Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates.

Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60 days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3-4 months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.

Pathogenesis of equine herpesvirus-1 infection in the mouse model.

Equine herpesvirus-1 (EHV-1) is a major equine pathogen causing respiratory diseases, abortions and severe neurological disorders. The basis of neurological disturbances is, as in other organs, infection of endothelial cells, followed by vasculitis, thrombosis and ischaemic damage of the parenchyma. Here, a murine model was used to explore the mechanism of entry to, and spread within the brain, the cell affinity of the agent and the modulating role of the immune defence, which are all factors governing the pathogenesis of the neurological disease. Because controversial views exist about these mechanisms, we undertook a neuropathological study with intranasally infected adult mice. EHV-1 entered the brain through the olfactory neuroepithelium and along the olfactory nerves, and spread transsynaptically in rostro-caudal direction, using olfactory and limbic neuronal networks. Exclusively neurons were infected. The cellular immune reaction exerted a restraining effect on virus dissemination. Following nasal infection, the olfactory route was the major pathway for virus entry and dissemination, involvement of the trigeminal nerve in virus spread seems much less probable. In the adult mouse brain EHV-1 behaves as a typical neurotropic agent, using, similarly to other herpesviruses, the neuronal networks for dissemination. Vasculitis, the predominant type of lesion in natural infection, and endothelial cell positivity for EHV-1 were detectable only in the lung. Thus, this agent exhibits in the mouse a dual affinity: it is neurotropic in the brain, and endotheliotropic in visceral organs. Consideration of pathogenetic aspects of equine and experimental murine EHV-1 infections also helps a better understanding of human herpetic brain disease.

Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid.

The case of a 12-year-old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was undertaken with an oncolytic virus, MTH-68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far-reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention. Under continuous MTH-68/H - VPA administration the thalamic tumor remained under control, but the rhombencephalic one progressed relentlessly and led to the fatal outcome. In the final stage, a third tumor manifestation appeared in the left temporal lobe. The possible reasons for the antagonistic behavior of the three manifestations of the same type of glioma to the initially most successful therapy are discussed. The comparative histological study of the thalamic and rhombencephalic tumor manifestations revealed that MTH-68/H treatment induces, similar to in vitro observations, a massive apoptotic tumor cell decline. In the rhombencephalic tumor, in and around the declining tumor cells, NDV antigen could be demonstrated immunohistochemically, and virus particles have been found in the cytoplasm of tumor cells at electron microscopic investigation. These findings document that the oncolytic effect of MTH-68/H treatment is the direct consequence of virus presence and replication in the neoplastic cells. This is the first demonstration of NDV constituents in an MTH-68/H -treated glioma.

Intracranial meningiomas developing at long intervals following low-dose X-ray irradiation of the head.

Five patients are reported who underwent X-ray epilation in childhood for tinea capitis and who developed meningiomas after about four decades. X-ray irradiation resulted in permanent alopecia in four of the five patients. In four patients the tumors were found on the convexity, one patient had a tuberculum sellae meningioma. All five patients underwent surgery. Recurrence was noted in three of the five patients, one of them was reoperated. No malignant features, but signs of atypia were found at histopathological examination. The development of meningiomas after low-dose irradiation with long latency periods, the predominant calvarial location of the tumors, the high recurrence rates, the absence of malignant traits but the presence of atypias are features overwhelmingly common with similar cases published in the literature. The fact that two of the five patients were sisters stresses the importance of genetic factors in the evolution of these tumors.

Stephan Környey's contribution to the study of encephalitides.

A considerable part of Környey's work deals with the problem of encephalitides. HIs interest in this topic was roused by Heinrich Pette and in collaboration they studied the histopathology and pathogenesis of experimental and human poliomyelitis. On the basis of their findings they advocated the neural spread of the poliomyelitis virus. THey described the distribution of the poliovirus within the nervous system, its close affinity to the voluntary motor system and analysed the influence of the portal of entry and special neurotropism on the development of the distribution pattern of the process. THe encephalitic process changes as a function of time; the significance of this observation was expressed in the concept of the time factor. Környey designated the affinity of the poliovirus towards the neurons among the cellular components of the nervous tissue as gangliocytotropism. Based on his observation, he characterized the features of neural spread of virsuses and the selective character of this spread within the central nervous system. THe study of two other polioencephalitides with predilectional involvement of the brain stem, Borna disease and tickborne encephalitis, allowed him further pathogenetic assessments. Környey described the first manifestation of subacute panencephalitis in the Carpathian basin. He devoted special attention to the clinical and neuropathological analysis of various forms of leukoencephalomyelitides and closely followed the development of the principle of neuro-allergy (Pette) and the change in the pathogenetic view of these diseases. His excellent synthesising ability enabled him to write comprehensive review articles and textbook chapters on the various aspects of encephalitides.