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PubMed2006

Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin.

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.

Animals↗

PubMedDate not supplied

Protease inhibitor-induced carbamazepine toxicity.

Neurologic manifestations of HIV infection are quite diverse and can develop into seizures. Because new drug therapies have been developed, it is important to know the interactions between antiretroviral and antiepileptic agents. A 36-year-old patient with HIV developed a set of progressive left hemiparesis and secondarily generalized partial seizures related to progressive multifocal leukoencephalopathy. Phenytoin and carbamazepine were necessary to control the seizures. Instead of diverse antiretroviral therapies, the viral load was increased. Protease inhibitors (ritonavir and saquinavir) were added to the treatment and the patient developed progressive ataxia related to carbamazepine toxicity. Carbamazepine was discontinued and the patient remained asymptomatic. The patient was diagnosed with carbamazepine toxicity related to the introduction of ritonavir. Ritonavir is a potent inhibitor of hepatic cytochrome P450, mainly the CYP3A4 isoform. Carbamazepine is metabolized by this subsystem. Ritonavir acted as a CYP3A4 inhibitor, diminishing carbamazepine metabolism and provoking an increase in serum levels and clinical toxicity. We present a case of interaction between ritonavir and carbamazepine. Interaction between antiepileptic and antiretroviral agents is an emergent problem caused by the increasing association of the two therapies. We recommend strict monitoring of serum antiepileptic drug (AED) levels to avoid toxicity and inadequate seizure control.

Adult↗

PubMed1997

[Radiological diagnosis of viral encephalitis].

Most of viral encephalitis may demonstrate no specific change on CT and MR images. Brain swelling, edema, abnormal density (CT) and abnormal intensity (MR) can be detected in herpes simplex encephalitis and enterovirus encephalitis (coxsackie, echo, polio). The common finding on CT and MRI in patients with HIV encephalopathy are atrophy, leukomalacia. Progressive multifocal leukoencephalopathy (PML) shows multifocal oval or round white matter T2-hyperintensities on MR images. Subacute sclerosing panencephalitis (SSPE) may present slight changes in the subcortical and periventricular white matter, as well as basal ganglia. Progressive disorder makes widespread T1-low, T2-high intensity area and atrophy. MRI of acute disseminated encephalomyelitis (ADEM) shows multifocal subcortical hyper intense foci on T2-weighted studies. The deep white matter, brainstem, thalamus and cerebellum can be affected. Most of ADEM lesions resolve. Imaging findings of acute lymphocytic meningitis by echovirus and coxsackievirus are usually normal.

Encephalitis, Viral↗

PubMed2000

Profile of neurologic disorders associated with HIV/AIDS from Bangalore, south India (1989-96).

One hundred patients (95 males, 5 females, mean age at presentation 31.6 +/- 9.4 yr) with various neurological disorders associated with HIV infection during 1989-1996 were evaluated at NIMHANS, Bangalore. Eighty patients belonged to group I associated with opportunistic neuroinfections and 20 to group II--non infectious neurological disorders. Cryptococcal meningitis either alone (n = 31) or associated with tuberculous meningitis (n = 6) was the most common (46.3%) followed by neurotuberculosis either alone (n = 24) or with cerebral toxoplasmosis (n = 4) accounting for 35 per cent. Other opportunistic neuroinfections included cerebral toxoplasmosis, herpes zoster, fulminant pyogenic meningitis and neurosyphilis. Clinical characteristics, diagnostic clues, their laboratory and radiological profiles and problems encountered in diagnosis and management of these opportunistic infections are highlighted. In group II (19 males and one female; mean age of 32.6 +/- 9.4 yr), two patients had cortical dementia, three acute brain stem involvement, two epilepsy and one had features suggestive of progressive multifocal leukoencephalopathy. Two patients of group I during follow up developed cortical dementia. Six had peripheral nervous system involvement similar to Guillain-Barre syndrome. Sixty six patients (63 of group I and 3 of group II) progressed to AIDS, 33 patients from group I and one patient from group II succumbed to the disease. With the rapid increase in the incidence of HIV/AIDS and an increase in the neurological manifestations of HIV/AIDS it is important to recognise the magnitude of the problem for health planning in India.

AIDS-Related Opportunistic Infections↗

PubMed1996

Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system.

Amplification of viral nucleic acids from the cerebrospinal fluid (CSF) has considerably improved the diagnosis of several acute, subacute and chronic viral infections of the nervous system. In herpes simplex virus (HSV) encephalitis (HSE) the polymerase chain reaction (PCR) has become the method of choice for the rapid, non invasive diagnosis. Other herpes virus associated diseases which can now be reliably diagnosed are encephalitis, ventriculoencephalitis, polymyeloradiculitis, myelitis and an inflammatory polyradiculoneuropathy caused by cytomegalovirus (CMV), HSV, varicella-zoster virus (VZV) or Epstein-Barr virus (EBV), EBV associated primary B-cell-lymphoma of the brain, acute aseptic meningitis in young adults allied with VZV, and meningoencephalitis with recurrent seizures due to human herpes virus type 6 (HHV-6). In AIDS patients, PCR has helped to differentiate lesions either due to the human immunodeficiency virus (HIV) itself or to opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) or CMV related complications. HIV can be detected early in the course of infection in the CSF and the amount of proviral DNA in CSF cells seems to be correlated with the severity and/or progression of neurological signs and symptoms. Acute epidemic aseptic meningitis caused by enterovirus infections can now be reliably diagnosed and typed by reverse transcriptase PCR (RT-PCR). Meningitis cases caused by vaccination with the Jeryl Lynn and Urabe vaccine strain of mumps virus have been identified using RT-PCR and sequencing of the amplified products (amplicon).

Central Nervous System↗

PubMed1997

Cytomegalovirus disease presenting as a focal brain mass: report of two cases.

OBJECTIVE AND IMPORTANCE: Although the differential diagnosis of intracranial lesions in patients who have tested positive for human immunodeficiency virus is extensive, toxoplasmosis, lymphoma, and progressive multifocal leukoencephalopathy comprise approximately 90% of such cases. Cytomegalovirus infection of the central nervous system may be difficult to diagnose and rarely presents as mass lesions revealed by radiographic studies. CLINICAL PRESENTATION: Two patients who had tested positive for human immunodeficiency virus presented with progressive focal neurological deficits. Radiographic studies revealed solitary contrast-enhancing lesions in the right basal ganglia and right cerebellar hemisphere, respectively. INTERVENTION: The first patient underwent a stereotactic biopsy but died despite appropriate therapy. The second patient died without tissue having been obtained for diagnosis. Postmortem examinations revealed necrotizing lesions with diffuse areas of infiltrating histiocytes containing eosinophilic cytomegalovirus inclusion bodies. CONCLUSION: Although rare, cytomegalovirus infection should be considered in patients who have tested positive for human immunodeficiency virus and who present with enhancing intracranial lesions.

AIDS Dementia Complex↗

PubMed1993

Inborn errors and demyelination: MRI and the diagnosis of white matter disease.

The progress and extent of myelination can be assessed using magnetic resonance imaging (MRI). Myelination is delayed or diminished in several inherited metabolic abnormalities presenting in early life. Only minimal myelination of the CNS occurs in Pelizaeus-Merzbacher disease. Dysmyelination tends to produce fairly symmetrical lesions affecting white matter. In many mitochondrial enzyme and some lysosomal defects, the grey matter is also involved. The appearances and in particular the distribution on MRI and/or CT are characteristic in some conditions and the diagnosis is limited in others. Demyelination due to inflammatory disorders typically causes multifocal white matter lesions, recurrent in multiple sclerosis, monophasic in acute disseminated encephalomyelitis, extending in progressive multifocal leukoencephalopathy and classically involving the pons or corpus callosum in myelinolysis. Hypoxic ischaemic lesions may be metabolically induced and simulate primary demyelinating disorders. Mitochondrial enzyme defects in particular may present with stroke-like appearances. In many of these conditions, diagnosis is biochemical, but imaging has a significant role in suggesting the diagnosis, and documenting progression, response to therapy or complications.

Basal Ganglia↗

PubMed2002

Reversible posterior leukoencephalopathy secondary to indinavir-induced hypertensive crisis: a case report.

Reversible posterior leukoencephalopathy syndrome (RPLS) is an uncommon entity related to multiple and different pathologies, the most common being hypertensive crisis. It is believed to be secondary to the breakdown on the blood-brain barrier. At the beginning, it is undistinguishable from other leukoencephalopathies. However, the disappearance of brain lesions after removal of the potential cause, establish the differential diagnosis with other leukoencephalopathies. We present the case of an HIV-infected patient with a RPLS related to a hypertensive crisis short after the initiation of indinavir-containing highly active antiretroviral therapy. Once blood pressure was controlled and indinavir replaced by nelfinavir, white matter lesions at magnetic resonance imaging disappeared. The clinical and radiologic evolution excludes other diagnosis as progressive multifocal leukoencephalopathy and points indinavir as a potential hypertension-inducing agent in HIV-infected predisposed subjects.

Adult↗

PubMed1998

Cerebellar degeneration associated with human immunodeficiency virus infection.

Cerebellar disorders associated with HIV infection are typically the result of discrete cerebellar lesions resulting from opportunistic infections such as toxoplasmosis and progressive multifocal leukoencephalopathy or primary CNS lymphoma. Clinical symptoms and pathologic abnormalities related to the cerebellum may also be observed with HIV dementia. A primary cerebellar degeneration with HIV has not previously been reported. Ten patients were identified over an 8-year period at five medical centers. All patients had clinical, laboratory, and radiologic evaluations, and three had neuropathologic examinations. Patients presented with progressively unsteady gait, slurred speech, and limb clumsiness. Examination revealed gait ataxia, impaired limb coordination, dysarthria, and abnormal eye movements. Cognition, strength, and sensory function remained normal. CD4 lymphocyte counts varied between 10 and 437 cells/mm3. Neuroimaging studies showed prominent cerebellar atrophy. Neuropathology showed focal degeneration of the cerebellar granular cell layer and unusual focal axonal swellings in the brainstem and spinal cord. Cultures, histopathology, and immunochemical studies showed no conclusive evidence of infection. We report a syndrome of unexplained degeneration of the cerebellum occurring in association with HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed2000

BK virus infection in AIDS.

The BK virus (BKV) belongs to the family of the polyoma group, which contains three species: JC, which is responsible for progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome (AIDS); simian virus 40 (SV40), which is a simian virus of little pathologic significance in humans; and BKV, which is usually not pathogenic and is found in the urine of asymptomatic individuals. Recently BKV has been reported to cause symptomatic infection in renal transplant patients. The authors report a rare case of a 14-year-old boy with AIDS who developed a BKV infection of the lung and kidney that progressed to diffuse alveolar damage and death. The infected type II pneumocytes in the lung and the tubular epithelial cells in the kidney showed large, homogenous purple intranuclear inclusions. The absence of necrosis and destruction made it possible to distinguish BKV infection from herpes simplex. The size of the infected cells and the lack of a halo around the nuclear inclusion helped rule out cytomegalovirus as the cause of infection. Electron microscopy detected the presence of 40-nm intranuclear viral particles compatible with BKV, and in situ hybridization established the diagnosis.

AIDS-Related Opportunistic Infections↗

PubMed1989

Acquired immune deficiency syndrome in childhood. Neurological aspects.

Central nervous system (CNS) involvement is very frequently observed in pediatric AIDS. Clinical manifestations include encephalopathy, cognitive deficits, acquired microcephaly, neurological signs, myelopathy, and peripheral neuropathy. Neurological complications can be related to opportunistic viral infections such as encephalitis, atypical aseptic meningitis, progressive multifocal leukoencephalopathy, and myelitis. Nonviral syndromes include: toxoplasmosis, cryptococcal meningitis, candidiasis, Mycobacterium tuberculosis meningitis, and Mycobacterium avium subacute encephalitis. Bacterial infections, tumors, cerebrovascular complications, and peripheral neuropathies are not frequently observed in pediatric AIDS. The most severe complications of HIV infection is encephalopathy resulting from HIV infection of brain tissue. Direct HIV invasion of the CNS has been demonstrated. Clinical features of HIV encephalopathy are classified into three categories: (1) normal neurological findings; (2) static encephalopathy; and (3) progressive encephalopathy. AIDS dementia complex can be differentiated from the predominance of behavioral and cognitive disabilities.

AIDS Dementia Complex↗

PubMed2001

The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes.

In the absence of pathognomonic clinical features or a definitive laboratory test, multiple sclerosis (MS) remains ultimately a diagnosis of exclusion. Accurate diagnosis is increasingly important with available disease modifying therapy. Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS. In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both. Conditions often confused with MS may be inflammatory (systemic lupus erythematosus, Sjögren's syndrome, vasculitis, sarcoidosis, Behçet's disease), infectious (Lyme disease, syphilis, progressive multifocal leukoencephalopathy, HTLV-1 infection, herpes zoster), genetic (lysosomal disorders, adrenoleukodystrophy, mitochondrial disorders, CADASIL), metabolic (vitamin B12 deficiency), neoplastic (CNS lymphoma) and spinal (degenerative and vascular malformations) diseases. The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.

Central Nervous System Diseases↗

PubMed1998

JC virus excreted by multiple sclerosis patients and paired controls from Hungary.

JC virus (JCV), a human polyomavirus, is the agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV exists in four main genotypes in the USA. Type 1, including subtypes Type 1A and Type 1B, makes up about 64% of strains in the USA and is thought to be of European origin. Type 2 is found in Asia, and Type 3 in Africa. A fourth type is found only in the USA. In general, these genotypes differ in 1-2.5% of their DNA sequence. Thirty MS patients and 30 paired controls from Budapest were studied. The clinical course of MS was mainly secondary progressive, and patients were stable at the time of testing. Most of the controls were relatives of the probands: a spouse, parent, or child. Overall, 25 of 60 (42%) of the urines tested positive for JCV by PCR. These included 13 of 30 MS patients, and 12 of 30 controls. Genotyping in the VPI gene showed all 25 JCV strains to be Type 1. Among the MS patients, seven were Type 1A and six were Type 1B. Among the controls, nine were Type 1A and three were Type 1B. In five pairs of MS patients and controls, both were positive for JCV by PCR. Two of these were husband/wife pairs of which one pair was matched for subtype (both Type 1A), and the other was not. Two of them were mother/daughter pairs, and both were matched for subtype (both Type 1B). These findings demonstrate that JCV Type 1 predominates among Hungarians, and suggest that parent/child pairs can be used to trace JCV transmission within the MS family.

Adult↗

PubMed1997

Neuropathological syndromes in the course of full blown acquired immune deficiency syndrome (AIDS) in adults in Poland (1987-1995).

Morphological analysis of the brains from 100 cases of full blown AIDS patients observed in the course of 1987-1995 years was performed. The material comprised 96 males, 3 females and 1 infant, 11 months old. Early material consisted almost exclusively of homo- and bisexuals, while in the last years heterosexual drug addicts prevailed. Gross brain examination revealed focal changes in 25% of cases, most of them being connected either with opportunistic infections or primary proliferating malignancies. Brain atrophy with an evident regional differences was observed macroscopically in 35 cases. Microscopic examination allowed detection of pathological changes in the brains of 87 cases, although in the remaining 13 cases there occurred some slight abnormalities taking the form of non-specific neuronal degeneration and loss, considered as resulting from perimortal cardio-pulmonary insufficiency or bleeding. Specific HIV-related changes in the form of HIV-encephalitis, HIV-encephalopathy or coexistence of both and HIV-leptomeningitis as well as HIV-vasculitis were present in 35 cases. They were accompanied by HIV-associated changes (vacuolar myelopathy, vacuolar leukoencephalopathy and selective poliodystrophy). Very seldom they appeared as independent pathological features and were characterized by very low frequency. Opportunistic infections composed the largest group of 59 cases. Proliferative malignancies occurred altogether in eleven cases, 10 of which were primary and secondary brain lymphomas. One case of Kaposi sarcoma completed the neoplastic series. Sixteen cases revealed various types of brain pathology such as hepatogenic encephalopathy, traumatic cortical scars, central pontine myelinolysis etc. The 59 cases of opportunistic infections consisted of a wide spectrum of viral and bacterial as well as fungal and protozoan infections. Among viral infections cytomegalovirus encephalitis was the most common, way ahead the progressive multifocal leukoencephalopathy. The second in frequency among opportunistic infections was brain toxoplasmosis and some fungal infections such as cryptococcosis and aspergillosis. Bacterial infections were in fact limited to tuberculosis, taking the form of granulomatous leptomeningitis with severe vascular pathology and/or tuberculoma formation. Many pathological processes appearing in a single case was characteristic feature of our collection. There was coexistence of HIV-specific CNS pathology and opportunistic infections, malignant neoplastic growth and other types of pathology. Various opportunistic infections coexisted without HIV-specific changes as well as malignant proliferation with opportunistic infections. Similarities and differences of our series were compared with data characterizing other, earlier collections of NeuroAIDS.

AIDS Dementia Complex↗

PubMed2002

A case of neurotoxicity following 5-fluorouracil-based chemotherapy.

5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy.

Adult↗

PubMed2005

Expression of JC virus regulatory proteins in human cancer: potential mechanisms for tumourigenesis.

JC virus (JCV) is a human polyomavirus that is the etiologic agent of the fatal demyelinating disease of the central nervous system known as progressive multifocal leukoencephalopathy (PML). JCV is also linked to some tumours of the brain and other organs as evidenced by the presence of JCV DNA sequences and the expression of viral proteins in clinical samples. Since JCV is highly oncogenic in experimental animals and transforms cells in culture, it is possible that JCV contributes to the malignant phenotype of human tumours with which it is associated. JCV encodes three non-capsid regulatory proteins: large T-antigen, small t-antigen and agnoprotein that interact with a number of cellular target proteins and interfere with certain normal cellular functions. In this review, we discuss how JCV proteins deregulate signalling pathways especially ones pertaining to transcriptional regulation and cell cycle control. These effects may be involved in the progression of JCV-associated tumours and may represent potential therapeutic targets.

Antigens, Viral, Tumor↗

PubMedDate not supplied

Analysis of a mutant p53 protein arising in a medulloblastoma from a mouse transgenic for the JC virus early region.

BACKGROUND: JC virus (JCV) is a polyomavirus that causes progressive multifocal leukoencephalopathy (PML) in humans and is highly oncogenic in experimental animals. Transgenic mice with JCV T-antigen develop cerebellar tumors, which resemble human medulloblastomas, containing two distinct cell subpopulations, T-antigen positive and negative. In T-negative clones, a novel mutant p53 was detected (p53(mt)). MATERIALS AND METHODS: We have compared p53(mt) to wild-type p53 (p53wt) in p53-null cells. RESULTS: p53(mt) had lost the transcriptional transactivation activity of p53(wt), and unlike p53(wt), partially localized to the cytoplasm. Unlike mutant p53 from many human cancers, p53(mt) did not show a gain of function or a dominant negative phenotype. Adenovirus expressing p53(wt) but not p53(mt) inhibited cell growth and induced apoptosis of p53-null cells. CONCLUSION: During the course of tumor evolution of the JCV T-antigen mouse medulloblastoma, a mutation occurred that inactivated p53 allowing tumor progression even in the absence of continued T-antigen expression.

Animals↗

PubMed1998

The clinical profile of end-stage AIDS.

The purpose of this study was to describe the clinical profile of end-stage AIDS in patients 12 months before death. A cross-sectional examination of HIV-infected patients who attended a public HIV outpatient clinic between 1990 and 1996 and who died was conducted. The prevalence and first-time acquisition of AIDS-defining conditions 12 months before death were evaluated. The AIDS-defining conditions with the highest percentages of first-time acquisition in the last 12 months of life were progressive multifocal leukoencephalopathy (100%), lymphoma (96%), dementia (78.6%), Mycobacterium avium complex (MAC) infection (74.0%), toxoplasmosis (72.6%), and cytomegalovirus (CMV) infection (69.6%). Of the concomitant conditions studied, those with the highest percentages of first-time acquisition in the last 12 months of life were CMV with MAC (99%) and CMV with wasting (88%). Patients who acquire these AIDS-defining conditions may be eligible to receive information about end-stage options, such as hospice care. However, administration of aggressive antiretroviral treatments, such as the protease inhibitors, may affect this profile in the future, as the majority of the patients in this study were receiving the standard antiretroviral treatments of the time, primarily zidovudine.

AIDS-Related Opportunistic Infections↗