MTH-68/H oncolytic viral treatment in human high-grade gliomas.

Application of virus therapy to treat human neoplasms has over a three decade history. MTH-68/H, a live attenuated oncolytic viral strain of the Newcastle disease virus, is one of the viruses used in the treatment of different malignancies. Here we report on the administration of MTH-68/H to patients with glioblastoma multiforme, the most common and most aggressive neuroectodermal neoplasm with a poor prognosis, averaging six months to a year. Four cases of advanced high-grade glioma were treated with MTH-68/H after the conventional modalities of anti-neoplastic therapies had failed. This treatment resulted in survival rates of 5-9 years, with each patient still living today. Against all odds, each patient resumed a lifestyle that resembles their previous daily routines and enjoys a good quality of life, Each of these patients has regularly received MTH-68/H as their sole form of onco-therapy for a number of years now without interruption.

Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs.

Drug abuse and human immunodeficiency virus (HIV) infection seem to cause cumulative damage in the central nervous system (CNS). Elevated extracellular dopamine is thought to be a prime mediator of the reinforcing effects of addictive substances. To investigate the possible role of increased dopamine availability in the pathogenesis of HIV dementia, simian immunodeficiency virus (SIV)-infected monkeys were treated with dopaminergic drugs (selegiline or L-DOPA). Both substances increased intracerebral SIV expression, combined with aggravation of infection-related neuropathology and ultrastructural alterations of dendrites in dopaminergic areas (spongiform polioencephalopathy) in asymptomatic animals. Moreover, this treatment resulted in enhanced TNF-alpha expression in the brains of SIV-infected animals. These findings indicate a synergistic interaction between dopamine and SIV infection on microglia activation, leading to increased viral replication and production of neurotoxic substances. Our results suggest that increased dopamine availability through dopaminergic medication or addictive substances may potentiate HIV dementia.

Expression of Leu-19 (CD56, N-CAM) and nitric oxide synthase (NOS) I in denervated and reinnervated human skeletal muscle.

Neural cell adhesion molecule (N-CAM, Leu-19, CD 56) expression appears during muscle fiber regeneration and after denervation. Sarcolemma-associated nitric oxide synthase (NOS) I, however, disappears from denervated myofibers. The dynamics of expression of both proteins were studied in 5 cases of acute/subacute denervation, 28 cases of chronic denervation with and without collateral reinnervation, 5 cases of the intermediate type spinal muscular atrophy (SMA 2), and in 2 normal biopsies. NOS I and its NADPH diaphorase (NADPHd) activity disappeared from the sarcolemma region shortly after denervation, and before the appearance of denervation atrophy. N-CAM was found diffusely distributed in the sarcoplasm at the most severe phase of denervation atrophy in the majority of highly atrophic fibers. During reinnervation, NOS I expression remained absent and in part of the cases the target/targetoid phenomenon appeared. In parallel with the increase in volume of the reinnervated muscle fibers, the intensity of N-CAM immunoreactivity decreased progressively. After full restitution of muscle fiber caliber, the target/targetoid phenomenon and N-CAM immunostaining disappeared completely, and, finally, NOS I reappeared in the sarcolemma region. The sarcolemmal expression of dystrophin and dystrophin-associated proteins was unchanged during denervation. NOS I was completely absent in children with SMA 2, since the protein does not appear before 5 years of age in skeletal muscle, while N-CAM was very intensely expressed in the sarcoplasm of highly atrophic denervated muscle fibers. In conclusion, this study suggests that innervation is an important factor for selective gene expression and positioning of NOS I and N-CAM in skeletal muscle and gives practical information for the assessment of the phase and developmental stage of the denervation and reinnervation process.

Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs.

Human immunodeficiency virus infection (HIV) at late stages of the disease is accompanied by neurological complications, including motor, behavioral and cognitive impairment. Using simian immunodeficiency virus (SIV)-infected rhesus monkeys, an animal model of HIV infection, we found that during the asymptomatic SIV infection dopamine (DA) deficits are early components of central nervous system (CNS) dysfunction. To investigate the role of the DA system in SIV infection and to restore the DA deficiency, we administered selegiline, an agent with DAergic and neuroprotective properties, to SIV-infected monkeys. Selegiline increased DA availability but induced CNS vacuolization, SIV encephalitic lesions, and enhanced CNS viral replication during early SIV infection. The pathological changes seem to be mediated by DA, as treatment with L-DOPA, the precursor of DA, had similar effects. We propose that any natural or induced DAergic dysregulation which results in increased DA availability may potentiate HIV-associated neurological disease (ND). Our findings raise new questions regarding the pathogenesis of HIV-ND and generate concerns about the safety of dopaminergic drugs in the clinical management of HIV-infected patients.

Calcineurin A and calbindin immunoreactivity in the spinal cord of G93A superoxide dismutase transgenic mice.

A qualitative immunohistochemical study was performed on calcineurin A- and calbindin-positive neurons in the spinal cord of transgenic mice, an animal model of amyotrophic lateral sclerosis, carrying the G93A mutation of the Cu/Zn-superoxide dismutase gene. The results show that calcineurin A-immunoreactive motoneurons are affected by the neurodegenerative process; in contrast, calbindin-positive cells are selectively spared. The findings suggest that calcineurin plays a role as an accessory factor responsible for selective vulnerability in the neurodegenerative process of amyotrophic lateral sclerosis.

Clinicopathological study of atypical motor neuron disease with vertical gaze palsy and ballism.

The case of a 38-year-old patient with rapidly progressing motor neuron disease, complicated by major dysfunction of the extrapyramidal system and of vertical gaze is described. Neuropathological examination revealed a degenerative process that severely affected the lower motor neurons, as well as the neurons of the pars compacta of the substantia nigra, the nucleus of Darkschewitsch, the nucleus interstitialis of Cajal, the colliculi superiores, and the pallidum. The long tracts were unaffected at all levels of the brain stem and spinal cord. There was no convincing evidence for the presence of a multiple system atrophy or progressive supranuclear palsy; the results rather revealed a pattern of vulnerability characteristic of a variant of motor neuron disease.

Abundant defective viral particles budding from microglia in the course of retroviral spongiform encephalopathy.

A pathogenetic hallmark of retroviral neurodegeneration is the affinity of neurovirulent retroviruses for microglia cells, while degenerating neurons are excluded from retroviral infections. Microglia isolated ex vivo from rats peripherally infected with a neurovirulent retrovirus released abundant mature type C virions; however, infectivity associated with microglia was very low. In microglia, viral transcription was unaffected but envelope proteins were insufficiently cleaved into mature viral proteins and were not detected on the microglia cell surface. These microglia-specific defects in envelope protein translocation and processing not only may have prevented formation of infectious virus particles but also may have caused further cellular defects in microglia with the consequence of indirect neuronal damage. It is conceivable that similar events play a role in neuro-AIDS.

Effects of Selegiline in a retroviral rat model for neurodegenerative disease.

Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-inflammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which--under different conditions--exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) significantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

Herpes simplex virus encephalitis: cranial magnetic resonance imaging and neuropathology in a mouse model.

We performed a long-term magnetic resonance imaging (MRI) study in a mouse model of herpes simplex virus encephalitis. Mice were infected with herpes simplex virus type 1 (HSV-1) strain F. A 1.5-T cranial MRI scanner with standard spin-echo sequences was used. Neuropathological studies included immunohistochemistry. The presence of HSV DNA in brain tissue was determined with a polymerase chain reaction assay. Clinical assessment was performed daily: within the first 2 weeks the animals were severely affected and recovered thereafter. MRI and histopathological abnormalities corresponded well. HSV DNA was detectable initially and at 6 months. Extent and severity of structural abnormalities increased at 6 months. MRI offers a new in vivo approach for the detection of structural changes in the disease course of experimental herpes simplex virus encephalitis.

[Effect of ACTH on long-term outcome of muscle regeneration after nerve injuries]. / Der Einfluss von ACTH auf das Langzeitergebnis von Muskelregeneraten nach Nervenverletzungen.

An experimental investigation was performed to examine the influence of ACTH on the long-term results of muscle regeneration after nerve repair. Twenty albino-rabbits ("White Russians") served as the animal model. The epi-perineural neurorrhaphy of the fibular nerve was carried out under microscopic control with 11x0 sutures. A computer-supported light-microscopic analysis of representative muscle-fiber diameters was performed for detection of nerve regeneration on the effector muscle of the peroneal nerve, the anterior tibial muscle, after 3, 4, 5 1/2, 7, and 8 months. In addition, the nerves were examined by light microscopy using not only standard techniques but also surgical immunohistological staining techniques (APAAP). The acceleration of nerve regeneration already described in the literature was confirmed by our investigations. However, the results observed after eight months were similar, regardless of the ACTH dosage applied. Muscle regeneration was not influenced by the injection of ACTH. It therefore does not appear justifiable to clinically apply ACTH for improvement of nerve and muscle regeneration.

Absence of nitric oxide synthase I despite the presence of the dystrophin complex in human striated muscle.

Recently, it has been shown that in human striated muscle the signalling enzyme, brain-type nitric oxide synthase I (NOS I), is associated with the sarcolemma and complexes with dystrophin and/or members of the dystrophin complex. In order to find out whether there exists a regular association between NOS I and the complex, muscle biopsies from patients with various muscle disorders were analysed by enzyme histochemistry and immunohistochemistry. In patients suffering from Duchenne muscular dystrophy, and to a lesser extent in those with Becker-type dystrophy, NOS I and dystrophin complex components were absent or drastically reduced in the sarcolemma region. In other dystrophies, as well as in metabolic and inflammatory myopathies, NOS I and dystrophin complex constituents were expressed normally, while in the case of neurogenic diseases leading to denervation atrophy and especially congenital idiopathic clubfoot, the immunohistochemical patterns of the distribution of the dystrophin complex constituents were normal, but NOS I activity and protein were deficient or dramatically diminished. The results can be interpreted as indicating that, in general, NOS I targeting to the sarcolemma is dependent on particular members of the dystrophin complex, such as alpha-1 syntrophin, yet the expression and/or positioning of NOS I may be under the control of further factors, probably of neurogenic origin. NOS I-associated diaphorase may thus be a useful complementary tool in the diagnosis of muscle disorders.

A mouse model of herpes simplex virus encephalitis: diagnostic brain imaging by magnetic resonance imaging.

Herpes simplex virus encephalitis is a severe sporadic encephalitis in man with high mortality and morbidity. A critical step in the establishment of therapy is early diagnosis. Magnetic resonance imaging is a noninvasive, accurate diagnostic test for the detection of central nervous system disease. In an effort to monitor morphological changes in vivo we present a new diagnostic neuroimaging model of experimental herpes simplex virus encephalitis. A mouse model of herpes simplex virus encephalitis was used. 40 SJL mice were intranasally inoculated with an infectious dose of wild-type strain HSV-I F. Morphological abnormalities were studied by cranial magnetic resonance imaging (MRI). These findings were correlated with sequential neuropathological studies. 95% of animals developed cerebral abnormalities on MRI. resembling human HSVE. Areas of increased signal intensity on T2-weighted sequences and focal pathological contrast enhancement were mostly found in the frontal and temporal lobes and thalamic and cerebellar regions. All animals with MRI abnormalities had neuropathological signs of neuronal degeneration and reactive astrocytosis in corresponding regions. The described monitoring system offers a new approach for studies on neurovirulence and therapeutic strategies.

Muscular involvement in Behçet's disease: case report and review of the literature.

Acute necrotizing myositis is described in a 22-yr-old man with clinically diagnosed Behçet's disease. Light microscopic examination revealed a prominently granulocytic-monocytic infiltration of the muscle with severe necrosis. An infectious (bacterial, fungal or parasitic) etiology could be excluded by specific staining techniques and by immunohistochemistry. Vascular deposition of immune complexes was detected by direct immunofluorescence. Electron microscopy revealed severe structural damage and phagocytosis of muscle fibers. In the endomysium, leukocytes and occasional erythrocytes were found. Virus-like particles were not seen. The relevant literature on muscular involvement in Behçet's disease is reviewed. It is suggested that two different stages of inflammation occur in Behçet's disease. In the acute stage it presents as a granulocytic-monocytic necrotizing reaction developing from a neutrophil-mediated vasculitis. In the later phase lymphocytic infiltrations predominate. Despite the rare involvement of muscles the diagnosis of Behçet's disease should be considered particularly in younger patients presenting with muscular symptoms like pain and swelling pre-dominantly of the lower extremities.

[Loss of innervation of the anterior cruciate ligament in idiopathic gonarthrosis]. / Innervationsstörungen des vorderen Kreuzbandes bei der idiopathischen Gonarthrose.

This study quantifies the neurological structures of the ACL from proximal to distal in the zones A, B and C. 37 knee cadavers of healthy patients were analyzed to determinate the innervation for each age decade. This investigation was undertaken with high specific immuno-histologic sections (APAAP method). Neurofilaments and Schwann cells were isolated identified. In a second group consisting of 15 patients with idiopathic arthritis the ACLs were analyzed. This showed a significant loss of innervation, often, there was a complete deficit. In conclusion, this study revealed that idiopathic arthritis of the knee is associated with a significant deficit of the innervation of the ACL. If this is the reason for the arthritis or a secondary phenomenon is still unknown.

Nitric oxide synthase I (NOS-I) is deficient in the sarcolemma of striated muscle fibers in patients with Duchenne muscular dystrophy, suggesting an association with dystrophin.

Previously, we have demonstrated the expression of the brain-type nitric oxide synthase (NOS-I) in the sarcolemmal region of somatic and visceral striated muscle fibers in a variety of mammalian species through the use of enzyme histochemical and immunochemical techniques. Here we report that NOS-I protein and its NADPH diaphorase (NADPHd) activity are co-localized in the sarcolemma of human skeletal muscles. NOS-I immunolabeling and NADPHd activity showed no significant variation between type I and II fibers. In muscle biopsy specimens from patients with Duchenne muscular dystrophy (DMD), both NOS-I protein and activity were absent or markedly reduced. We, therefore, propose that NOS-I is complexed with dystrophin and/or dystrophin-associated proteins, adding a novel member to the sarcolemmal dystrophin-glycoprotein complex (DGC). The nature of the NOS-I-DGC link, and its role in skeletal muscle physiology and pathophysiology remain to be elucidated.

Staggering disease in cats: isolation and characterization of the feline Borna disease virus.

A Borna disease virus (BDV)-like agent was isolated from the central nervous system (CNS) of cats with a spontaneous non-suppurative encephalomyelitis ('staggering disease'). In contrast to the rabbit-adapted BDV strain V, which can be propagated in several primary and permanent cell cultures, the cat virus grew only in embryonic mink brain cells. Infection of adult Wistar rats with feline brain tissue material did not result in clinical disease during a period of 5 months, nor in growth of infectious virus in the brain. However, using the brain suspension of a newborn rat inoculated with feline brain tissue material, it was possible to induce typical Borna disease (BD) in four adult rats. This indicates a possible adaptation of the cat virus during passages in rats. By the use of an RT-PCR technique, BDV-specific RNA could be detected in a majority of brain samples from diseased cats. BDV-specific antigen was demonstrated in feline CNS samples both by immunohistochemistry and ELISA. However, the amount of BDV RNA and BDV antigen was less in the cats as compared to horses with BD, providing further support for the notion that a distinct feline BDV strain exists.

The neuropathology and epidemiology of AIDS. A Berlin experience. A review of 200 cases.

The brains of 200 patients who died with Acquired Immunodeficiency Syndrome (AIDS) from Berlin were examined retrospectively. This study was specifically intended to evaluate and document the prevalence of neuropathologic abnormalities, establishing the frequency of the various types of structural lesions, their combinations, their relative incidence, and the risk factors involved in different age groups. The data were compared and contrasted with the findings reported from other parts of the world and other German cities. It was found that the mean age of this group of patients was 41.4 years old, 75% were homosexual/bisexuals (H/B) and 18.5% were drug abusers (DA). Only 5.5% were women. Brain parenchymal changes, called in this report, HIV-related encephalopathy (HIVRE), characterized by vacuolization or spongy changes and astrocytosis in the subcortical white matter, and occasionally in gray matter, were found in 67 patients (33.5%). Drug abusers had a higher incidence of HIVRE (59.5%) compared with homosexual/bisexuals (28%). This is statistically significant (p < 0.0005). CMV encephalitis was found in 26 patients (13%) (8% of the drug abusers in contrast to 13% in the homosexual/bisexuals group). Primary central nervous system lymphoma (PCNSL) was seen in 28 patients (14%) regardless of the risk factor involved. 20 (13%) of the 150 H/B and 3 (8%) of the 37 DA had CMV encephalitis. Of the 150 H/B, 24 (16%) had PCNSL compared with only 4 of 37 (11%) of the DA. A significant incidence of opportunistic infections, both protozoal and viral was found in all groups. Cerebral toxoplasmosis occurred in 68 patients (34%). Microglial (phagocytic) nodules, probably related to CMV or cerebral Toxoplasmosis, were observed in 40 cases (20%). Diffuse microglial proliferation was noted in 104 patients (52%). Cerebral cryptococcosis was found in three patients. Progressive multifocal leukoencephalopathy was seen in 16 patients (8%). Various combinations of CNS pathological processes were found in 44 of the patients (22%). These include concomitant infections with Toxoplasma gondii and HIVRE in 13 patients; Toxoplasmosis and PCNSL in 8 patients; Toxoplasmosis with CMV and HIVRE in 4 patients; Toxoplasmosis with CMV in 2 patients; Toxoplasmosis with PCNSL and CMV in 2 patients; Toxoplasmosis with PCNSL and HIVRE in 2 patients and Toxoplasmosis with PML and HIVRE in 2 patients; Cerebral CMV with PCNSL and HIVRE in 4 patients; Cerebral CMV with HIVRE in 2 patients; PML with PCNSL in one patient; PML with HIVRE in 2 patients; and PML with PCNSL and HIVRE in one patient. Cerebrovascular lesions were found in 34 patients (17%).(ABSTRACT TRUNCATED AT 400 WORDS)