Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.

Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study.

PURPOSE: To evaluate the activity and tolerability of dimethylsulfoxide (DMSO) in the prevention of soft tissue toxicity after extravasation of cytotoxic drugs. PATIENTS AND METHODS: From June 1991 to December 1994, all patients who had an extravasation during intravenous (IV) infusion of cytotoxic drugs in our institution were considered for an open, prospective study of preventive treatment with 99% DMSO, applied topically on the extravasation site every 8 hours for 7 days. Intermittent local cooling (for 1 hour three times daily) on the first 3 days was also used. RESULTS: One hundred forty-four patients with extravasations of doxorubicin (n = 11), epirubicin (n = 46), mitomycin (n = 5), mitoxantrone (n = 13), cisplatin (n = 44), carboplatin (n = 6), ifosfamide (n = 14), and fluorouracil (n = 5) entered the study; 127 were assessable. Only one patient suffered an ulceration. The treatment was well tolerated, with mild local burning and a characteristic breath odor being the only side effects of DMSO application, even in cases in which treatment continued for up to 6 weeks to obtain remission of the symptoms of extravasation. CONCLUSION: Topical DMSO is an effective and safe antidote that may be used with local cooling after extravasations of vesicant drugs other than those drugs for which standard interventions are defined.

Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging.

To establish correlations among cognitive states and neuropathology, we have examined 22 subjects (69-97 years of age) from the Baltimore Longitudinal Study of Aging (BLSA), of whom 15 had normal and stable cognitive performances and seven had dementia of variable severity. In the majority of normal subjects, few or no beta-amyloid (A beta) deposits or senile plaques (SP) were present in the neocortex, but neurofibrillary tangles (NFT) were consistently found in CA1 of hippocampus and layer II of entorhinal cortex. In two (15%) normal individuals, the densities of SP were consistent with the diagnosis of possible Alzheimer's disease (AD). We speculate that these cases with normal cognitive states and abundant neocortical SP may represent preclinical AD. We conclude that the neocortex of a majority of cognitively intact individuals can remain free of A beta deposits or SP, even into the tenth decade of life.

Cognitive decline strongly correlates with cortical atrophy in Alzheimer's dementia.

Alzheimer's disease (AD) is characterized by progressive dementia and distinct neuropathology at autopsy. In order to test the relationship between dementia severity and loss of brain volumes, we prospectively documented the neurological/medical health of 26 male and 26 female controls and AD cases, and evaluated a subset of controls and AD cases using the Mini Mental State Examination (MMSE). At autopsy, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria confirmed diagnoses in 33 AD cases and 19 controls, and using unbiased stereology we quantified total volumes of cortical gray matter, subcortical grey matter including white matter, and forebrain. For ages of death between 50 to 100 years, controls showed minor cortical atrophy in the absence of cognitive decline. Cortical atrophy in AD cases was 20 to 25% greater than that in controls; AD patients dying at older ages showed less severe cortical atrophy than those dying at younger ages. Across all AD cases there was a strong correlation between cognitive performance on the Mini Mental State Examination and cortical volume loss. These findings confirm fundamental differences in the temporal patterns of cortical volume loss in aging and AD, and support cortical degeneration as the primary basis for cognitive decline in AD.

Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.

BACKGROUND: The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles. OBJECTIVE: To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. SETTING: Alzheimer's Disease Research Center. SUBJECTS: One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline. MEASUREMENTS: The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale. DESIGN: The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures. RESULTS: The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results. CONCLUSIONS: The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.

APOE genotype and survival in men and women with Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of the APOE gene (APOE) is more frequent in patients with AD than in the general population, but studies are inconclusive as to whether it affects rate of progression or survival. Because survival in AD is generally longer in women than in men, the authors investigated whether APOE affects 10-year survival equally in men and women. METHODS: APOE testing was performed on 125 patients with probable AD enrolled in the Johns Hopkins AD Research Center between November 1984 and March 1987. The 39 men and 86 women were followed at 6-month intervals until censoring (by death or withdrawal from the study) or March 1997. Patients were dichotomized into those with and those without at least one epsilon 4 allele. For each sex, a Cox proportional hazards regression, allowing for delayed entry and covarying for age at onset, was used to examine the effect of epsilon 4 on survival. RESULTS: All patients who died during the study period and had autopsy (n = 92) were found to have definite AD. Average survival from disease onset did not differ by sex (12.1 years in men; 12.3 years in women). In neither sex were differences found between epsilon 4-positive and epsilon 4-negative subgroups in education, duration of AD at entry, or severity of dementia. However, in both sexes the epsilon 4-positive subgroup was approximately 3 years older at onset of AD and at entry to the study than the epsilon 4-negative subgroup. Adjusting for age at onset, the presence of an epsilon 4 allele significantly increased the relative risk of death only for men (RR = 2.69; 95% CI = 1.23 to 5.87). CONCLUSIONS: In this sample of mostly white, well-educated research participants with AD, the APOE epsilon 4 allele was associated with shorter survival in men but not in women.

Elevation of serum copper levels in Alzheimer's disease.

OBJECTIVE: To determine whether serum trace metals and oxidative species are related to abnormal cognition in AD. METHODS: The authors studied serum peroxides, copper, iron, transferrin, and antioxidant capacity in 79 patients with AD (mean age 74.3 years; 25 men, 54 women) and in 76 cognitively normal individuals (mean age 70.1 years; 33 men, 43 women). The relation of these oxidative and trace metals to APOE epsilon4 allele frequency, neuropsychological performance, and cerebrovascular or atrophic burden, as estimated by brain MRI and ultrasonography of cerebral vessels, was evaluated. RESULTS: Copper level was higher (p < 0.001) in subjects with AD than control subjects (specificity = 95%, sensitivity = 60%) with a cutoff serum level of 16 micro mol/L (1.02 mg/L). An increase of 1 micro mol/L in serum copper accounted for 80% of the risk of having AD and correlated with poor neuropsychological performance and medial temporal lobe atrophy (p < 0.03). Antioxidant capacity decreased and correlated with medial temporal lobe atrophy (p < 0.009) and with APOE epsilon4 allele (p = 0.004). CONCLUSIONS: Copper may play a role in neurodegenerative processes in AD, and serum copper measurement may prove to be a peripheral diagnostic marker for AD.

Analysis of the CCKB receptor antagonism of virginiamycin in guinea-pig ileum longitudinal myenteric plexus.

1. Virginiamycin, a macrolide reported to bind selectively to CCKB/gastrin receptors has been studied in a functional test, namely cholecystokinin-induced contraction of guinea-pig ileum myenteric plexus (LMMP). 2. Virginiamycin (1-10 microM) antagonized the selective CCKB agonist cholecystokinin tetrapeptide (CCK-4). The antagonism appeared not to be competitive as the highest concentration (10 microM) caused a reduction of its maximal effect. An apparent pA2 of 6.64 +/- 0.06 (s.e.) could be estimated if this depression was ignored. The selective CCKB antagonist, L-365,260 (0.01-0.3 microM) antagonized competitively the CCK-4 induced contraction and a pKB of 8.60 +/- 0.16 (s.e.) was estimated. 3. The combined dose-ratio analysis for virginiamycin, tested at 3 and 10 microM in association with 0.03 and 0.1 microM L-365,260, respectively, resulted in observed log dose-ratios of 1.39 and 1.53. That was consistent with both antagonists acting on the same receptor in LMMP. 4. These data, represent the first evidence of the antagonism of virginiamycin in a functional assay and they support the hypothesis of homogeneity between CCKB receptors in the CNS and in peripheral tissues.

Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results.

Skin necrosis is a recognized potential consequence of an inadvertent extravasation of Vinca alkaloids in the surrounding tissues during i.v. administration. Experimental studies suggest that hyaluronidase, an enzyme that degrades hyaluronic acid and improves the absorption of locally injected drugs, can reduce the risk of progressing to skin necrosis. On this basis, we used this enzyme as a local treatment after extravasations of Vinca alkaloids in seven patients. No patient suffered from subsequent skin necrosis. To the best of our knowledge, this is the first clinical report confirming the positive findings of experimental studies on the effectiveness of this antidote.

Receptor binding characteristics of the novel NMDA receptor glycine site antagonist [3H]GV150526A in rat cerebral cortical membranes.

Binding of the glycine site antagonist 3-[2-(Phenylamino-carbonyl)ethenyl]-4,6-dichloro-indole-2-carboxylic acid sodium salt ([3H]GV150526A) was characterised in rat cerebral cortical membranes. Saturation experiments indicated the existence of a high affinity binding site, with a pK(d) value of 9.08 (K(d)=0. 8 nM) and a B(max) of 3.4 pmol/mg of protein. A strong linear correlation was observed between the displacement potencies for [3H]GV150526A and [3H]glycine of 13 glycine site ligands (r=0.991). The association kinetics of [3H]GV150526A binding was monophasic, with a k(on) value of 0.047 (nM)(-1) min(-1). Dissociation was induced by the addition of an excess of glycine, GV150526A, or 5,7-dichlorokynurenic acid (DCKA), another glycine antagonist. With GV150526A and DCKA, the dissociation curves presented similar k(off) values (0.068 and 0.069 min(-1), respectively), as expected from ligands binding to the same site. Conversely, a significantly lower k(off) value (0.027 min(-1)) was found with glycine. Although these data may suggest that glycine agonists and antagonists bind to discrete sites with an allosteric linkage (rather than interacting competitively), the reason for this difference remains to be elucidated. It is concluded that [3H]GV150526A can be considered a new valuable tool to further investigate the properties of the glycine site of the NMDA receptor.

Treatment of metastatic colorectal carcinoma with lymphoblastoid interferon and 5-fluorouracil: data of a phase II study.

Many clinical trials have tested the combination of 5-fluorouracil and recombinant alpha-interferons in metastatic colorectal carcinoma. The efficacy of 5-fluorouracil and lymphoblastoid interferon was evaluated in a phase II study in which 31 patients with advanced colorectal carcinoma were enrolled. 5-Fluorouracil was administered at the dose of 600 mg/sqm bolus weekly and lymphoblastoid interferon was given intramuscularly at 3 million units every two days. All patients were evaluable for toxicity. Thirty patients were available for response: no complete response was recorded, three patients reached a partial response (10%), three a minor response (10%) and 18 progressed (59.4%). Overall median survival was 8 months. No grade IV toxicity was observed: in 2 patients grade III occurred and in 8 patients grade III fever and fatigue attributable to interferon developed. It appears that this combination does not yield better results than 5-fluorouracil alone.

Management of acute radiodermatitis. Pharmacological or nonpharmacological remedies?

The medical and nursing literature suggests a wide variety of pharmacological and nonpharmacological approaches to treatment of acute radiation skin damages (erythema, dry and moist desquamation, ulceration), but no specific and standardized therapy. The incidence of radiodermatitis has decreased with mega-voltage instruments, but it can nevertheless influence the therapeutic program and impair quality of life of patients. A study has been conducted to evaluate the tolerability and effectiveness of a nonpharmacological remedy, a mixture of hydrophobic (stearic acid) and hydrophilic (propylene glycol, glycerol, and polyunsaturated alcohols) components in a foam emulsion for the treatment of acute skin injuries following radiotherapy. Thirty-eight of 42 initial patients were evaluable: we observed a complete response in 22 (57.9%), improvement in 14 (36.8%), and failure in only two (5.3%).

Colorectal, lung, and breast cancer care during the three years following the diagnosis: a population-based study.

AIMS: We evaluated a number of basic parameters of care during hospitalization that contribute to the total cost of therapy during the 3 years after the first diagnosis of cancer. METHODS: The study examined a sample of cases of cancer of the colon-rectum (164 cases), lung (160 cases) and breast (144 cases) diagnosed in 1987, taken from the data base of the Tuscany Cancer Registry. All the information collected by the Registry was examined and the sample was further validated by reviewing original clinical records. The agreement between the two sources was very high, confirming the adequacy of the Registry as a source of information. The parameters evaluated for each patient were the number of cytohistologic examinations, surgery, hospital admissions and days spent in hospital during the 3 follow-up years. RESULTS: The average number of admittances in 3 years was 1.93 for colorectal, 3.39 for lung and 2.15 for breast cancer. The mean number of days spent in hospital in the 3 follow-up years was 39.9 for colorectal, 50.1 for lung and 21.1 for breast cancer. The parameters differed among subjects still alive, those deceased and those in various stages of the illness. CONCLUSIONS: The costs of the time spent in hospital, based on the number of days during the first 3 years of the illness, were higher in cases of lung cancer than of the other sites, and more so for patients diagnosed in an advanced phase of the disease.

On the predictability of violent behavior: considerations and guidelines.

Following a semantic discussion of dangerousness, and having established its dynamic concept, the authors define the prediction of dangerous behavior as the anticipation of an antisocial act towards others. The present-day dilemma of predicting dangerous behavior is discussed. An extensive review of sociological and psychiatric studies is presented. Further, the authors stress the vital importance of predicting violent behavior in view of statistical data concerning rampant violent crime in the United States. They encourage more cooperation between psychiatric experts and the judicial system in view of the common social problem all are faced with. Better diagnostic procedures and more logically deductive factual expert reports are hoped for. The authors postulate that prediction is strictly connected with the possible prevention of dangerous behavior and the continuation of a civilized, secure society.

[Sulodexide in the prevention of post-mastectomy lymphedema]. / Il sulodexide nella prevenzione del linfedema post-mastectomia.

Post-mastectomy lymphedema of the upper limb, that can be noticed by 10 to 20 percent of patients with breast cancer, is usually related to some risk factors: use of radiotherapy on the axilla, obesity, venous outflow obstruction, delayed wound healing or infection. The most important contributing factor to postsurgical edema is the development of lymphangitis in the upper limb. Although literature contains numerous accounts on the use of pharmacological agents for the treatment of postmastectomy lymphedema, the results are not satisfactory in term of clinical response and side effects. In the present study we investigate tolerability and feasibility of the use of suledexide in patients, submitted to mastectomy for breast cancer, with an initial lymphedema of the limb omolateral to surgery or other risk factors for the development of a clinical remarkable lymphedema. Our results show that sulodexide is a very satisfactory therapy in term of lack of side effects and good compliance.