Maria Puopolo

Genetic prion disease: the EUROCJD experience

A total of 10–15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt–Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann–Sträussler–Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12–88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt–Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term “gTSE” is preferable to “familial TSE”. Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.

Mortality from Creutzfeldt–Jakob disease and related disorders in Europe, Australia, and Canada

Background: An international study of the epidemiologic characteristics of Creutzfeldt–Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. Methods: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. Results: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. Conclusions: This study has established overall epidemiologic characteristics for Creutzfeldt–Jakob disease (CJD) of all types in a multinational population–based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.

Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis

Abstract In a prospective study, plasma interleukin-6 (IL-6) and interleukin-10 (IL-10) levels were measured by enzyme-linked immunosorbent assay in 45 premature neonates (25–34 weeks gestational age) with signs and symptoms of suspected sepsis at 0, 12 and 24 h; C-reactive protein (CRP) was measured at 0–24 h after enrolment. Six subjects were excluded due to insufficient blood sampling. The remaining 39 neonates were assigned to one of three groups: 25 newborns with sepsis (blood culture positive), seven with pneumonia (positive results on broncho-alveolar lavage fluid culture and characteristic chest radiography) and seven with necrotising enterocolitis (NEC) (characteristic intestinal and radiological signs according to the criteria of Bell et al.). A group of 20 healthy preterm neonates represented control subjects. On admission, higher levels of IL-6, IL-10 and CRP were observed in neonates with sepsis: IL-6 (median 1500 pg/ml, range 487–10000 pg/ml), IL-10 (median 113 pg/ml, range 70–196 pg/ml), CRP (median 22 mg/l, range 4–80 mg/l); pneumonia: IL-6 (median 1500 pg/ml, range 747–8000 pg/ml, IL-10 (median 84 pg/ml, range 76–92 pg/ml), CRP (median 10 mg/l, range 8–33 mg/l) and NEC: IL-6 (median 6650 pg/ml, range 1595–7950 pg/ml), IL-10 (median 80 pg/ml, range 61–147 pg/ml), CRP (median 3 mg/l, range 2.8–8 mg/l) as compared to controls (IL-6 median 208 pg/ml, range 198–349 pg/ml; IL-10 median 36 pg/ml, range 19–50 pg/ml; CRP median <2 mg/l) (P < 0.05). In neonates with sepsis, IL-6 levels were significantly correlated with IL-10 levels (r=0.65; P=0.04) at the time of the second sample. The highest IL-6 levels were observed at onset, while IL-10 was predominant 12 h later. On admission, IL-10 and CRP levels were significantly higher in non-survivors (IL-10 median 507 pg/ml, range 422–753 pg/ml; CRP median 123 mg/l, range 20–219 mg/l) than in survivors (IL-10 median 76 pg/ml, range 61–143 pg/ml; CRP median 8 mg/l range 3–46 mg/l), while IL-10 levels were significantly higher (P < 0.05) also 12 h after admission (non-survivors: IL-10 median 600 pg/ml, range 538–800 pg/ml; survivors: IL-10 median 74 pg/ml, range 53–161 pg/ml). IL-6 and IL-10 levels were significantly correlated with CRP levels on admission (r=0.45; P=0.05). Conclusion Preterm neonates with sepsis, pneumonia or necrotising enterocolitis showed increased interleukin-6, interleukin-10 and C-reactive protein levels. High interleukin-10 concentration was associated with mortality and could be an early indicator of prognosis.

Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer’s disease

Background: Although epidemiological, clinical, and experimental evidence indicates that the inducible isoform of cyclo-oxygenase (COX-2) may be involved in the pathogenesis of several neurodegenerative disorders, the mechanisms whereby COX-2 contributes to Alzheimer’s disease are largely unknown. Objective: To undertake a longitudinal study of CSF levels of a major product of COX activity, prostaglandin E2 (PGE2), in relation to cognitive decline and survival in patients with Alzheimer’s disease. Methods: CSF PGE2 was measured on at least three annual visits in 35 controls and 33 Alzheimer patients (26 necropsy confirmed) who completed the Cambridge cognitive assessment (CAMCOG). Results: Compared with controls, CSF PGE2 was higher in patients with mild memory impairment, but lower in those with more advanced Alzheimer’s disease. The median survival time of patients with higher initial PGE2 levels was five years longer than those with lower levels. Conclusions: COX activity in Alzheimer’s disease varies with stage of the disease. PGE2 levels correlate positively with patient survival. These findings suggest that inhibition of COX activity does not represent a major target for the pharmacological treatment of Alzheimer’s disease.

High incidence of genetic human transmissible spongiform encephalopathies in Italy

Objective: To assess the incidence and mortality rates of genetic transmissible spongiform encephalopathy (TSE) diseases in Italy. Methods: The authors have sequenced the prion protein gene (PRNP) in 643 patients referred to the Italian Registry of Creutzfeldt-Jakob disease (CJD) and related disorders between 1993 and 2002. Crude age- and sex-specific incidence and mortality rates were calculated. Differences in morbidity from genetic TSE diseases in the 20 Italian regions were assessed by the standardized morbidity ratio (SMR). Results: A total of 130 cases were classified as genetic TSE diseases with a mean yearly incidence rate of 0.28 cases per million people. Genetic TSE diseases represent 17.7% of all TSE diseases, including sporadic, iatrogenic, and variant CJD. The most frequent mutation was the V210I (n = 54), and the second most common the E200K (n = 42). Mortality rates for genetic TSE diseases did not increase in any of the age groups under examination over the 10 years of surveillance. The analysis of regional distribution of genetic cases by place of birth revealed that in Campania and Calabria regions the number of genetic TSE cases was higher than in other regions. Conclusions: In Italy the incidence of genetic transmissible spongiform encephalopathy (TSE) diseases is the second highest among European countries. Genetic analysis is important for a correct classification of patients with TSE.

The role of high resolution pulsed and color Doppler ultrasound in the differential diagnosis of benign and malignant lymphadenopathy

The role of high resolution pulsed and color Doppler ultrasound in the differential diagnosis of benign and malignant lymphadenopathy is still unclear.

Impairment of Verb Processing in Frontal Variant-Frontotemporal Dementia: A Dysexecutive Symptom

Object and action naming and comprehension were tested in frontotemporal dementia (frontal variant, FTD), in Alzheimer’s disease (AD) and in controls. Although lower scores were obtained by all groups, we can confirm that actions were proportionally more impaired in FTD. The correlation between action naming deficit and severity of dementia was stronger in this group than in AD. The correlation analysis also suggested that the naming disorder was different in nature in FTD (mostly a dysexecutive deficit) and in AD (mostly a linguistic disorder). Our explanation is that since verbs are supposed to be more demanding of executive resources than nouns, a higher sensitivity to verbs should be expected in any brain pathology, but mostly in FTD in which executive resources are typically reduced.

Local and/or distant recurrences in T1-2/N0-1 non-small cell lung cancer

Data from a series of 181 patients subjected to long-term follow-up after surgical resection for non-small cell stage I and II lung cancer were analyzed to evaluate the statistical incidence and the prognostic factors of recurrence. The recurrence rate/year was particularly high in the first 2 years after surgery: the 2-year recurrence rate was 35.1% in stage I tumors and 51.8% in stage II, whereas the 5- and 7-year recurrence rates were 46.1 and 55.9% and 65.8 and 70.7%, respectively, for the same groups. Recurrences were observed more frequently in non-epidermoid carcinomas with multiple nodules (100% at 5 years) and in carcinomas classified as stage II (70.7% at 5-7 years), particularly when defined as adenocarcinoma (100% at 3 years). In the overall recurrence rate we observed no significant difference dependent on the type of resection even though limited segmental or wedge resection appeared to be related to a higher risk rate (true recurrence rate ratio: 0.6). Over two-thirds of the first observed recurrences were located at a distant site, with a slightly higher incidence of non-epidermoid carcinoma (72.5%). Isolated local recurrence mostly occurred in epidermoid carcinoma (47.6%). The most frequent sites of recurrence were the brain, bone and mediastinum. On multivariate analysis, independently significant adverse prognostic factors regarding the recurrence incidence were: tumor size greater than 3 cm, bronchial or hilar lymph node involvement, tumor histologically defined as adenocarcinoma, and the presence of satellite nodules.

Increased CSF levels of prostaglandin E2 in variant Creutzfeldt–Jakob disease

The concentration of the cyclooxygenase product prostaglandin E2 was sixfold higher in CSF samples from 18 cases of variant Creutzfeldt–Jakob disease (CJD) than in a group of eight subjects with other noninflammatory neurologic diseases, and comparable to those found in a group of six patients affected by diseases with a known inflammatory component. This finding suggests that cyclooxygenase activity may have a role in variant CJD pathogenesis, as previously reported in sporadic CJD.

p53 over-expression identifies a subset of nodal peripheral T-cell lymphomas with a distinctive biological profile and poor clinical outcome.

Peripheral T‐cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non‐Hodgkins lymphoma cases in Western countries, and also to the paucity of specific molecular‐genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra‐nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21WAF1, BCL‐2 and p‐glycoprotein (MDR‐1 gene product) in a series of 45 cases of nodal peripheral T‐cell lymphomas (PTCL) with ‘high‐grade’ histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over‐expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl‐2 (p<0.01) and less frequent expression of p21WAF1 than p53 negative cases. Mdm2 and p‐glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event‐free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over‐expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21WAF1 and more frequent expression of Bcl‐2, Mdm2 and p‐glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low‐cost method which may provide information of potential clinical and prognostic value in nodal peripheral T‐cell lymphomas. Copyright