Biomedical subjects
Publications and source records attributed to M Pocchiari.
This short review takes in consideration the role played by the cerebral white matter in Creutzfeldt-Jakob disease (CJD) and analyzes three different hypotheses on the meaning of the involvement of the white matter only as secondary phenomenon or as primary neuropathological damage related to the causative agent(s) of the disease.
Pharmacological treatment with polyanions or amphotericin B in hamsters with experimental scrapie reveals that it is possible to delay the appearance of the disease only when the drug is given before the invasion of the agent into the clinical target areas of the brain. We suggest such early treatment may be possible for individuals at high risk of acquiring the disease, such as healthy mutation-positive relatives of patients with familial Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome, or recipients of potentially contaminated pituitary-extracted human growth hormone.
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A simple, sensitive, and reproducible assay for the measurement of the amphotericin B concentration in tissue extracts was developed by using the fourth derivative of the absorption spectrum of amphotericin B between wavelengths of 330 and 430 nm. The amphotericin B concentration in spleen and brain was proportional to the total amount administered. The amphotericin B concentration in the brain was highly correlated with the increase in the mean incubation period of intracerebrally scrapie-infected hamsters.
Although genetically engineered human growth hormone (hGH) is now commercially available, native pituitary-derived hGH is still used by physicians in many countries for the treatment of hormone deficiency states. We describe a method using ultrafiltration and 6 M urea that reduced infectivity in human pituitary tissue that had been deliberately contaminated with scrapie virus (an animal analogue of human Creutzfeldt-Jakob disease virus) from an initial level of 10(9.7) infectious units to just 5 infectious units. Based on estimates of the frequency of contamination and infectivity levels in batches of human pituitaries, the use of this protocol to prepare GH from cadaveric human glands yields a calculated probability of exposure to a contaminated vial of not greater than 1 in 3.2 million recipients; therefore, native hormone prepared by this method may be considered to be essentially risk-free. The same methodology may be useful in the preparation of other hormones, such as prolactin, for which no synthetic substitutes are currently available, as well as biological products derived from sheep or cattle, that may be infected with scrapie or bovine spongiform encephalopathy.
This study describes what needs to be considered in order to make a proper risk estimate of a human/animal-derived biological product from the contamination with unconventional slow virus(es). Several factors are important for this estimate. The first points regard the source of raw material (whether of human or animal origin), the kind of tissue (brain and other neural tissues being a higher risk), and in which way the tissue is collected. Then, the possibility, although remote, is taken into consideration of performing a quality control on the raw material through the measurement of PrP27-30, which is considered a specific marker of these diseases. Unfortunately, the detection of PrP27-30 is not yet so sensitive compared to the measurement of infectivity. Finally, the design of the validation experiments on the extraction and purification procedures of human/animal-derived products which gives the best estimate of safety is described. The conclusion of this study is that each biological product needs to be individually evaluated and therefore, it will be difficult to give standard guidelines for the judgement of their safety.
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Viremia is found in intraperitoneally scrapie-injected hamsters. The absence of a viremic peak before the beginning of scrapie replication in the brain suggests either that the spread of the agent to the brain is not via the blood or that early after infection, circulating monocytes carry the agent to the brain where it remains silent until the neural cells start replicating it.
Amphotericin B (AmB) has been able to lengthen the incubation period of intracerebrally (ic) scrapie-injected hamsters to 45 d. This article reports a linear relationship between AmB doses and the duration of the incubation periods of ic-treated animals compared with controls, a greater effect of AmB treatment administered 2 w before or the same day of ic scrapie incubation, and the ineffectiveness of mepartricin, an AmB analogue, in prolonging the incubation period of ic scrapie-injected hamsters. The beneficial effect of AmB appears due to a delay in the replication of the scrapie agent in the brain of infected hamsters. Moreover, AmB suppresses scrapie replication in the spleen of treated animals. Three hypotheses may explain these results: (1) AmB alters a hypothetical scrapie receptor, preventing the entry of the agent into central nervous system (CNS) target cells; (2) AmB interferes with mechanisms involved in scrapie replication; (3) AmB prevents the formation and accumulation of a scrapie-specific amyloid protein responsible for the disease. Whatever the mechanism of action, AmB is the only currently available drug to modify experimental CNS scrapie infection, so AmB is proposed as a novel class of antiscrapie drugs.
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In a retrospective study of Creutzfeldt-Jakob disease (CJD) in Italy from 1972 to 1986, we found 79 cases which fulfilled the diagnostic criteria for CJD. The annual mortality rate was 0.09 cases per million inhabitants. In this series the female to male ratio was 2.59, a value significantly higher than that found in Italian population (1.05). The mean age at death was 62.1 +/- 9.4 years and the mean duration of the disease was 5.3 +/- 3.0 months. No familial cases of CJD were found in our series. Mental deterioration was present in all of our cases, myoclonus in 85% and the other clinical signs were present at a lower rate. Periodic EEG activity was found in 92% of the cases. Two patients had had neurological or ophthalmic surgery and 17% of our cases had undergone general surgery within 5 years prior to the clinical onset of CJD.
Scrapie infectivity is reduced 5-6 logs following filtration through 100,000 MW cut-off filter plus overnight treatment with 6 M urea. These steps, applied to purified human Growth Hormone (hGH), increase the margin of safety of hGH.
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The scrapie-infected hamster has been considered an excellent model for the study of slow virus diseases of man (Creutzfeldt-Jakob disease) and animals. At the moment no therapy is available for the cure of these fatal central nervous system diseases, although several drugs have been tested. We found that amphotericin B (AmB), a polyene antibiotic, increased the incubation time of scrapie disease in animals infected by either the intraperitoneal or intracerebral route. Hamsters inoculated with a 10% brain suspension of the 263K strain of scrapie showed clinical signs of disease in 54.6 +/- 4.7 days. Under AmB treatment (1 mg/kg for 6 days a week) the incubation time increased with the length of treatment, up to a maximum delay of 45 days. AmB may interact with the scrapie agent on cell plasma membranes and may thereby decrease the rate of scrapie replication. However, AmB did not have any effect when administered after the clinical onset of scrapie disease.
Acetylcholinesterase, pseudocholinesterase and their molecular forms were measured in the CSF of patients affected by Alzheimer's disease and of matched neurological controls. Three different molecular forms of ChE were found in the CSF of both groups of patients, but only two of them belonged to 'true' AChE. No differences were found between Alzheimer's disease patients and neurological controls in all the examined parameters.
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Isonicotinic hydrazide, a drug that decreases the level of GABA, when injected subcutaneously in control and scrapie-infected hamsters induced tonic-clonic seizures in scrapie hamsters significantly earlier (P less than 0.0001) than in control animals. This suggests depression of the GABAergic system in scrapie-infected hamsters. To determine whether this lesion is pre or postsynaptic we measured the level of GABA, glutamate, cGMP and cAMP and the GABA-benzodiazepine receptor complex.