Oligodendroglial degeneration in distemper: apoptosis or necrosis?

Canine distemper virus (CDV) causes a multifocal demyelinating disease in dogs. It was previously shown that the initial demyelinating lesions are directly virus induced since a correlation between the occurrence of demyelination and CDV replication in white matter cells was observed. During the course of infection oligodendrocytes undergo distinct morphological alterations, partly due to a restricted CDV infection of these cells, and eventually disappear from the lesions. This phenomenon has been described in vivo as well as in vitro. However, the reason for the morphological alterations and the following oligodendroglial depletion remained unclear. Since virus infection can induce cell death, it was investigated whether apoptosis or necrosis plays a role in the pathogenesis of demyelination in canine distemper. In brain tissue sections from dogs with acute distemper apoptotic cells were not detected within the demyelinating lesions using morphological and biochemical cell death criteria. In chronic distemper, apoptotic cells – presumably inflammatory cells – were seen within the perivascular cuffs. These in vivo findings were correlated to the in vitro situation using CDV-infected primary dog brain cell cultures as well as Vero cells. Infection with culture-adapted CDV lead to massive necrosis but not to apoptosis. After infection with virulent CDV neither apoptosis nor necrosis was a predominant feature in either culture system. These findings suggest that virus-induced demyelination in canine distemper is not the direct consequence of apoptosis or necrosis. It is speculated that another mechanism must be responsible for the observed morphological alterations of oligodendrocytes, ultimately leading to demyelination. Received: 29 April 1998 / Revised, accepted: 27 August 1998     

Neuronal nuclear DNA fragmentation in the aged canine brain: apoptosis or nuclear DNA fragility?

Neuronal DNA fragmentation, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation (TUNEL), has been reported in both the canine and human brains in normal ageing, and in some human age-related neurodegenerative diseases. These results have suggested that apoptosis plays an important role in age-related neuronal loss. It is not clear, however, whether the TUNEL method is highly specific for apoptosis, as DNA fragmentation also occurs in the late stages o necrosis. In this study we have examined 27 dogs aged from 8 to 18 years, to investigate the occurrence of nuclear DNA fragmentation. An autolysis index based on current histological criteria was assigned to each animal to evaluate the effects of autolysis on nuclear DNA integrity. Our results have shown that neuronal nuclear DNA fragmentation is frequent in aged dogs, although it is not accompanied by apoptotic morphology. Yet, a positive relation between TUNEL labelling and the degree of tissue autolysis was observed. In contrast, no TUNEL labelling was detected in young control dogs despite autolysis indices being similar to those in aged dogs. Taken together, these results suggest that neuronal nuclear DNA fragmentation is an age-related phenomenon, not due to apoptosis, whenever other factors render neuronal DNA more susceptible to autolytic fragmentation. We confirm the effect of autolysis in a subpopulation of neurons in the aged canine brain, inducing nuclear DNA fragmentation.     

Nonenzymatic derived lipid peroxide, 8-iso-PGF2α, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model

Abstract

We studied whether 8-iso-PGF_2α, nonenzymatic arachidonyl peroxide, participated in the pathogenesis of delayed vasospasm using a canine subarachnoid hemorrhage (SAH) model. Fourteen adult mongrel dogs were divided into two groups, two-hemorrhage SAH group (n = 8) and control group (n = 6). The contents of 8-iso-PGF _2α in CSF, the basilar artery segment, and subarachnoid clot were measured by enzyme immunoassay kit. The CSF 8-iso-PGF_2α content on Day 7 in the SAH group was 67.9 ± 29.9 pg ml^-1 (n = 8), which was significantly higher than 27.1 ± 13.8 (n = 8) on Day 0 in the SAH group, and 33.2 ± 14.4 pg ml^-1 (n = 5) on Day 7 in the control group. The 8-iso-PGF_2α content in the basilar artery segment with spasm on Day 7 in the SAH group was 13.5 ± 1.9 pg mg^-1 wet weight (n = 8), significantly higher than 8.7 ± 1.9 (n = 6) in the control group. The 8-iso-PGF_2α content in subarachnoid clot was 1.7 ± 1.4 ng g^-1 wet weight (n = 8). Significant elevation of the 8-iso-PGF_2α contents in the CSF and the basilar artery segment occurred on Day 7 in the SAH group. The subarachnoid clot enclosed the basilar artery on Day 7, contained a considerable amount of 8-iso-PGF_2α. These results suggested that 8-iso-PGF_2α could play a crucial role in the pathogenesis of the delayed cerebral vasospasm. [Neurol Res 2002; 24: 301-306]     

Hepatocyte growth factor gene transfer effects on the femoral and intramuscular nerve in a canine model of lower limb ischemia*☆

BACKGROUND： Recent advancements in gene therapy have provided new methodology for treating ischemia in lower extremities. Gene transfer of angiogenic factors to ischemic tissues may promote local proliferation of new vessels and form collateral circulation. OBJECTIVE： To observe histopathological changes in the femoral and intramuscular nerve three months after intramuscular injection of hepatocyte growth factor （HGF） into the peripheral skeletal muscle in a canine model of lower limb ischemia. DESIGN： Randomized occlusion modelled and verification animal study. SETTING： Experimental Center, Lanzhou General Hospital of Lanzhou Military Area Command of Chinese PLA. MATERIALS： This study was performed at Animal Experimental Center, Lanzhou General Hospital of Lanzhou Military Area Command of Chinese PLA from September to November 2006. A total of eight male mongrel dogs, weighing 12–15 kg and 1.5–3 years of age, were selected for this study. This experimental study was in accordance with local ethics standards. Recombinant plasmid carrying HGF （pUDKH） and occlusion model plasmid （pUDK） were provided by the Third Laboratory of Radiation Medical Institute, Academy of Military Medical Sciences of PLA. METHODS： Grouping and model establishment： under anesthesia, complete vascular occlusion models were established on the left lower extremities. The experimental dogs were randomly divided into a model group and a pUDKH treatment group, with four dogs in each group. Dogs in the pUDKH group were injected with 0.15 mg/kg pUDKH. Ten minutes later, intramuscular injections were performed at three spots into the peripheral skeletal muscle of the left hind limb, as well as lateral injections at two spots. The injection volume at each spot was 0.2 mL. Dogs in the model group were injected with pUDK, and dosage and injection method were identical to the treatment group. MAIN OUTCOME MEASURES： Histopathological changes in the femoral nerve, as well as internal and external intramuscular nerve tissue     

A canine model to evaluate efficacy and safety of γ-secretase inhibitors and modulators

Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid-β protein precursor (AβPP), is a therapeutic target for Alzheimer's disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are described in different species such as mouse, rat, and guinea pigs. All these models have their value in testing compounds with amyloid lowering properties, however, compound characteristics and pharmacokinetic properties, as well as other species characteristics such as limited sampling volumes of cerebrospinal fluid (CSF), recommended the use of a larger, non-rodent animal species. For this purpose, a screening model in dogs was developed for testing GSIs and GSMs. We showed that GSIs and GSMs had a dose- and time-dependent effect on Aβ(37), Aβ(38), Aβ(40), and Aβ(42) in CSF. Changes in liver function were evidenced by a transient increase in bilirubin with the GSMs and incidental increases in alanine aminotransferase for GSMs as well as GSIs. Microarray analysis of liver biopsies enabled to elucidate potential mechanisms behind the liver function changes. The relevance of the liver findings should be further evaluated in chronic pre-clinical safety studies and in humans. Based on our data, we can conclude that the dog is a very appropriate species to assess efficacy and safety of compounds which have an effect on AβPP processing such as GSMs, GSIs, and BACE-inhibitors.     

Three-dimensional and fractal analyses of assemblies of amyloid β protein subtypes [Aβ40 and Aβ42(43)] in canine senile plaques

The three-dimensional (3D) distribution of amyloid beta protein (Abeta) subtypes [Abeta40 and Abeta42(43)] in canine senile plaques (SP) was observed using a confocal laser scanning microscope. In diffuse plaques (DP), Abeta42(43) alone was deposited as an uneven nebula-like assembly of fine granules. The border of the Abeta42(43) assembly was unclear and diffusely merged to the surrounding area. Mature plaques (MP), on the other hand, showed two patterns of Abeta deposition. In some MP, only Abeta40 was deposited as a defined assembly of very short fibrillary structures. Other MP consisted of both Abeta40 and Abeta42(43), and the deposition patterns of the two Abeta species were the same as those in single-positive plaques; fine granular with unclear margin for Abeta42(43), and short fibrillary structures for Abeta40. Additionally, we calculated the fractal dimensions (FD) of both Abeta40 and Abeta42(43) assemblies, and examined the serial change of FD in each SP. The FD of Abeta42(43)-positive DP ranged from 1.05 to 1.27, and those of Abeta40-positive MP ranged from 1.13 to 1.54 in single-positive plaques. In one double-positive MP, FD ranged from 1.02 to 1.36 for Abeta42(43) and from 1.01 to 1.51 for Abeta40. These results showed that the FD of canine Abeta40 assemblies was higher than that of Abeta42(43) assemblies, and the spatial changes of FD values for Abeta40 and Abeta42(43) in double-positive plaques were quite different. These morphological analyses clearly showed that canine DP and MP have completely different 3D structures, suggesting that their processes of formation are different.     

Alaskan Husky encephalopathy – a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome)

The gross and histopathological findings in the brain and spinal cord of five Alaskan Husky dogs with a novel incapacitating and ultimately fatal familial and presumed hereditary neurodegenerative disorder are described. Four dogs presented with neurological deficits before the age of 1 year (7–11 months) and one animal at 2.5 years old. Clinical signs in all dogs were of acute onset and included ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia and difficulties in prehension of food. In animals allowed to survive, the disease was static but with frequent recurrences. Pathological findings were limited to the central nervous system. Grossly visible bilateral and symmetrical cavitated foci were consistently present in the thalamus with variable extension into the caudal brain stem. Microscopic lesions were more widespread and included foci of bilateral and symmetrical degeneration in the basal nuclei, midbrain, pons and medulla, as well as multifocal lesions at the base of sulci in the cerebral cortex and in the gray matter of cerebellar folia in the ventral vermis. Neuronal loss with concomitant neuronal sparing, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation and transient mixed inflammatory infiltration were the main histopathological findings. In addition, a population of reactive gemistocytic astrocytes with prominent cytoplasmic vacuolation was noted in the thalamus. Lesions of this nature in this distribution within the neuroaxis have not been reported in dogs. The neuropathological findings resemble Leigh’s disease/subacute necrotizing encephalomyelopathy of man. Neuronal sparing in conjunction with apparently transient astrocytic vacuolation point to the possible pathogenetic role of astrocytes in the evolution of these lesions. An inherited metabolic derangement of unknown nature is postulated as the cause of this breed-specific disorder. Received: 6 August 1999 / Revised, accepted: 18 October 1999     

Effect of a ‘vagomimetic’ atropine dose on canine cardiac vagal tone and susceptibility to sudden cardiac death

We manipulated the level of cardiac vagal tone in dogs with healed myocardial infarctions during exercise plus acute ischemia, to explore vagal involvement in the pathophysiology of sudden cardiac death. We occluded the circumflex coronary artery during the last minute of treadmill exercise in 32 dogs with healed anterior myocardial infarctions. Twenty-one dogs experienced ventricular fibrillation (susceptible) and 11 did not (resistant). On a subsequent day, we gave intravenous lowdose atropine to susceptible dogs to increase their levels of cardiac vagal tone, as estimated by moving polynomial timeseries analysis of R–R interval variability (0.24–1.04 Hz). We also measured vagal responses to coronary occlusion at rest, before and after low-dose atropine. In susceptible dogs, atropine increased the average vagal tone index at rest (atropine: 7.3±0.4 versus control: 6.6±0.5 ln ms²,P<0.01) and during maximum exercise (atropine: 2.5±0.4 versus control: 1.6±0.3 ln ms²,P<0.01), but failed to prevent ventricular fibrillation induced by exercise plus ischemia. Time to ventricular fibrillation actually decreased from 63±3 to 42±2 s (P<0.01), and R-R interval shortening elicited by coronary occlusion increased (atropine: –144±64 versus. control: –55±32 ms,P<0.01). In resting susceptible dogs, atropine significantly increased preocclusion indexes of vagal tone (atropine: 7.8±0.3 versus control: 6.9±0.4 ln ms²,P<0.01), but did not prevent large reductions of vagal tone during ischemia (atropine: –4.4±0.6 versus control: –3.8±0.4 ln ms²,P<0.05). We conclude that increases of resting vagal tone after low-dose atropine in dogs with healed anterior myocardial infarctions do not protect against sudden cardiac death. Quite the contrary, vagal tone is withdrawn more completely during ischemia, and the time to ventricular fibrillation during exercise plus ischemia is shortened. Clin Auton Res 8:155–164     

Physiologic-pathologic correlation in Guillain-Barré syndrome in children

OBJECTIVE: To correlate electrophysiologic patterns with sural nerve pathology in children with Guillain-Barré syndrome (GBS). BACKGROUND: Based on electrophysiologic and pathologic observations, GBS has been divided into demyelinating and axonal subtypes. The acute motor axonal neuropathy (AMAN) involves predominantly motor nerve fibers with a physiologic pattern suggesting axonal damage, whereas the acute inflammatory demyelinating polyneuropathy (AIDP) involves both motor and sensory nerve fibers with a physiologic pattern suggesting demyelination. In this study, we sought to confirm these observations by correlating sural nerve pathology with electrophysiologic findings in GBS patients. METHODS: Biopsies of sural nerve from 29 of 50 prospectively studied GBS patients were obtained. Nerves were examined by light and electron microscopy, and with immunocytochemistry for macrophages, lymphocytes, and complement activation products. RESULTS: Sural nerves from AMAN patients were normal or had only a few (0.1% to 0.7%) degenerating fibers without lymphocytic infiltration or complement activation. One patient with reduced sural sensory nerve action potential classified as acute motor sensory axonal neuropathy (AMSAN) had many degenerating fibers (2.3%) in the sural nerve. All three AIDP patients displayed active demyelination, and in two patients, lymphocytic infiltration and complement activation products were observed on the abaxonal Schwann cell surface. CONCLUSION: Classification of Guillain-Barré syndrome subtypes based on motor conduction studies correlates closely with pathologic changes seen in sural nerve. In acute motor axonal neuropathy cases, the sural nerve is almost completely spared pathologically. In acute inflammatory demyelinating polyneuropathy cases, macrophage-mediated demyelination and lymphocytic infiltration are common in the biopsies of sural nerves.     

Significant events in Polish psychiatry in 2003?

The aim of this paper was a reflection on the most significant events in Polish psychiatry in 2003. Reform in health care financing and its realisation in 2003 introduced a risk of inhibiting further development of mental health care. The endangerment is a result of allocation of resources, which is inadequate to real costs and promotes in-patient treatment. An additional risk is seen in a project of privatisation of health care institutions. Increasing orientation towards methodology of molecular biology, which is similar to a general global tendency, influences research in psychiatry. Nevertheless the low number of publications resulting from government sponsored studies is disturbing. The situation in forensic psychiatry calls for involvement and studies. Psychiatria Polska published a report indicating low standard of psychiatric expertise for courts and high probability of corruption. The same was reflected in mass media publications later on. Polish Psychiatric Association Board had appointed a special commission to study this problem.     

Trends in Attempted Suicide in Adolescents and Young Adults in Gent, 1986–1995

This paper describes gender-specific trends in the occurrence and methods of attempted suicide in adolescents and young adults between 1986 and 1995 in Gent. The overall pattern emerging from this study is that following a decrease in the rates of attempted suicide in the second half of the 1980s, rates have clearly increased in the 1990s, especially among adolescent males. A slight predominance of female attempters was found in the 15 to 19 age group while among young adults the female to male ratio was approximately 1.0. Deliberate self-poisoning was involved in the vast majority of attempts, although among young adults significantly more males than females used deliberate self-injury to attempt suicide. In view of increasing rates of suicide among young people in many countries and of the association between attempted suicide and suicide, further study of trends and characteristics of attempted suicide among young people is warranted.     

A comparative study of psychopathology in Greek adolescents in Germany and in Greece in 1980 and 1998—18 years apart

Abstract.Objective: In the 1980s, we assessed Greek adolescents living in Germany and Greek adolescents living in Greece. Data from this earlier study supported the hypothesis of selective migration with higher psychopathology self-rating scores in Greek adolescents in Greece as compared to Greek adolescents in Germany. The current study uses the same design and instruments so that the comparison of the mental health of populations in the same areas, almost two decades apart, becomes possible.Methods: In 1980, a total of 2631 Greek adolescents were assessed in Munich, Germany or Veria, Greece. In 1998, 2920 Greek adolescents were assessed in Munich, Germany and Veria, Greece. The General Health Questionnaire (GHQ-28) was used to assess mental health status at both times.Results: 1) GHQ-28 scores showed a significant increase from 1980 to 1998 in both locations. 2) While in 1980, Greeks in Veria, Greece had higher psychopathology scores than Greek adolescents in Munich, Germany, this (with the exception of depression) was no longer true for 1998. 3) At both times and both locations adolescent girls scored higher in the GHQ-28 than adolescent boys.Conclusions: While the 1980 data supported the selective migration hypothesis, this was no longer true for the 1998 data. The increase in psychopathology in both locations is alarming and deserves further exploration.     

Cytokine immunoreactivity in cortical and subcortical neurons in periventricular leukomalacia: are cytokines implicated in neuronal dysfunction in cerebral palsy?

The major neuropathological substrate associated with cerebral palsy (CP) is a form of white matter (WM) injury known as periventricular leukomalacia (PVL). Proinflammatory cytokines were recently shown to be implicated in PVL pathogenesis. Many PVL patients develop cortical and deep gray neuronal dysfunctions such as epilepsy, cognitive deficits and extrapyramidal disorders. The precise nature of the relationship between the WM lesion and the subsequent neuronal disorders is unclear. Cytokines were shown to exert neurotoxicity in experimental models. This raises the need to investigate a possible noxious effect by cytokines on neuronal cortical development. In situ immunohistochemical methods were applied on 22 brains from infants both with PVL (study group) and without PVL (control group) to detect any immunoreactivity for cytokines (TNF-alpha, IL-1beta, IL-6) in cortical and gray matter neurons. While cortical and other neuronal structures in PVL brains did not display noticeable pathological anomalies, strong cytokine immunoreactivity was detected in many neurons in the neocortex, hippocampus, basal ganglia and thalamus. There were, however, regional differences in cytokine labeling. In addition, there was more TNF-alpha staining than IL-1beta; IL-6 was negative. In contrast, neuronal cytokine labeling in the "control" brains was negligible. In conclusion, we report and characterize, for the first time, the in situ immunoreactivity for proinflammatory cytokines in cortical and deep gray neurons in PVL. These findings might provide insights into the neuro-anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL.     

Geschlechtsunterschiede in der Psychopharmakologie – Gendermedizin in der Psychiatrie

Zusammenfassung:  Dieser Beitrag aus dem Bereich der Gendermedizin gibt einen kurzen überblick über aktuelle Studienergebnisse und Entwicklungen der pharmakologischen Therapie bei psychiatrischen Erkrankungen. Drei der am h?ufigsten verschriebenen Medikamentengruppen, Antidepressiva, Stimmungsstabilisierer sowie Antipsychotika werden herausgegriffen und hinsichtlich ihrer geschlechtsspezifisch unterschiedlichen Wirkungsweisen, ihres Nebenwirkungsspektrums sowie speziell zu beachtender Aspekte in der Praxis beschrieben. Zus?tzlich werden Hinweise auf die Einnahme dieser Substanzen w?hrend der Schwangerschaft sowie ihr teratogenes Potential gegeben. Eingelangt am 9. Juli 2009, angenommen am 13. Juli 2009