Latest Treatment of Herpes

Stop Herpes Now

You'll discover: What foods are bad for you, encouraging outbreaks. What foods are good for discouraging outbreaks. The connection between genital herpes and stress. What herbs actually suppress the herpes virus. How to heal your body naturally and safely. How to manage stress in your life.

Stop Herpes Now Overview


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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...

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.

Primary Herpetic Gingivostomatitis


Primary herpetic gingivostomatitis is an infection of the oral cavity caused by Ihe herpes simplex virus type I (IISV-1).,S 11 It occurs most often in infants and c hildren younger than 6 years ol age,1 but it is also seen in adolescents and adults. It occurs with equal frequency in male and female patients. In most persons, however, the primary infection is asymptomatic . Alter the primary inteclion, the virus ascends through sensory and autonomic nerves and persists in neuronal ganglia that innervate the site as latent I1SV. In approximately one third ot the world's population, secondary manifestations occur as a result ol various stimuli such as sunlight, trauma, fever, or stress. Ihese secondary manifestations include herpes labialis d ig. 19-5), herpes genitalis, ocular herpes, and herpetic encephalitis. History. Recent acute infection is a common feature of the history of patients with primary herpetic gingivostomatitis. I he condition often occurs during and inune-diateh liter...

Synthesis of Heparin Oligosaccharides Recognized by Herpes Simplex Virus

Heparan sulfate serves as adhesion receptor for bacteria, parasites, and viruses. The negative charges of heparan sulfate can be recognized by viral proteins (154). Herpes simplex viruses are members of the neurotropic subgroup of the herpes virus family. Infection with herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) are most common in humans. HSV-1 binds to cells through interaction of envelope glycoprotein gB and gC with cell surface heparan sulfate. A third viral glycoprotein, gD, interacts with one of multiple specific receptors, which results in a viral entry of the virion envelope with a cell membrane. This fusion requires the concerted action of the three glycoproteins (gB, gH, and gL) and is triggered by the binding of gD to its cognate receptors. A heparan sulfate octasaccharide (160) that binds to HSV-1 gD was identified (Fig. 31) (155,156).

Treatment Of Acute Herpetic Gingivostomatitis

Flap Third Molar

Primary infection with herpes simplex virus in the oral cavity results in 1 condition known as acute herpetic gingivostomatitis, which is an oral infection often, accompanied by systemic symptoms (see Chapter 19). This infection typically occurs in c hildren, but it can and does occur in adults as well. It runs a 7- to 10-day course and heals without scars. A recurrent herpetic episode may he precipitated in individuals with a history of herpes virus infections and by respiratory infections, sunlight exposure, fever, trauma, exposure to chemicals, and emotional stress Various medications have been used to treat herpes gingivostomatitis with little success these have included local applications ol escharotics, vitamins, radiation and antibiotics. Limited success was initially reported with the use of herpesvirtis-specihc drugs, such as acyclovir ointment.8 However, a recent clinical report has suggested good results using systemic acyclovir to prevent (or lessen the severity of)...

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...

Herpes Simplex Virus Type

HSV-2 is the causative agent of genital herpes of which approximately 500,000 new cases arise annually 33 . It has been estimated that 33 of the adult population is seropositive for this sexually transmitted disease, making HSV-2 the most common sexually transmitted pathogen worldwide 33,73,78,92 . Genital herpes infection can result in complications including urinary retention and meningoencephalitis 33, 73, 78, 92 . Approximately 3,500 births in the United States are impacted by HSV-2 infection, which can lead to fatal infant encephalitis 18 . Even though a relatively large percentage of the population is seropositive for HSV-2, only a small percentage is subjected to these complications. Hormones have been implicated in the susceptibility to infection in the female host 86 . Specifically, mice exposed to progesterone are rendered more susceptible to infection 37 whereas estradiol-treated mice are found to be resistant to infection 27 . Although the role of ovarian sex hormones in...

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

Herpesvirus Encoded GPCRs

Herpesviruses have been isolated from a wide variety of vertebrates and are generally characterized by their strict specificity for a single host species (Davison 2002). Herpesviruses have been classified into three subfamilies, the a-, p-, and y-herpesvirinae, on the basis of their biological properties, Table 1 Herpesvirus-encoded GPCRs Table 1 Herpesvirus-encoded GPCRs a-Herpesvirinae Simplexvirus Human herpesvirus 1 Human herpesvirus 2 Human herpesvirus 3 -Herpesvirinae Cytomegalovirus Cercopithecine herpesvirus 8 (Rhesus cytomegalovirus) Simian cytomegalovirus cytomegalovirus) Pongine herpesvirus 4 (Chimpanzee cytomegalovirus) Human herpesvirus 5 (Human cytomegalovirus) Murid herpesvirus 1 (Mouse cytomegalovirus) Murid herpesvirus 2 (Rat cytomegalovirus) Tupaiid herpesvirus 1 (Tupaia herpesvirus) Human herpesvirus 6a HHV-6a Human herpesvirus 6b HHV-6b Human herpesvirus 7 y-Herpesvirinae Lymphocryptovirus Callitrichine herpesvirus 3 Human herpesvirus 4 Alcelaphine herpesvirus 1...

Acyclovir Acycloguanosine

Acyclovir is an antiviral drug used to treat herpesvirus infection. The basis of its action is that acyclovir resembles part of the guanosine nucleoside and is phosphorylated by the viral enzyme, deoxypyrimidine kinase. The phosphorylated triphosphate form of acyclovir is an inhibitor of the herpesvirus DNA polymerase. A related compound, ganciclovir, H2N works similarly. Uninfected cells do not efficiently phosphorylate acyclovir and ganciclovir, so DNA replication and virus growth are inhibited selectively in infected cells.

General Properties of Herpes Simplex Viruses

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are neurotropic viruses that are members of the subfamily a-Herpesvirinae 42 . Both types of HSV are transmissible from person to person via infectious mucosal secretions that come in contact with mucosal epithelia that line surface apertures of the body 9,42,57 . Herpes simplex viruses can cause a variety of diseases including keratitis, cold sores, encephalitis, genital herpes, cutaneous herpes, and meningitis 12, 42 . HSV-1 and HSV-2 enter the epithelium of the host and initiate a lytic replicative cycle 18, 40-42, 57, 70 . HSV enters its target cell through a multistep process that includes envelope glycoproteins (g) that surround the viral particle 42, 64 . The initial interaction begins with the binding of gC and gB to heparin sulfate proteoglycans that are found on the surface of target cells 42, 64 . After the attachment of the viral particle to the host cell, another viral glycoprotein, gD, interacts with other host cell...

Targeting the Nucleus using Motorproteins and the Microtubule Network Herpes Simplex Virus Poliovirus and Retroviruses

Herpes Simplex Virus Structure

Viruses which infect the large, polarized cells of the peripheral nervous system have the most dramatic need for a means of spreading over long distances, since the distance between their site of entry and their site of replication can reach several centimeters in length 12 . Herpes simplex virus type 1 (HSV-1) the causative agent of cold sores infects sensory neurons and spreads via synapses. Within a neuron, viral capsids must first move from the synapse, along the length of the axon to the cell body, where replication is possible. Progeny virus must then make the return journey, along the axon to the synapse, where they emerge in order to spread to neighboring cells (Figure 19.1). It has been calculated that were this movement to occur by diffusion alone, a journey of a single centimeter would take 231 years, and so it is essential that herpes virus moves by an active transport mechanism. HSV-1 capsids have long been observed to be aligned with axonal microtubules using the...


Ganciclovir is similar to aciclovir in its mode of action, but is much more toxic. It is given i.v. or orally and is eliminated in the urine, mainly unchanged (t' 2 4 h). Ganciclovir is active against several types of virus but because of toxicity, its i.v. use is limited to life- or sight-threatening cytomegalovirus (CMV) infection in immunocompromised patients, and (by mouth) for maintenance suppressive treatment of retinitis in patients with AIDS, and to prevent CMV disease in patients receiving immunosuppressive therapy following organ transplantation (especially liver transplants). Ganciclovir-resistant cytomegalovirus isolates have been reported. Foscarnet is used i.v. for retinitis due to CMV in patients with HIV infection when ganciclovir is contraindicated it has also been used to treat aciclovir-resistant herpes simplex virus infection (see p. 258). It causes numerous adverse effects, including renal toxicity, nausea and vomiting, neurological reactions and marrow...

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.

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 p-Herpesvirinae subfamily comprises two genera, namely Roseolovirus and Cytomegalovirus (CMV). Hitherto, four members of the Roseolovirus genus have been isolated, three of which are found in man. In contrast, host-specific cytomegaloviruses have been isolated from a wide variety of mammals from the orders Rodentia (e.g., mouse and rat), Scandentia (e.g., tree shrew), and Primates (e.g., rhesus macaque, African green monkey, chimpanzee, and human). CMV genomes are the largest of all herpesviruses (195-241 kb), whereas genomes of roseoloviruses are somewhat smaller (153-162 kb). The genomes of roseoloviruses and CMVs, share extensive characteristics, including position and orientation of large blocks of genes (Neipel et al. 1991 Gompels et al. 1995 Nicholas 1996 Weir 1998).


CMV primarily infects monocytes, smooth muscle cells, and endothe-lial and epithelial cells of the upper gastrointestinal, respiratory, or urogenital tracts (Landolfo et al. 2003), and disseminates throughout the body by latently infected monocytes in the blood (Streblow and Nelson 2003). Allogenic stimulation of these monocytes induces differentiation into macrophages, which in latently infected cells is accompanied by reactivation of HCMV leading to the release of infectious virions (Streblow and Nelson 2003). CMV, like other p-and y-herpesvirus subfamilies, appears to have pirated genes encoding key regulatory cellular proteins, showing highest homology to chemokine receptors (Murphy 2001 Sodhi et al. 2004b). HCMV encodes four GPCRs referred to as US27, US28, UL33, and UL78 (Chee et al. 1990). Two GPCR-encoding genes, i.e., UL33 and UL78, are conserved with respect to position and orientation in the genomes of all sequenced p-herpesviruses. Possibly, these genes have been captured...

Physiological Effects Of Heme Oxygenase And Carbon Monoxide

Lung transplantation has become an accepted treatment modality for end-stage lung disease. After lung transplantation, there remains a persistent risk of acute and chronic graft failure, as well as of complications of the toxic immunosuppressive regimen used (96). Compared to other solid organ transplants, the success of lung transplantation has been severely limited by the high incidence of acute and chronic graft rejection. The frequency and severity of episodes of acute rejection are the predominant risk factors for chronic airway rejection, manifested as obliterative bronchiolitis (OB) (97,98). Data from rodent allograft studies as well as from clinical lung transplantation show that the lung, in comparison to other solid organs, is highly immunogenic. Despite advances in immunosuppression, the incidence of acute rejection in lung graft patients can be as high as 60 in the first postoperative month (99,100). OB, which may develop during the first months after transplantation, is...

Products From Cell Culture Technology Viral Vaccines

Vaccination for the prevention of infectious diseases has been an effective strategy for many years. Polio vaccine was the first cell culture technology-based vaccine and was produced in cultured monkey kidney cells (7). The cell-based vaccine technology evolved in the last four decades the production of vaccines now utilizes primary cells, human diploid cells, and continuous or even recombinant cell lines. Vaccines against hepatitis B, measles and mumps, rubella, rabies, and FMD had been very effective in preventing life-threatening diseases. New vaccines target human immunodeficiency virus (HIV), herpes simplex virus, respiratory syncytial virus, cytomegal virus (CMV), and influenza, and continue to utilize cell culture technology for production. The latest developments in vaccine development include genetically engineered vaccines and DNA vaccines that will open new frontiers in this field. Development of new vaccines for HIV and cancer is very exciting and these efforts should...

Contraindications and Side Effects

Dactinomycin is contraindicated in the presence of chicken pox or herpes zoster, wherein administration may result in severe exacerbation, occasionally including death. The drug is extremely corrosive in soft tissues, so extravasation can lead to severe tissue damage (14). To avoid this the drug is usually injected into infusion tubing rather than being injected directly into veins. When combined with radiation therapy, exaggerated skin reactions can occur as can an increase in GI toxicity and bone marrow problems. Secondary tumors can be observed in some cases that can be attributed to the drug. Dactinomycin is carcinogenic and mutagenic in animal studies and malformations in animal fetuses have also been observed. Nausea and vomiting are common along with renal, hepatic, and bone marrow function abnormalities. The usual alopecia, skin eruptions, GI ulcerations, proctitis, anemia, and other blood dyscrasias, esophagitis, anorexia, malaise, fatigue, and fever, for example, are also...

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.

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.2223 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...

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...

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...

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.

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

A FDA Divisions that Receive INDs for Drugs

Initial INDs for investigational drugs are sent by the sponsor to the appropriate reviewing division of the FDA's Center for Drug Evaluation and Research (CDER). Each of the 15 reviewing divisions is responsible for sustaining medical scientific expertise and regulatory responsibility for drugs within a specific therapeutic area. For example, The Division of Neuropharmacological Drug Products reviews drug products that exert their effects through actions on the central or peripheral nervous systems, such as anxiolytics, antidepressants, and anticonvulsant drugs. The Division of Antiviral Drug Products reviews, for example, antiretroviral drugs, as well as drugs active against the herpes simplex virus. These 15 reviewing divisions are organized into five Offices of Drug Evaluation (ODE), each of which reports to the Office of Review Management within the CDER. The organizational structure of the CDER, as well as the names of the current Directors of each ODE, can be readily viewed on...

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.

Epidemiology and Pathogenesis

Risk determinants for HPV infection that have been identified in various cross-sectional and prospective cohort studies include the number of sexual partners (lifetime and recent), age at first intercourse, smoking, oral contraceptive (OC) use, other sexually transmitted infections (STIs) (e.g., chlamydia and herpes simplex vi

Prodrugs Under Development

To provide the drug in the monophosphate form. The need for an initial phosphorylation step to be carried out by a viral kinase provides a large degree of selectivity, but this approach is limited to viruses encoding such a kinase. One way to extend treatment to viruses lacking a suitable kinase is to develop nucleoside monophosphate analogs. In this case, the selectivity is limited to the difference in affinity for viral versus cellular polymerases, but if sufficient selectivity can be attained, the trade-off may be worthwhile for viruses where viral phosphorylation to the monophosphate is not an option (e.g., HBV), or for nucleoside ki-nase-deficient or -resistant herpesviruses. In this case, increasing the lipophilicity or masking the charge are essential considerations in developing the prodrug, because phosphorylated nucleosides are impermeable to cellular membranes. A series of methylenecyclopropane analogs of purine nucleosides and phosphoroalaninate prodrug forms of these...

Pvrimidines The most successful of

Sides show potent activity while lacking the toxicity of the D-enantiomers. Some of them are quite specific for HBV, whereas other show activity against HIV and certain herpesviruses as well. The structure-activity relationship cf these compounds as well as additional L-nucleosides have been elegantly examined by Bryant et al. (409), and the following conclusions can be drawn from their observations. (1)The specificity for HBV versus retroviruses derives primarily from the presence of L-dC (66), L-dT (67), and L-dA were tested for activity against a panel of 15 viruses, in-eluding herpesviruses, and were only active

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...

Comprehension Questions

20.3 A 33-year-old woman GI P0 at 39 weeks' gestation is in labor. She has been diagnosed with herpes gestationalis and has the characteristic pruritus and vesicular lesions on the abdomen. Which of the following precautions is best advised for this patient C. Vaginal delivery is permissible if the lesions are not in the introitus region and provided oral acyclovir is given to the baby.

TABLE 520 Abnormalities of the Lips

Herpes Simplex (Cold Sore, Fever Blister) The herpes simplex virus (HSV) produces recurrent and painful vesicular eruptions of the lips and surrounding skin. A small cluster of vesicles first develops. As these break, yellow-brown crusts form, and healing ensues within 10 to 14 days. Both of these stages are visible here.

HSV1 Latency in the Trigeminal Ganglion

During latent infection, real time (RT)-PCR detection of CXCR3 and CCR5 expression has been reported 12 . Although unproven, it is likely these chemokine receptors are found on the CD8+ T cells present in the TG during latency 29, 38 . Although ligands for CXCR3 including CXCL9 and CXCL10 have not been evaluated during latency, one ligand for CCR5, CCL5, has been detected 28 . Exposing latently infected mice to the potent antiviral compound acyclovir has been found to reduce CCL5 expression in the TG. Yet, the continued presence of CD8 cells suggests additional signals provide a stimulus for retainment of these effector cells within the tissue 29 .

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).

Immune Response to Genital HSV2 Infection

During initial infection of the mucosa of the vagina with HSV-2, the virus begins to replicate in the epithelium, typically restricted to the epidermis or cervicovaginal epithelium 43 . The initial host response to infection includes the induction of type I IFNs (i.e., IFN-a species) through TLR9 recognition of HSV-2 CpG motifs 52 . The IFN-responsive pathway, double-stranded RNA-dependent protein kinase but not 2',5'-oligoadenylate synthetases is essential for resistance to infection, as mice deficient in this pathway are highly susceptible to HSV-2-mediated mortality (D.J.J. Carr, L. Tomanek, R.H. Silverman, and B.R.G. Williams, manuscript in preparation). In addition to type I IFN production, IL-12,1L-15, IL-18, NK cells, and PMNs are important first lines of defense against HSV-2 replication and spread 1,31,59 . Current evidence suggests the resident populations of Langerhans cells 19 do not traffic to the inguinal iliac lymph nodes with most migrating cells consisting of B...

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...

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

Time and cost of drug development

Isolation of chemical compounds of value to the pharmaceutical or cosmetics industries can prove extraordinarily lucrative. Global sales of pharmaceuticals have been estimated at US 300 billion a year, of which the component derived from genetic resources accounts for between 75 billion and 150 billion (ten Kate and Laird, 1999). A compound derived from a sea sponge to treat herpes was estimated a few years ago to be worth US 50 million to 100 million annually. Current estimates of the potential value of anti-cancer agents found in marine organisms range to well over US 1 billion a year. The full potential of marine organisms to produce valuable compounds is unknown, because so few have been tested and because the ocean floor is largely unexplored. If regulators and policy makers think protecting local rights to plant genetic resources is a challenge, they have only to consider the complexities of marine life, its trans-boundary habits and its untapped potential to realize that...

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...

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.

Viral Budding out of the Host Cell

The assembled particles are released out of the host cell membrane by a process called budding, which leaves behind a hole, or several holes, in the T4 cell membrane, which may contribute to the CD4 cell death. The host cells normally do not survive the invasion by HIV. They either disintegrate because of the large number of viruses budding off, or the body's immune system recognizes the viral envelope proteins in the cell membrane and destroys the damaged cells. This destruction of CD4 cells causes severe immunodeficiency because of the role of helper T-cells in mediating the system immunity. This paves the way for the so-called opportunistic infections such as candidiasis in the bronchi or lungs, cryptococ-cus, cytomegalovirus retinitis, herpes simplex infections, and pneumonia.

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.

Marine Invertebrates of the Andaman and Nicobar Islands

The most interesting compounds of Tunicates are the cyclic oligopeptides. Lissoclinum patella has furnished several cyclic peptides.232 233 Of these ulicyclamide, ulithiacyclamide, and patellamide A, B, and C exhibit antitumor activity against L1210 murine leukemia culture in vitro. A new class of depsipeptides, some of them exhibited high order of antiviral (against RNA and DNA viruses) and antitumor (against L1210 P388 leukemia and B16 melanoma) activities, are obtained from Trididemnum species of the family Didemnidae.234,235 The compounds designated as eudistomins contain substituted condensed oxathiazepine ring system. These compounds show high order of antiviral activity against Herpes simplex virus type (HSV-1) and have been isolated from the colonial caribbean tunicate Eudistoma olivaceum.236 Other eudistomins having substituted P-carboline system and displaying modest activity against HSV-1 and Bacillus subtilis have been isolated from the same species.237

Bacterial And Virus Infection

Cancer remains a significant burden for human immunodeficiency virus-infected individuals. The discovery of a high incidence of Kaposi's sarcoma in patients with acquired immune deficiency syndrome (AIDS) is now believed to be caused by Kaposi's-sarcoma-associated herpesvirus human herpesvirus 8. AIDS-lymphoma is known to be associated with Epstein-Barr virus (EBV) and or KSHV infection. AIDS-related malignancies also include HPV-related cancer. The FDA considers human papillomavirus (HPV) to be a primary screening tool for cervical cancer (14).

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

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

Introduction of Foreign Genes into Osteoclasts see Note

The recombinant adenovirus carrying a foreign gene under the control of the CAG (cytomegalovirus IE enhancer + chicken P-actin promoter + rabbit P-globin poly A signal) promoter is constructed by homologous recombination between the expression cosmid cassette and the parental virus genome in 293 cells (22).

Maintenance and Management of the System

The next two cases differ significantly from the previous two in terms of family life-stage issues. The previous two cases represented the problems of families in their early forties with very young children in one family and a teenage daughter in the other. The next two cases represent a recently married young couple in which the wife suffered from severe migraine, and an older couple in their late sixties in which the husband had many chronic health problems including herpes zoster, which is a very painful condition.

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...

Cardiac Reporter Gene Imaging Studies

Drug Metabolism Phase1 Phase2 Reaction

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...

Antisense Oligonucleotides It has

Tides were used to create ribozyme-expressing CV-1 cells, which along with the original CV-1 cells, were then infected with influenza A Sin-gapore 1 57 (H2N2) or A WSN 33 (H1N1) for antiviral susceptibility. High levels ( 90 ) of inhibition of viral NP and NS1 proteins and influenza virus reproduction (by plaque assay) were noted in the cell lines expressing the functional ribozyme. Defective recombinant adenoviruses were also constructed carrying the genes of functional and non-functional ribozymes under the control of human cytomegalovirus promoter. Again, greater than 90 level of inhibition of the replication of influenza A WSN 33 virus in CV-1 cells pre-in-fected with the recombinant ribozyme-ex-pressing adenoviruses was observed compared with that in the non-infected cells. Analyzing the results with the cell line expressing the non-functional ribozyme suggested that the inhibition of influenza A virus reproduction with these ribozymes results mostly from the effect of RNA...

Mr Friesen A Case of Doing Ones Best

Friesen, a retired senior civil servant, presented with a multitude of pain complaints, the worst of them being his persistent pain from herpes zoster. He also had a long history of emphysema and periodic episodes of clinical depression. The marriage had a checkered history. The couple attributed their marital problems mainly to his long-standing health issues. Previously they had a daughter living with them who suffered from Down syndrome and was entirely dependent on them. The history revealed that the marriage ran into problems soon after their disabled daughter was born. Mrs. Friesen received very little practical or emotional support from her husband in raising the child, who subsequently died in her late teens.

Other Systemic Conditions

Bismuth Discolouration Gingiva

Chronic bismuth intoxication is characterized by gastrointestinal disturbances, nausea, vomiting, and jaundice, as well as by an ulcerative gingivostomatitis, generally with pigmentation and accompanied by a metallic taste and burning sensation of the oral mucosa. Ihe tongue may be sore and inflamed. Urticaria, e.xanthematous eruptions of different types, bullous and purpuric lesions, and herpes zoster-like eruptions and pigmentation of the skin and mucous membranes are among the dermatologie lesions attributed to bismuth intoxication. Acute bismuth intoxication, which is less commonly seen, is accompanied by met hemoglobin format ion, cyanosis, and dyspnea.91 Hismuth pigmentation in the oral cavity usually appears

Approach To Suspected Meningitis

These include enteroviruses, which tend to be more common in the summer and fall, when patients may present with severe headache, accompanied by symptoms of gastroenteritis. The CSF w hite blood cell (WBC) count will be elevated, with a predominance of lymphocytes, and usually glucose and protein levels are normal (Table 29-1). Either herpes simplex virus (HSV)-l or HSV-2 can cause herpes simplex meningitis. The CSF of these patients will also have a normal glucose level, whereas protein and WBC counts will be elevated with a predominance of lymphocytes. Typically, these patients have a high CSF red blood cell count, which is not seen in bacterial meningitis in the absence of a traumatic spinal tap. In a patient with HIV infection, fungal meningitis, specifically caused by Cryptococcus, should be considered. Tuberculous meningitis presents subacutely and is more common in older, debilitated patients, or in patients with HIV. Rickettsial disease, specifically Rocky Mountain spotted...

The Use of Lysine in Other Serious Diseases

In infectious diseases caused by viruses, such as flu, herpes, and AIDS or caused by bacteria, such as lung, inner ear, and bladder infections lysine can stop or slow down an aggressive spread of infection. A combination of high dosages of vitamin C and other dietary supplements can bring additional benefits.

On Pelvic Examination The Cervix Is Anteriorly Displaced. An Irregular Midline Mass Approximately 18 Weeks Size Seems

Cesarean delivery should be offered to a woman with a history of herpes simplex virus who has prodromal symptoms or suspicious lesions of the genital tract. Herpes simplex virus is the most common cause of infectious vulvar ulcers in the United States. The cervix, vagina, and vulva must be inspected carefully for lesions in a laboring patient with a history of herpes simplex virus. American College of Obstetricians and Gynecologists. Management of herpes in pregnancy. Practice Bulletin No. 8. Washington. DC American College of Obstetricians and Gynecologist., 1999.

Iga And Cervical Cancer

These studies suggest that HPV and possibly EBV have a causative role in cervical carcinoma and that IgA levels and IgA antibody levels may be useful in the diagnosis and monitoring of this disease. IgA levels are increased in dysplasia and early neoplastic lesions of cervical cancer. The IgA responses appear to be antigen driven, specifically targeted to HPV, EBV and herpes viruses (Table 3).

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

Nucleoside Analogs it94Hy

Ogen was tolerated with no loss of activity. Use of a phenyl group para-substituted with an alkyl chain increased potency a further 100-fold, with selectivity indexes of more than 106. The optimal chain length decreased from 8-10 to 4-7 with the insertion of the phenyl group. These compounds were inactive against other herpesviruses and required the VZV thymidine kinase for activity. Modification of the side chain of ACV or GCV, forming the 9-alkoxy derivative (13), (14), produces isomers that retain activity ainst herpesviruses. The ACV isomer is In contrast to L-nucleoside analogs, which have been shown to have activity against HIV reverse transcriptase and HBV polymerase with useful therapeutic indices, D-isomers have demonstrated potent antiviral activity, but with excessive toxicity. Variations on this theme, apio dideoxydidehydronucleosides(15) have been evaluated as herpesvirus inhibitors.

Osteotropism Of Metastatic Dissemination

A development with much promise is the use of toxic gene therapy for cancer, with osteocalcin promoter for targeting the expression of the toxic gene in the treatment of tumours of osteoblastic lineage and metastatic tumours. Ko (1996) made an adenovirus construct with the TK gene under the control of an osteocalcin promoter (Ad-OC TK). When this viral construct was introduced into cells of osteoblastic lineage, e.g., murine ROS cells and human MG-63 cells, the TK gene was expressed. In contrast, no TK expression occurred in nonosteoblastic cell lines. The addition of acyclovir (ACV) caused cell death in vitro. Similar growth inhibition

Bioactivity of Marine Organisms

Marine algae from the French Mediterranean coast have been tested for antibacterial and antifungal activities.82 Seaweeds of South Florida have been evaluated for antimicrobial and antineoplastic activities.77 Carrageenan, a cell wall polysaccharide of marine red algae, exhibits several types of properties. It is co-internalised into infected cells with the Herpes simplex virus (HSV), and inhibits the growth of this DNA containing virus. Carrageenan interferes with fusion between cells infected with human immunodeficiency virus (HIV), an RNA-containing virus, and inhibits the retroviral enzyme (reverse transcriptase). The sulphated polysaccharides from red algae have a broad spectrum antiviral activity. There is considerable evidence to support that carrageenan bind to and modulate cell-cell interactions of various kinds, including sperm-egg fusion in the brown alga Fucus. It inhibits fertilisation in sea urchins, hamsters, and guinea pigs, embryogenesis in the green alga shipboard.94...

Viral Vehicles For Gene Delivery Into Central Neurones

Vectors for gene delivery into the brain have been derived from a number of viral genomes, such as adenoviruses, adeno-associated viruses (AAVs), retroviruses and related lentiviruses, herpes simplex virus, and some others. So far, studies of central mechanisms of cardiovascular control have mainly employed adenoviral vectors (AVV) and retroviral vectors, including lentiviral vectors (LVV) (3,5,10-12,29-33). These viruses can infect various cell types present in the brain (i.e., neurones, glia, endothelial, and vascular muscle cells) and result in long-lasting gene expression without noticeable adverse effects. Vectors derived from the AAV have been successfully used for gene delivery to peripheral targets (34,35), but they are also well-equipped for gene delivery into central neurones (36). Finally, a replicating pseudorabies virus has been used to retrogradely transfect vagal cardioinhibitory neurones (13).

Infection As An Alternate Hypothesis For Ms

Antibodies are found in the CSF and not in the serum, migrate to the cathodal regions on isoelectric focusing (IEF) gels, and are called oligoclonal bands (OCBs). OCBs occur in approximately 90 of MS patients, but are not specific for MS, as such bands are also found in the CSF of patients with a wide variety of CNS infections. In general, the presence of OCBs in CSF is thought to represent an intrathecal immune response to an infectious agent. A number of chronic infections of the CNS are characterized by the presence of OCBs in the CSF. These CNS infections include tuberculosis, syphilis, neuroborreliosis, crypto-coccal meningitis, herpes simplex encephalitis, HTLV-1 myelitis, and subacute sclerosing panencephalitis (SSPE).(13,14,33)

Nonspecific Oral Ulcerations And Recurrent Aphthae

Recent evidence indicates that many nonspecific oral ulcerations may be ol viral origin with herpes simplex, Bpstein-Barr virus, and cytomegalovirus being most common.' For this reason, the practitioner should consider viral culturing of such lesions and the use of antiviral agents in treatment where appropriate. Oral viral infections in immunocompromised individuals are often treated with acyclovir (200 to 800 ntg administered live times daily for at least 10 days). Subsequent daily maintenance therapy (200 mg two to five times daily) may be required to prevent recurrence. Resistant viral strains are treated with toscarnet. ganciclovir, or valacyclovir hydrochloride.

Mhc Class Ii Expression On Autoimmune And Malignant Thyroid Cells

Reovirus, SV40 and cytomegalovirus have been demonstrated to induce MHC class II expression on cultured thyrocytes in the absence of T cells 50 52 , A direct correlation between high expression of MHC class II and dense inflammatory infiltration has been observed in autoimmune thyroiditis, but not in most tumor specimen 53 , This suggests that MHC class II expressions on tumor cells, whether virally induced or caused by the neoplastic transformation, may, in many cases, be independent of immunological processes 54 , whereas MHC class II expression in autoimmunity is always associated with triggering of immune response.

Cook Pj Honeyborne D Chlamydia Pneumoniae. Int J Syst Bacteriol 39 88-90 1989

Smieja M, Chong S, Natarajan M, Petrich A, Rainen L, Mahony JB. Circulating nucleic acids of Chlamydia pneumoniae and cytomegalovirus in patients undergoing coronary angiography. J Clin Microbiol 2001 39(2) 596-600. 69. Churchill AE, Biggs PM. Herpes-type virus isolated in cell culture from tumors of chickens with Marek's disease. II. Studies in vivo. J Natl Cancer Inst 1968 41(4) 951-956. 70. Minick CR, Fabricant CG, Fabricant J, Litrenta MM. Atheroarteriosclerosis induced by infection with a herpes virus. Am J Pathol 1979 96(3) 673-706. 71. Adam E, Melnick JL, Probtsfield JL, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 1987 2(8554) 291-293. 72. Melnick JL, Hu C, Burek J, Adam E, DeBakey ME. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J Med Virol 1994 42(2) 170-174. 73. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated...

Risk Factors In Alzheimers Disease

Other, nongenetic risk factors have been identified for sporadic AD. Although age remains the number one risk factor, atherosclerosis, neurotrauma resulting from head injury, and chronic inflammation all have been implicated in the development of AD neurodegeneration. One of the most elusive risk factors may be the association of infection with the development of sporadic AD. Herpes Simplex Virus 1 (HSV-1) infection in the brain in individuals expressing the apoE-4 allele is considered to be a risk factor for development of AD,(18) although specifics as to how the viral infection leads to neurodegeneration are

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.

Defects in Cellular Immunity

Infections associated with impaired cellular immunity such as tuberculosis, cryptococcosis, listeriosis, and herpes zoster have been reported in CLL patients even before intensive therapy was available and before techniques were available to identify specific components of cellular immunity. Prominent among these abnormalities are decreased concentrations of circulating CD4+ lymphocytes, which may occur secondary to the disease process but are a significant consequence of therapy with purine analogs.

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.

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...

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...

Measures Against Infection

During periods of increased immunosuppression within the initial 6 to 12 months, most centers prescribe medical prophylaxis against cyto-megalovirus, herpes simplex reactivation, pneu-mocystis, aspergillus and candida species. It should be stressed, however, that the recipient of a transplant is expected to show an increased responsibility for himself by complying with the recommendations of his transplant center concerning personal hygiene and general measures to avoid those infections that are not due to latent viruses (Table 49-2). Medical personnel dealing with HTRs should be aware of the immunosup-pression-induced impairment of the inflammatory response, which attenuates the signs and symptoms of invasive infection.

Cardiac Allograft Vasculopathy

Risk factors for the development of CAV on the donor's side are hypertension and higher age, on the recipient's side coronary artery disease, number of rejection episodes in first year, symptomatic and asymptomatic cytomegalovirus infection, young age, hyperlipidemia, obesity, smoking, hypertension, and diabetes The latter five are amenable to lifestyle changes, exercise training, and adequate medication. Hypercholes-terolemia is present in 52 by 1 year and 90 by 7 years.1 Statins (pravastatin, simvastatin) not only lowered LDL cholesterol levels but also decreased the incidence of CAV and significantly improved survival. In addition, pravastatin reduced the number of rejection episodes.28 Statins are now part of standard therapy, but dose-related myopathy and myolysis due to interaction with ciclosporin has not only been a theoretical danger. Most centers prefer pravastatin in doses up to 40 mg because its metabolism is less dependent on

An Older Retired Couple

Friesen, in his late sixties and a retired senior civil servant, had multiple health problems, which included chronic back pain, herpes zoster, and a history of depression. Mr. Friesen was disabled to the point that Mrs. Friesen had taken responsibility for all aspects of their day-to-day life. They had an intellectually challenged daughter who subsequently died. The following analysis will show that on the basis of the MMFF, they were found wanting on virtually all dimensions of the MMFF. Yet, given the circumstances, Mrs. Friesen

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...

Mental institution correctional or longterm facilities etc The recommended doses of INH are 10mgkg for children and

Anticoagulants, acetaminophen, barbiturates, carbamazepin, cyclosporine, corticosteroides, diazepam, didanosine, disulfiram, flucitosine, ketoconazole, methyldopa, phenitoin, rifampicin, pyrazinamide, theophylline, vidarabine, zalcitabine t Didanosine, isoniazid, ketokonazole, viridazole, thiazine diuretics Analgesic, anticoagulants, anticonvulsant, azathioprine, barbiturates, beta-adrenergic blockers, chloramphenicol, oral contraceptives, corticosteroides, cyclosporine, dapsone, diazepam, digoxin, disopyramide, estrogens, haloperidol, methadone, protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir), quinidine, zidovudine I Didanosine, isoniazid, zalcitabine Less interaction than rifampicin. I clarithromycin, cyclosporine, protease inhibitors f Acyclovir, amphothericin, nephrotoxic beta-lactams, carboplatinum, cisplatinum, cyclosporine, loop diuretics, 5-fluorocytosine neuromuscolar blocking agents, NSAID, vancomycin

Clinical Approach

Genital herpes is a recurrent sexually transmitted disease that currently has no cure. The two types are HSV-1 and HSV-2. HSV-1 usually affects the epithelium in the oral or facial region (above the waist), whereas HSV-2 usually affects the genital region (below the waist). However, up to one third of the time, the above-the-waist versus below-the-waist rule does not hold true. HSV is the most common cause of infectious vulvar ulcers in the United States. Primary genital infection has both local and systemic effects. It usually affects people between the ages of 15 and 35 years. After an incubation period of 2 to 7 days, the herpes infection usually induces paresthesias of vulvar skin then formation of vesicles, which become shallow ulcers. Often, the vagina, cervix, and perineal area may be involved. The ulcers of the primary infection may persist for 2 to 6 weeks, and viral shedding generally continues for 2 to 3 weeks after lesions appear. Local symptoms include pruritus, inguinal...

Treatment of intercurrent illness

Viral infections contracted during steroid therapy can be overwhelming because the immune response of the body may be largely suppressed. This is particularly relevant to immunosuppressed patients exposed to varicella herpes zoster virus, which may cause fulminant illness they may need passive protection with varicella zoster immunoglobulin, VZIG, as soon as practicable. Continuous use of prednisolone 20 mg day (or the equivalent) is immunosuppressive. But a corticosteroid may sometimes be useful in therapy after the disease has begun (thyroiditis, encephalitis) and there has been time for the immune response to occur. It then acts by suppressing unwanted effects of immune responses and excessive inflammatory reaction. Vomiting requires parenteral administration. In the event of surgery being added to that of adrenal steroid therapy the patient should receive hydrocortisone 100-200 mg i.m. or i.v. with premedication. If there is any sign suggestive that the patient may collapse, e.g....

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.

PET imaging in gene expression

A general (indirect) imaging approach for gene expression is by using 'reporter genes', which can track the expression of both endogenous and exogenous genes. These reporter genes can be classified into two broad categories reporter genes that lead to the production of an enzyme that is capable of metabolizing and trapping a probe (such as a PET-labelled compound) or reporter genes that lead to the production of a protein receptor that can selectively interact with a probe. A well-studied example of a 'reporter gene' that produces an enzyme capable of metabolizing and trapping a probe is the Herpes Simplex virus type 1 thymidine kinase gene (HSV1-tk). This gene can be introduced into the cell using one of several potential vehicles (e.g. an adenovirus). Once inside, it is transcribed to HSV1-tk mRNA and then translated on the ribosomes to the protein (enzyme) HSV1-TK. A radio-labelled reporter probe (e.g. 8 18F -fluoroganciclovir- 18F FGCV) is also introduced into the cell, where it...

Virusmediated Centrosomal Damage

More recently, centrosome destruction was also observed in HSV-1-infected cells, where VP22-dependent microtubule reorganization may be involved. In this case, MTOCs have been shown to return after prolonged infection, suggesting that the process of destruction is reversible 58 . Centrosomal defects have also been described by electron microscopy in cytomegalovirus (CMV)-infected cells, where disruption of centriole structure and detachment of fibrillar material occur 59 . Whether these changes are also seen during vaccinia- or HSV-1-mediated centro-some destruction, and so represent a general response to a variety of different viral infections, remains to be seen.

Immune Reconstitution And Infections

To date, few reports have analyzed immune reconstitution after nonmyeloablative HCT. Mohty et al. showed that early CD8+ T lymphocyte and NK-cell recoveries after HCT with a reduced-intensity conditioning regimen take place, whereas naive CD4+CD45RA+ T lymphocytes remained below normal values during the first months after the transplant.52 Similar results were reported by Baron et al.44 We recently compared immune reconstitution after conventional and non-myeloablative transplantation.53 During the first 6 months, absolute lymphocyte subset counts were similar, but counts of cytomegalovirus (CM V)-specific T-helper lymphocytes were higher at days 30 and 90 in the nonmyeloablative patient group. Conventional transplant recipients had higher na ve CD4 and CD8 counts 1 year after the HCT, probably reflecting lower counts of recent thymic emigrants in nonmyeloabla-tive recipients this finding might be related to the older age of nonmyeloablative recipients.

Therapeutic Angiogenesisvasculogenesis Promises And Limitations

Adeno-associated virus (AAV) is a small single-strand DNA parvovirus that is defective, nonpathogenic, and largely diffused in the general population. More than 90 of the parental viral genome is deleted in AAV-based vectors. Consequently, no viral protein is expressed from AAV vectors in transduced cells. Recent advances enhanced the production capability of high-titer stocks of AAV. Accordingly, vectors that express different genes canbe mixed before transduction in order to obtain the simultaneous statement of two or more different proteins in the same tissue. AAV has been shown to infect primate hematopoietic progenitor cells with reasonable efficiency but its use involves coinfection with a helper virus, such as adenovirus or herpes simplex virus. Use of recombinant AAV will require the development of optimized cotransfection and helper plasmid strategies for productive infection. Finally, AAV has a broad host range, but displays an exquisite tropism for nervous and muscular...

Prophylaxis And Therapy

Acyclovir prophylaxis is indicated for all HSV-seropositive HSCT candidates and has been shown to reduce the occurrence of viral reactivation.35 Prophylaxis should commence at the initiation of the preparative regimen and continue to engraftment or to the resolution of mucositis.2 Valacyclovir has not been FDA-approved for this indication.

Vectors for Regulated Expression of Genes in Mammalian Cells

Mammalian Cell Transplantation

The promoters described in the preceding text are employed to drive constitutive transcription of cDNA, leading to continuous mRNA and protein synthesis. However, there are situations where regulated or induced gene expression is desired for instance, when an expressed protein is cytotoxic or cytostatic to host cells. To address these situations there have been several inducible mammalian expression systems developed. Early systems relied on inducers that had pleiotropic effects on host cells, for example, heat shock induction of the heat shock promoter, heavy metal induction of the metallothionine promoter, or glucocorticoid induction of steroid responsive promoters (34-36). These systems often displayed high basal or leaky expression and suffered from the broad effects of inducers on a spectrum of cellular genes. More recently developed inducible systems including the Lac IPTG system (37,38), the tetracycline (tet) system (39-43), the streptagramin system (44), and the ecdysone...

Autoimmune Manifestations Following alloBMT

The pathogenesis of autoimmune manifestations post-alloBMT may be related to transfer of abnormal Band T-cell clones from the donor or to dysregulation of the newly developing immune system of donor origin in the host across minor or major histoin-compatibility barriers, frequently further perturbed by immunosuppressive agents administered to prevent or treat GVHD. The general immune imbalance seen during the first period following alloBMT, which may last several years, may contribute to an acceleration of autoimmune manifestation including organ specific autoimmune dysfunction. In addition cytomegalovirus (CMV) or possible other viral infections have been suggested to be possible important etiologies that may be associated with certain autoimmune phenomena post-alloBMT 45 . CMV disease is associated with various autoimmune manifestations including autoimmune hemolytic anemia, autoimmune granulocytopenia and the formation of autoantibodies 46 . It was found that CMV induces a...

Viral Chemokines And Chemokine HbLtHIURS

Herpesviruses, -poxviruses, and lentiviruses all encode chemokine and chemokine recep- Chemokine homologs are mostly encoded rhy herpesvirus and include three CC-type chemokines, vMIP-I, vMIP-II, and vMIP-III. yMIP-I is encoded by HHV-8 and binds and induces calcium signals in T-cells through CCR8. This same receptor also shows high affinity for vMIP-II. However, vMIP-I seems to as an agonist for the receptor and vMIP-II behaves as an antagonist (348). vMIP-II is a proad-spectrum chemokine receptor antago-1 vMIP-III acts as a potent CCR4 agonist attracts mainly Th2 T-cells. r Molluscum contagiosum virus (MCV) is a human poxvirus that encodes a chemokine ho-named vMCC-I (gene product of (349,350).This protein is related to DC chemokines but the mature protein lacks Jive amino acids in the N-terminus that are priticalfor receptor activation. Thus, this molecule binds to several receptors such as CCR1, CCR2, CCR5, CCR8, CXCR1, and CXCR2 but not able to induce signaling, acting instead an...

Deoxypyrimidine Kinase

Deoxypyrimidine kinase is a pyrimidine salvage pathway enzyme in herpesvirus and is a target for antiviral drugs. Its normal substrates are thymidine and dTMP. The enzyme readily phosphorylates the drugs 5-iododeoxyuridine, acycloguanosine (acyclovir), and ganciclovir . When the viral DNA polymerase attempts, in turn, to incorporate them into DNA in place of the corresponding dNTPs all three of the triphosphates of these drugs interfere with DNA replication. Uninfected cells do not efficiently phosphorylate acyclovir and ganciclovir and they phosphorylate 5-iododeoxyuridine only weakly, so DNA replication and virus growth are inhibited selectively in infected cells.

Effects Of Cyanide On Neural Tissue

Since the previous review, several significant papers further implicating elevated cellular calcium in CN-induced neurotoxicity have appeared.1 Ferger and Krieglstein exposed chick telencephalic neurons to 1 mM NaCN for up to 2 h.46 Increases in Ca i were measured with Fura-2, and viability was estimated by trypan blue exclusion. Elevation of Ca i paralleled neuronal damage.46 On the other hand, insertion into PC12 cells of a herpes simplex vector expressing cDNA for calbindin did not prevent the rise in calcium or cell survival after exposure to 1 -5 mM sodium CN (18 h) even though these calbindin-containing cells were protected against the effects of gluta-mate.47 Compared to the neurotoxicity of cyanide, glutamate-induced neurotoxicity may be more intimately related to increases in cell calcium.

Leukocytereduced Blood Components

Cytomegalovirus (TT-CMV) infection.22,23 Other clinical uses of leukocyte-reduced blood components, such as reducing transfusion-related immunomodulation, or reducing other transfusion-transmitted infections (e.g., EBV, HHV-8, HTLV-I II, etc.), should be considered experimental until additional studies are performed. Leukocyte reduction has not been shown to prevent transfusion-associated GVHD (TA-GVHD see below).3637

Complications 71 Infections

Infections represent the major cause of morbidity and of mortality of CLL patients. In our series, we observed the same rate of fatal infections in young and old CLL patients (9). Heavily treated patients and refractory patients, particularly if they are treated with purine analogs, are subgroups with an increased risk of developing infections (42,43). In young CLL patients receiving intensive treatment, the risk of infectious complications should be always considered. Adequate supportive management, including prophylaxis against herpesviruses, fungi, and Pneumocystis carinii and the use of granulocyte colony-stimulating factor in the presence of neutropenia may reduce the occurrence of fatal infections that could have an adverse impact on the outcome of patients treated with curative intent (44,45).

Spinal sympathetic interneurons are identified both physiologically and anatomically

More recently, spinal sympathetic interneurons have been identified by the retrograde, trans-synap-tic transport of herpes viruses (Strack et al., 1989a, b Schramm et al., 1993 Clarke et al., 1998 Tang et al., 2004). Herpes simplex and pseudorabies virus are two herpes viruses that are rapidly taken up by the axons of sympathetic postganglionic neurons and by the axons of preganglionic neurons projecting to the adrenal medulla. Virus is transported back to the somas of these neurons where it replicates and moves trans-synaptically to the neurons' synaptic antecedents. Thus, virus taken up from a peripheral organ or tissue by sympathetic postganglionic neurons infects the sympathetic pre-ganglionic neurons that synapse on those neurons. Virus replicates in the sympathetic preganglionic neurons, and spinal and brainstem interneurons that synapse on infected sympathetic preganglionic neurons are infected by further retrograde, trans-synaptic movement of virus. Antibodies to the viruses...

Long propriospinal pathways affecting sympathetic activity are multisynaptic

The majority of spinal sympathetic interneurons projecting monosynaptically to sympathetic pre-ganglionic neurons are located either among or just dorsal to their functionally related populations of sympathetic preganglionic neurons. Not only are the longitudinal distributions of spinal sympathetic interneurons and their related sympathetic preganglionic neurons similar, but the densities of spinal sympathetic interneurons are greatest in or near the spinal laminae that contain their associated sympathetic preganglionic neurons. Thus, Cabot et al. (1994) localized spinal sympathetic interneurons to the sympathetic pre-ganglionic neuron-rich lateral portion of lamina VII and the reticulated (lateral) portion of lamina V, just dorsal to the intermediolateral column. Clarke et al. (1998) used the retrograde transport of modified Herpes simplex virus to identify spinal sympathetic interneurons that were presynaptic to adrenal sympathetic preganglionic neurons. Infected