changed dramatically with the introduction of the purine analogs. Unfortunately, although these agents are highly efficacious, they are associated with substantial risks of infection even for prolonged periods after cessation of therapy. Fludarabine has been combined with prednisone, which proved to be no more effective than fludarabine alone but was associated with a higher risk of infections (11). What is most impressive and probably related to reduced CD4+ lymphocyte numbers, is the increased frequency of infections that are also seen in AIDS patients such as Pneumocystis carinii, cytomegalovirus, herpesviruses, and Listeria monocytogenes infections (46). The largest amount of information on infectious complications following purine analog therapy has been obtained from CLL patients receiving fludarabine. Early studies focused on the increased frequency of L. monocytogenes and P. carinii infections (47). Subsequently, a variety of infections, most of which...

Ocular Surface Disorders

When a modification of the tear film structure occurs, with consequent tear film instability, ocular surface stress will develop, resulting in a clinical condition known as dry eye. The classification of this disorder was carried out in 1995 by the National Eye Institute, dividing dry eye into two different types aqueous layer disorders and tear evaporation disorders (32). This classification is very useful to focus on the main causative factors of the disorder, although the clinical presentation is often a mix of the two pathogenic pathways (i.e., a reduced aqueous production often results in an inadequate lipid layer spreading and in excessive tear film evaporation meibomian gland disease is commonly associated with reduced aqueous secretion by the lacrimal gland). Aqueous layer deficiency is the most common cause of dry eye and is dependent on decreased secretion of the lacrimal glands, although increased evaporation of tears may also be involved. Main causes of tear aqueous...

Acquired Immune Deficiency Syndrome AIDS

Ocular features occur in 75 of patients with AIDS. The major ocular complications of AIDS occur later in the disease and can be predicted by CD4 T-cell levels. At CD4 level > 200 x 106 L common ocular complications are toxoplas-mosis and herpes zoster ophthalmicus and retinitis, while at CD4 levels < 50 x 106 L cytomegalovirus (CMV) retinitis is common. Figure 21.15. Cytomegalovirus retinitis in acquired immune deficiency syndrome (AIDS).EQ Figure 21.15. Cytomegalovirus retinitis in acquired immune deficiency syndrome (AIDS).EQ In western countries,the commonest ophthalmic complication of AIDS is CMV retinitis, while in developing countries (such as Africa), CMV is not a major problem. Herpes zoster ophthalmicus and conjunctival carcinoma are common in AIDS patients in Africa and AIDS patients die of other complications, for example tuberculosis. Therefore, short-term survival from AIDS itself is a problem in developing countries, while in western countries quality of life for the...

Antimicrobial Prophylaxis

Herpes simplex infections are painful, interfere with nutrition, and may become superinfected with bacterial pathogens. Hence, patients who receive therapy with purine analogs should be considered for prophylaxis with acyclovir or valcyclovir if they have had previous infection (46). Long-term prophylaxis to prevent herpes zoster infections is probably not necessary since nearly all infection is localized to a few dermatomes.

Markers of chronic allograft rejection

Chronic allograft rejection typically occurs several months to a year posttransplantation and is characterized by the histological manifestations of ductope-nia and a decrease in the number of hepatic arteries in portal tracts in the presence of foam cell (obliterative) arteriolopathy. In contrast to kidney or heart transplantation, this does not initially present as a vascular process but as a biliary phenomenon and is manifested clinically and biochemically as cholestatic jaundice. The incidence in adults is decreasing, and is currently 4 , but remains at more than double this in children. Some of the clinical risk factors could be amenable to modification by improvements in management. These risk factors include donor-recipient human leucocyte antigen and sex matching, positive lymphocyto-toxic cross-match, cytomegalovirus infection, frequency and intensity of acute