Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease.

Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1-/- mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1-/- mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1-/- mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

Is letrozole needed for controlled ovarian stimulation in patients with estrogen receptor-positive breast cancer?

OBJECTIVE: To assess the advantages and disadvantages of using letrozole for controlled ovarian stimulation (COH) in young patients with estrogen receptor-positive (ER+) breast cancer, wishing to cryopreserve oocytes. DESIGN: Retrospective cohort analysis. SETTING: Sixteen Italian units for reproductive medicine and in vitro fertilization. METHODS: Data of 50 ER+ breast cancer patients undergoing COH to cryopreserve oocytes before gonadotoxic chemotherapy with a letrozole plus gonadotropins (Le+Gn) protocol were compared with those of 25 young women with ER- breast cancer, submitted to COH using a protocol with gonadotropins alone (Gn-only). RESULTS: The Le+Gn protocol implied a significantly lower total Gn consumption and allowed to maintain significantly lower circulating E2 levels at all checkpoints throughout stimulation (peak E2 value 446 ± 357 versus 1553 ± 908 pg/ml, respectively; p = 0.001). On the other side, the Le+Gn protocol allowed a significantly lower yield of oocytes available for cryostorage (6.6 ± 3.5 versus 8 ± 5, respectively; p = 0.038). CONCLUSIONS: In breast cancer patients, the association of letrozole to Gn significantly reduces the number of oocytes available for cryostorage in comparison with the use of Gn alone. On the other side, it is associated with significantly lower E2 levels during the whole stimulation cycle, a safety issue that has been traditionally considered advantageous in case of ER+ cancers.

Breast cancer incidence trends in European women aged 20-39 years at diagnosis.

An increase in the incidence of breast cancer in women aged<40 years has been reported in recent years. Increased incidence could be partly explained by subtle detection biases, but the role of other risk factors cannot be ruled out. The purpose of the present study was to investigate the changes in temporal trends in breast cancer incidence in European women aged 20-39 years at diagnosis. Age specific breast cancer incidence rates for 17 European Cancer Registries were retrieved for the calendar period 1995-2006. Cancer registries data were pooled to reduce annual fluctuations present in single registries and increase incidence rates stability. Regression models were fitted to the data assuming that the number of cancer cases followed the Poisson distribution. Mean annual changes in the incidence rate (AIC) across the considered time window were calculated. The AIC estimated from all European registries was 1.032 (95% CI=1.019-1.045) and 1.014 (95% CI=1.010-1.018) in women aged 20-29 and 30-39 years old at diagnosis, respectively. The major change was detected among women aged 25-29 years at diagnosis: AIC=1.033 (95% CI=1.020-1.046). The upward trend was not affected when registries with high or low AIC were removed from the analysis (sensitivity analysis). Our findings support the presence of an increase in the incidence of breast cancer in European women in their 20s and 30s during the decade 1995-2006. The interpretation of the observed increase is not straightforward since a number of factors may have affected our results. The estimated annual increase in breast cancer incidence may result in a burden of the disease that is important in terms of public health and deserves further investigation of possible risk factors.

Second-line treatment with intravenous gemcitabine and oral etoposide in platinum-resistant advanced ovarian cancer patients: results of a phase II study.

OBJECTIVE: The outcome of advanced ovarian cancer patients has not significantly improved since the introduction of platinum. One of the major reasons for this failure is the lack of an effective second-line treatment. In this phase II trial we tested the combination of gemcitabine and etoposide in 2 different groups of patients. Group 1 consisted of patients showing disease progression or relapse within 6 months of first-line platinum-based chemotherapy. Group 2 comprised heavily pretreated patients showing progression during the last chemotherapy attempt. METHODS: Thirty-four patients were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) on days 1 and 8 and etoposide was administered orally at 100 mg/day on days 8-12 for 6 courses. RESULTS: Eighteen patients (52.9%) had an objective response and the median duration of the response was 10.3 months. Our chemotherapy regimen showed a low toxicity and good patient compliance. In 5 patients the treatment had to be delayed and in only 2 patients it was discontinued. CONCLUSIONS: The combination of gemcitabine and oral etoposide seems to be a safe and effective second-line treatment for platinum-resistant ovarian cancer patients. Additional data on larger series are warranted to better define the activity of this combination regimen.

Phaseolin gene from bean is expressed after transfer to sunflower via tumor-inducing plasmid vectors.

Sequences coding for the bean seed protein phaseolin were inserted into transferred DNA regions of tumor-inducing plasmids. Constructions were devised in which the coding region of phaseolin was fused in the correct reading frame with the coding region of octopine synthase and placed under the transcriptional control of the octopine synthase promoter. Other plasmids were prepared to permit expression of the phaseolin-encoding sequences from the flanking phaseolin promoter region. The RNA transcribed in sunflower cells transformed with these constructions was characterized by hybridization procedures, SI nuclease mapping, and by translation in vitro of extracted RNA. These tests showed that the genomic intervening sequences were correctly excised. Immunoreactive phaseolin polypeptides were detected by enzyme-linked immunosorbent assay and by antibody hybridization to electrophoretically separated protein extracts of sunflower tissues isolated from crown gall tumors and of transformed sunflower cells grown in tissue culture. These results demonstrate the expression of a plant gene after transfer to a taxonomically distinct botanical family.

Early effects of low benzene exposure on blood cell counts in Bulgarian petrochemical workers.

OBJECTIVES: Only few studies have examined early hematological effects in human populations exposed to low benzene levels and their findings are controversial. We evaluated hematological outcomes (WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, RBC, Hb, HCT MCV, platelets and MPV) in a population of 153 Bulgarian petrochemical workers exposed to benzene (range 0.01-23.9 ppm) and 50 unexposed subjects. METHODS: Written informed consent was obtained and a self-administered questionnaire used to collect information on current smoking habits, lifestyle, and occupational activities. Exposure assessment was based on personal monitoring sampling the day before phlebotomy. Urinary trans-trans-muconic acid (t,t-MA) was determined at the beginning and end of the work shift. Based on individual airborne benzene measurements, study subjects were categorized in three exposure categories (referents, <1 and > or =1 ppm). Mean values of each hematologic outcomes in each exposure category were compared with the referent group using a multiple linear regression model adjusted for age, gender, current smoking habits and environmental toluene level. The influence of the CYP2E1 (RsaI and DraI) and NQO1 609C>T genetic polymorphisms on differential hematological parameters was also investigated. RESULTS: No dose-response effect was observed for most of the examined hematological outcomes (WBC, lymphocytes, neutrophils, monocytes, RBC, Hb, HCT, MCV, platelets and MPV). The eosinophil count was inversely related to benzene exposure only among smokers. Conversely, basophils increased with increasing exposure. No effect on benzene hematotoxicity was found for any of the investigated polymorphisms. CONCLUSION: In our study we did not find a decline in WBC and lymphocytes related to benzene exposure. A myeloproliferative effect of benzene is highly unlikely to explain the observed reduction in eosinophils and increase in basophils as it would lead to a concordant depression in all granulocyte subpopulations. Whether benzene effects at low doses are present in Caucasian populations remains uncertain, thus warranting further investigations.

Genomic damage in children accidentally exposed to ionizing radiation: a review of the literature.

During the last decade, our knowledge of the mechanisms by which children respond to exposures to physical and chemical agents present in the environment, has significantly increased. Results of recent projects and programmes focused on children's health underline a specific vulnerability of children to environmental genotoxicants. Environmental research on children predominantly investigates the health effects of air pollution while effects from radiation exposure deserve more attention. The main sources of knowledge on genome damage of children exposed to radiation are studies performed after the Chernobyl nuclear plant accident in 1986. The present review presents and discusses data collected from papers analyzing genome damage in children environmentally exposed to ionizing radiation. Overall, the evidence from the studies conducted following the Chernobyl accident, nuclear tests, environmental radiation pollution and indoor accidental contamination reveals consistently increased chromosome aberration and micronuclei frequency in exposed than in referent children. Future research in this area should be focused on studies providing information on: (a) effects on children caused by low doses of radiation; (b) effects on children from combined exposure to low doses of radiation and chemical agents from food, water and air; and (c) specific effects from exposure during early childhood (radioisotopes from water, radon in homes). Special consideration should also be given to a possible impact of a radiochemical environment to the development of an adaptive response for genomic damage. Interactive databases should be developed to provide integration of cytogenetic data, childhood cancer registry data and information on environmental contamination. The overall aim is to introduce timely and efficient preventive measures, by means of a better knowledge of the early and delayed health effects in children resulting from radiation exposure.

Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy.

BACKGROUND: The occurrence of spontaneous tumors in pet animals has been estimated in a few European and North American veterinary cancer registries with dissimilar methodologies and variable reference populations. OBJECTIVES: The Animal Tumor Registry (ATR) of Genoa, Italy, was established in 1985 with the aim of estimating the occurrence of spontaneous tumors in dogs. METHODS: Six thousand seven hundred and forty-three tumor biopsy specimens were received from local veterinarians in the Municipality of Genoa between 1985 and 2002. Three thousand and three hundred and three (48.9%) biopsy specimen samples were diagnosed as cancer and were coded according to the International Statistical Classification of Diseases (ICD-9). RESULTS: Mammary cancer was the most frequently diagnosed cancer in female dogs, accounting for 70% of all cancer cases. Incidence of all cancers was 99.3 per 100,000 dog-years (95% CI: 93.6-105.1) in male dogs and 272.1 (95% CI: 260.7-283.6) in female dogs. The highest incidence rates were detected for mammary cancer (IR = 191.8, 95% CI: 182.2-201.4) and for non-Hodgkin's lymphoma (IR = 22.9, 95% CI: 19.7-26.5) in bitches and for non-Hodgkin's lymphoma (IR = 19.9, 95% CI: 17.4-22.7) and skin cancer (IR = 19.1, 95% CI: 16.6-21.8) in male dogs. All cancer IR increased with age ranging between 23.7 (95% CI: 18.4-30.1) and 763.2 (95% CI: 700.4-830.1) in bitches and between 16.5 (95% CI: 12.8-21.1) and 237.6 (95% CI: 209.1-269.0) in male dogs aged < or =3 years and >9-11 years. CONCLUSION: This study summarizes the work done by the ATR of Genoa, Italy, between 1985 and 2002. All cancer incidence was 3 times higher in female than in male dogs, a difference explained by the high rate of mammary cancer observed in bitches. Because a biopsy specimen was required to make a cancer diagnosis, cancer rates for internal organs cancers, such as respiratory and digestive tract cancers may have been underestimated in the study population.

GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1.

Controlling the number of functional gamma-aminobutyric acid A (GABA(A)) receptors in neuronal membranes is a crucial factor for the efficacy of inhibitory neurotransmission. Here we describe the direct interaction of GABA(A) receptors with the ubiquitin-like protein Plic-1. Furthermore, Plic-1 is enriched at inhibitory synapses and is associated with subsynaptic membranes. Functionally, Plic-1 facilitates GABA(A) receptor cell surface expression without affecting the rate of receptor internalization. Plic-1 also enhances the stability of intracellular GABA(A) receptor subunits, increasing the number of receptors available for insertion into the plasma membrane. Our study identifies a previously unknown role for Plic-1, a modulation of GABA(A) receptor cell surface number, which suggests that Plic-1 facilitates accumulation of these receptors in dendritic membranes.

Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery.

BACKGROUND: Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. OBJECTIVES: The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. METHODS: Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing-remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing-remitting multiple sclerosis patients were evaluated using linear mixed models. RESULTS: Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline (p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test (p<0.001). In relapsing-remitting multiple sclerosis patients, reaction time slowed over 12 months (p<0.001) for the CogState Brief Battery Detection (mean change -34.23 ms) and Identification (-25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. CONCLUSIONS: The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting.

Retrospective mortality cohort study of Italian workers compensated for silicosis.

OBJECTIVES: To estimate cause specific mortality in a large cohort of Italian workers compensated for silicosis. METHODS: The cohort included 14 929 subjects (14,098 men and 831 women) compensated for silicosis between 1946 and 1979, alive on 1 January 1980, and resident in Tuscany (a region of central Italy with 3,547,000 inhabitants). Mortality follow up ranged from 1980 to 1999. Vital status and the causes of death were determined by linkage with the regional mortality registry and with the national mortality database. The cohort mortality rates were compared to the rates of the local reference population. SMRs and their 95% confidence intervals were computed assuming a Poisson distribution of the observed deaths. Specific SMR analyses were performed according to the level of disability, the year of compensation assignment, and the job type. RESULTS: A significant excess mortality was observed in male silicotics for cancer of the lung, trachea, and bronchus and cancer of the liver, respiratory diseases (silicosis, asbestosis, antracosilicosis, and other pneumoconiosis), and for tubercolosis. Statistically significant mortality excess was observed in female silicotics for respiratory diseases (specifically silicosis and other pneumoconiosis) and tuberculosis. Analyses for period of compensation assignment showed a twofold increased SMR for biliary tract cancer among female workers and for liver cancer among male workers compensated before 1970. CONCLUSIONS: The excess mortality from respiratory tract cancers and respiratory tract diseases detected in Italian compensated silicotics are in agreement with previous epidemiological studies. Although the twofold increased risk for liver cancer among males is suggestive of a possible association with silica dust exposure, the finding needs to be confirmed.

Cloning and analysis of the spinosad biosynthetic gene cluster of Saccharopolyspora spinosa.

BACKGROUND: Spinosad is a mixture of novel macrolide secondary metabolites produced by Saccharopolyspora spinosa. It is used in agriculture as a potent insect control agent with exceptional safety to non-target organisms. The cloning of the spinosyn biosynthetic gene cluster provides the starting materials for the molecular genetic manipulation of spinosad yields, and for the production of novel derivatives containing alterations in the polyketide core or in the attached sugars. RESULTS: We cloned the spinosad biosynthetic genes by molecular probing, complementation of blocked mutants, and cosmid walking, and sequenced an 80 kb region. We carried out gene disruptions of some of the genes and analyzed the mutants for product formation and for the bioconversion of intermediates in the spinosyn pathway. The spinosyn gene cluster contains five large open reading frames that encode a multifunctional, multi-subunit type I polyketide synthase (PKS). The PKS cluster is flanked on one side by genes involved in the biosynthesis of the amino sugar forosamine, in O-methylations of rhamnose, in sugar attachment to the polyketide, and in polyketide cross-bridging. Genes involved in the early common steps in the biosynthesis of forosamine and rhamnose, and genes dedicated to rhamnose biosynthesis, were not located in the 80 kb cluster. CONCLUSIONS: Most of the S. spinosa genes involved in spinosyn biosynthesis are found in one 74 kb cluster, though it does not contain all of the genes required for the essential deoxysugars. Characterization of the clustered genes suggests that the spinosyns are synthesized largely by mechanisms similar to those used to assemble complex macrolides in other actinomycetes. However, there are several unusual genes in the spinosyn cluster that could encode enzymes that generate the most striking structural feature of these compounds, a tetracyclic polyketide aglycone nucleus.

miR-34a regulates cell proliferation, morphology and function of newborn neurons resulting in improved behavioural outcomes.

miR-34a is involved in the regulation of the fate of different cell types. However, the mechanism by which it controls the differentiation programme of neural cells remains largely unknown. Here, we investigated the role of miR-34a in neurogenesis and maturation of developing neurons and identified Doublecortin as a new miR-34a target. We found that the overexpression of miR-34a in vitro significantly increases precursor proliferation and influences morphology and function of developing neurons. Indeed, miR-34a overexpressing neurons showed a decreased expression of several synaptic proteins and receptor subunits, a decrement of NMDA-evoked current density and, interestingly, a more efficient response to synaptic stimulus. In vivo, miR-34a overexpression showed stage-specific effects. In neural progenitors, miR-34a overexpression promoted cell proliferation, in migratory neuroblasts reduced the migration and in differentiating newborn neurons modulated process outgrowth and complexity. Importantly, we found that rats overexpressing miR-34a in the brain have better learning abilities and reduced emotionality.

Antagonists of P2 receptor prevent NGF-dependent neuritogenesis in PC12 cells.

The pheochromocytoma PC12 cell line that develops neuronal characteristics of sympathetic cells after treatment with nerve growth factor (NGF) represents a well-established cellular model system for studying NGF signalling. Interesting information on the different mechanistic pathways of NGF can be obtained by adopting the pharmacological approach of inhibiting P2 receptors, expressed in naive PC12 cells and recognised as important biological mediators of neurotransmitters and growth factors. We show here that Basilen Blue, an antagonist of P2 receptor, reversibly prevents NGF-dependent neurite outgrowth with an IC(50) in the 5-10 microM range. Suramin, oxidised-ATP and diisothiocyanatostilbene-disulfonic acid, differently from other purinoceptor ligands, are also effective in this regard. NGF-dependent regeneration and stability of neurites, selected NGF-dependent extracellular and intracellular protein phosphorylations, binding of [(3)H] ATP to PC12 cell membranes are also modulated by Basilen Blue. On the contrary, cell adhesion, cellular duplication, 5'-nucleotidase activity, NGF-induced tyrosine autophosphorylation of TrkA receptors are not affected. NGF furthermore directly modulates the extracellular release of ATP and especially the levels of P2X(2) receptor protein in PC12 cells. In addition, extracellular ATP improves the neuritogenic effect of sub-optimal concentrations of NGF. Our study identifies P2 receptor ligands, particularly Basilen Blue, as useful tools to dissect different NGF-evoked functions, suggesting a mechanistic role for P2 receptors in the signalling pathways of NGF.

Involvement of cholinergic and gabaergic systems in the fragile X knockout mice.

Fragile X syndrome is an inherited cause of mental retardation. We used extra- and intracellular recordings in brain slices obtained from wild type and fragile X knockout mice to establish whether bath application of the cholinergic agent carbachol (5 microM) induces different responses in neurons of the subiculum, a limbic structure involved in learning and memory. We found that carbachol diminished excitatory post-synaptic responses induced by CA1 stratum radiatum stimulation in wild type mice, but caused an unexpected increase in knockout animals. Moreover, these responses augmented in knockout mice after carbachol washout, a phenomenon that resembled the muscarinic long-term potentiation seen in wild type mice during application of carbachol and GABA(A) receptor antagonists. We also used paired-pulse stimulation to determine whether the changes in synaptic excitability induced by carbachol were caused by pre- or post-synaptic mechanism. Under control conditions, this protocol induced facilitation in both wild type and knockout mice; in contrast, during carbachol application, this facilitatory effect was seen in wild type mice only. In conclusion, our data highlight for the first time differences in cholinergic and GABA-ergic mechanisms that may contribute to the phenotype of fragile X patients.

Expression of GABA(A) receptor subunits in rat brainstem auditory pathways: cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus.

Inhibition by GABA is important for auditory processing, but any adaptations of the ionotropic type A receptors are unknown. Here we describe, using in situ hybridization, the subunit expression patterns of GABA(A) receptors in the rat cochlear nucleus, superior olivary complex, and dorsal and ventral nuclei of the lateral lemniscus. All neurons express the beta3 and gamma2L subunit messenger RNAs, but use different alpha subunits. In the dorsal cochlear nucleus, fusiform (pyramidal) and giant cells express alpha1, alpha3, beta3 and gamma2L. Dorsal cochlear nucleus interneurons, particularly vertical or tuberculoventral cells and cartwheel cells, express alpha3, beta3 and gamma2L. In the ventral cochlear nucleus, octopus cells express alpha1, beta3, gamma2L and delta. Spherical cells express alpha1, alpha3, alpha5, beta3 and gamma2L. In the superior olivary complex, the expression profile is alpha3, alpha5, beta3 and gamma2L. Both dorsal and ventral cochlear nucleus granule cells express alpha1, alpha6, beta3 and gamma2L; unlike their cerebellar granule cell counterparts, they do not express beta2, gamma2S or the delta subunit genes. The delta subunit's absence from cochlear nucleus granule cells may mean that tonic inhibition mediated by extrasynaptic GABA(A) receptors is less important for this cell type. In both the dorsal and ventral nuclei of the lateral lemniscus, alpha1, beta3 and gamma2L are the main subunit messenger RNAs; the ventral nucleus also expresses the delta subunit. We have mapped, using in situ hybridization, the subunit expression patterns of the GABA(A) receptor in the auditory brainstem nuclei. In contrast to many brain regions, the beta2 subunit gene and gamma2S splice forms are not highly expressed in auditory brainstem nuclei. GABA(A) receptors containing beta3 and gamma2L may be particularly well suited to auditory processing, possibly because of the unique phosphorylation profile of this subunit combination.

Repair of the uterine cavity after hysteroscopic septal incision.

We performed a follow-up hysteroscopy with multiple biopsies at different intervals after surgery in 19 women who underwent hysteroscopic septal incision. Seven days after operation the sectioned areas were very evident and not epithelialized (3 patients). At 14 days, the incised zone was depressed with scattered epithelialization (5 subjects). At 1 month, the sectioned surfaces were still depressed and uniformly covered by thin endometrium (5 cases). After 2 months the uterine cavity was almost normal with minimal tendency to central fundal adhesions (6 women). Thus, spontaneous healing processes after hysteroscopic metroplasty progressed regularly and completely and there is probably no reason to delay attempts at pregnancy for longer than two cycles after surgery.

LiCl promotes survival of GABAergic neurons from cerebellum and cerebral cortex: LiCl induces survival of GABAergic neurons.

Previous studies showed that LiCl promotes short-term survival of PC12 cells after NGF or serum deprivation. In the present work, we investigate the survival effect of lithium on cerebellar granule primary cultures. While the total population of cerebellar neurons, mainly granule cells, showed only a short-term survival (about 20 h) in the presence of LiCl, the survival of 65-100% of the GABAergic interneurons originating from cerebellum and cerebral cortex at two different developmental stages was prolonged by 1-2 weeks. Optimal activity was elicited between 5 and 7 mM LiCl. The action of lithium required the presence of serum and persisted also after medium renewal. By direct visual inspection, LiCl promoted neuronal survival without apparently altering the morphological differentiation of the cells. Our studies thereby suggest a means to obtaining enriched populations of GABAergic neurons.

A mortality cohort study among workers in a graphite electrode production plant in Italy.

BACKGROUND: Graphite electrode manufacturing workers are exposed to coal tar and its volatiles containing a variety of polycyclic aromatic hydrocarbons (PAH), silica and graphite dusts, and asbestos. AIMS: To investigate mortality from cancer and other diseases among workers in a graphite electrode production plant in Italy. METHODS: A total of 1291 males actively employed between 1 January 1950 and 31 December 1989 who had worked at the plant for at least one year were studied. The follow up extended from 1950 to 1997. Standardised mortality ratios (SMR) and their 95% confidence intervals (CI) were computed using mortality rates for the Italian and regional male population. RESULTS: Excess mortality was observed for all causes (SMR 1.44, CI 1.32 to 1.56), all cancers (SMR 1.27, CI 1.07 to 1.50), liver cancer (SMR 4.19, CI 2.68 to 6.23), silicosis (SMR 66.39, CI 52.56 to 82.7), and cirrhosis and other chronic diseases of the liver (SMR 1.87, CI 1.31 to 2.59) in comparison with the national male population. When regional rates were used to calculate the number of expected deaths, SMRs remained higher for silicosis (SMR 57.32, 42.11 to 76.22), and liver cancer (SMR 2.57, 1.57 to 3.97). Mortality from silicosis was increased in workers hired at young ages (<25 years, SMR 81.79; 25-34 years, SMR 82.73), and in workers aged <45 at death (SMR 333.3, CI 159.8 to 613). Mortality from liver cancer increased threefold (SMR 3.11, CI 1.78 to 5.05) in workers with more than 10 years of employment at the plant during the manufacture of Karbate products. CONCLUSIONS: Results support the association between excess mortality from silicosis and occupational exposure to siliceous sands experienced during graphite electrode manufacturing. The observed excess mortality from liver cancer is compatible, to some extent, with exposures that may have occurred during the manufacture of phenolic and furfuryl resins treated products, although a role of lifestyle factors and viral infections cannot be excluded.

Epithelial neoplasia of the endometrium in pregnancy. A case report.

A case of focal severe atypical hyperplasia-carcinoma in situ discovered during voluntary abortion is described. The patient did not undergo hysterectomy; after abortion, menses were regular and the endometrium was histologically normal at a control. Ten cases of endometrial epithelial neoplasia in pregnancy (9 cases) or in puerperium (1 case) found in the literature were reviewed. Although in some of them stromal invasion, which actually is the main prognostic indicator of endometrial neoplasia, was absent or not documented, all lesions were designated as adenocarcinoma. There is evidence that young women with a noninvasive neoplasm and desiring children or preservation of the uterus may be treated conservatively even if the lesion is detected in pregnancy or puerperium.