Modeling hypoxia-related inflammation scenarios.

Cells respond to hypoxia via the activation of three isoforms of Hypoxia Inducible Factors (HIFs), that are characterized by different activation times. HIF overexpression has many effects on cell behavior, such as change in metabolism, promotion of angiogenic processes and elicitation of a pro-inflammatory response. These effects are driving forces of malignant progression in cancer cells. In this work we study in detail hypoxia-induced dynamics of HIF1α and HIF2α, which are the most studied isoforms, comparing available experimental data on their evolution in tumor cells with the results obtained integrating the deduced mathematical model. Then, we examine the possible scenarios that characterize the link between hypoxia and inflammation via the activation of NFkB (Nuclear Factor k-light-chain-enhancer of activated B cells) when the dimensionless groups of parameters of the mathematical model change. In this way we are able to discuss why and when hypoxic conditions lead to acute or chronic inflammatory states.

Greening MSW management systems by saving footprint: The contribution of the waste transportation.

Municipal solid waste (MSW) management constitutes a highly challenging issue to cope with in order of moving towards more sustainable urban policies. Despite new Standards call for recycling and reusing materials contained in the urban waste, several municipalities still use landfilling as a waste disposal method. Other than the environmental pressure exerted by these plants, waste transportation from the collection points to the landfill needs a specific attention to correctly assess the whole burden of the waste management systems. In this paper, the Ecological Footprint (EF) indicator is applied to the actual MSW of the city of Palermo (Sicily). Results show that the effects produced by the involved transportation vehicles are not negligible, compared to those generated by the other segments of the waste management system. This issue is further deepened by analysing the role of transportation in an upgraded waste management system that is represented by the newly designed waste management plan of Palermo. The computed saved ecological footprint is used here for suitably comparing the environmental performances of the MSW system in both scenarios. Finally, the suitability of the EF method to address not only complete waste management plans but also single segments of the waste management system, is also discussed.

Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study.

A CRISPR/Cas9 gene editing strategy has been remarkable in excising segments of integrated HIV-1 DNA sequences from the genome of latently infected human cell lines and by introducing InDel mutations, suppressing HIV-1 replication in patient-derived CD4+ T-cells, ex vivo. Here, we employed a short version of the Cas9 endonuclease, saCas9, together with a multiplex of guide RNAs (gRNAs) for targeting the viral DNA sequences within the 5'-LTR and the Gag gene for removing critically important segments of the viral DNA in transgenic mice and rats encompassing the HIV-1 genome. Tail-vein injection of transgenic mice with a recombinant Adeno-associated virus 9 (rAAV9) vector expressing saCas9 and the gRNAs, rAAV:saCas9/gRNA, resulted in the cleavage of integrated HIV-1 DNA and excision of a 978 bp DNA fragment spanning between the LTR and Gag gene in the spleen, liver, heart, lung and kidney as well as in the circulating lymphocytes. Retro-orbital inoculation of rAAV9:saCas9/gRNA in transgenic rats eliminated a targeted segment of viral DNA and substantially decreased the level of viral gene expression in circulating blood lymphocytes. The results from the proof-of-concept studies, for the first time, demonstrate the in vivo eradication of HIV-1 DNA by CRISPR/Cas9 on delivery by an rAAV9 vector in a range of cells and tissues that harbor integrated copies of viral DNA.

Size at birth by gestational age and hospital mortality in very preterm infants: results of the area-based ACTION project.

BACKGROUND: Size at birth is an important predictor of neonatal outcomes, but there are inconsistencies on the definitions and optimal cut-offs. AIMS: The aim of this study is to compute birth size percentiles for Italian very preterm singleton infants and assess relationship with hospital mortality. STUDY DESIGN: Prospective area-based cohort study. SUBJECTS: All singleton Italian infants with gestational age 22-31 weeks admitted to neonatal care in 6 Italian regions (Friuli Venezia-Giulia, Lombardia, Marche, Tuscany, Lazio and Calabria) (n. 1605). OUTCOME MEASURE: Hospital mortality. METHODS: Anthropometric reference charts were derived, separately for males and females, using the lambda (λ) mu (µ) and sigma (σ) method (LMS). Logistic regression analysis was used to estimate mortality rates by gestational age and birth weight centile class, adjusting for sex, congenital anomalies and region. RESULTS: At any gestational age, mortality decreased as birth weight centile increased, with lowest values observed between the 50th and the 89th centiles interval. Using the 75th-89th centile class as reference, adjusted mortality odds ratios were 7.94 (95% CI 4.18-15.08) below 10th centile; 3.04 (95% CI 1.63-5.65) between the 10th and 24th; 1.96 (95% CI 1.07-3.62) between the 25th and the 49th; 1.25 (95% CI 0.68-2.30) between the 50(h) and the 74th; and 2.07 (95% CI 1.01-4.25) at the 90th and above. CONCLUSIONS: Compared to the reference, we found significantly increasing adjusted risk of death up to the 49th centile, challenging the usual 10th centile criterion as risk indicator. Continuous measures such as the birthweight z-score may be more appropriate to explore the relationship between growth retardation and adverse perinatal outcomes.

Home injuries in Italy: patterns of injury and the most exposed people.

Home injuries are a significant public health problem in developed and developing countries. To support future policies for reducing their occurrence and controlling their consequences, this study investigated the home injuries situation in Italy in 1999, using a nation-representative sample. The weighted correspondence analysis showed four different patterns of injury and seven profiles of the people most exposed to them. As results of this study falls were followed by bumps and cuts requiring specialist assistance then burns. Women were the most exposed to burn and fall risks and men to the risk of cuts and bumps. Among the elderly and children, falls and bumps leading to fractures, wounds or other consequences were frequent. The risks were highest for people with a lower level of education. Bumps and cuts were prevalent among unmarried and with the highest education level subjects. These injury risks were higher for young males. Cuts in adults doing do-it-yourself jobs had the worst consequences, while domestic work cuts generally did not need medical treatment. Burns occurred almost exclusively in the kitchen (90%) and did not need specialist assistance. Because home injuries are largely preventable, an efficient public health policy could promote and disseminate home safety culture.

Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the central nervous system, caused by the reactivation of the ubiquitous JC virus. PML usually occurs during severe immunosuppression, and the most common causes are represented by human immunodeficiency virus infection, lymphoproliferative disorders and other forms of cancer. Recently, the introduction of monoclonal antibodies (e.g. natalizumab, rituximab, efalizumab) in the treatment of several dysimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, has led to an increased incidence of PML. This phenomenon has had severe consequences, leading, for example, to the withdrawal from the market of Efalizumab, and important restrictions in the use of the other compounds, all of which are characterized by high efficacy in improving prognosis and quality of life. In this review we will discuss clinical, laboratory and imaging findings of PML. In addition, proposed pathogenetic mechanisms promoting the reactivation of JC virus in the context of treatment with monoclonal antibodies will be described.

Neuropsychological evaluation and follow up in jcv- and non-jcv-related leukoencephalopathies in HIV infection.

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis.

Search for genomic sequences of microbial agents in atherosclerotic plaques.

Atherosclerosis is a complex, multifactorial disease. Several studies have reported a possible association between infection with microbial agents and atherogenesis. Chlamydia pneumoniae (C. pneumoniae), Herpes Simplex Virus 1 (HSV1), Human Cytomegalovirus (HCMV), and Epstein Barr Virus (EBV) have been widely investigated for their possible role in atherosclerosis development, but the results obtained to date are contradictory. The aim of our study is to search DNA of the aforementioned infectious agents by means of Quantitative Real Time PCR in atherosclerotic plaques from carotid arteries obtained from 17 patients. Genomic sequences of C. pneumoniae, HSV1, HCMV were not found in any atherosclerotic lesion. Therefore, our results do not support the hypothesis of an association between these infectious agents and atherosclerosis. Conversely, three patients were found to be positive for EBV DNA, thus indicating that, at least in a limited number of patients, EBV could play a role in atherogenesis.

Acute transient inflammatory leukoencephalopathy in HIV.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) is characterized by abrupt onset of symptoms generally associated with focal brain lesions and inflammatory CSF findings. A previously asymptomatic 31-year-old HIV+ woman presented with acute cognitive difficulties, right hemiparesis and dysphasia. Brain MRI showed a large contrast-enhancing lesion in the left frontal lobe; brain biopsy revealed an inflammatory process. No etiological agent was found in blood, CSF or brain tissue. The patient was given systemic steroids and gammaglobulins and put on HAART. Clinical conditions progressively and completely recovered. Further brain MRI showed the shrinkage of the lesion with no contrast enhancement. Our case could be classified as AIL in HIV resembling ADEM pattern and highlights the importance of taking into consideration. ADEM in the diagnostic process of HIV-related leukoencephalopathy even if the typical features are lacking, as immunodeficiency could modify both presentation and disease course.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin: review of the literature.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) has been anecdotally described in literature as being responsible for cognitive and motor deficits. We carried out a review of all the cases of AIL published in literature. Articles were selected according to 2 criteria: acute onset of symptoms; undetermined aetiology and non-fulfilment of multiple sclerosis diagnostic criteria. They were then analyzed in terms of clinical, biological and instrumental features, therapy, diagnostic classification and prognosis. Although rare (21 patients out of about 4,000 publications), AIL is of particular interest, as the comprehension of its mechanisms could give some insight into the direct and immune-mediated actions of HIV within the brain. All the reported patients share several clinical, histopathological, radiological and CSF features, leading to hypothesize a similar aetiopathogenetic mechanism. Conversely, we observed a high heterogeneity of treatment and diagnostic classification, which could have conditioned the broad prognostic variability. The absence of a defined aetiology leads to consider these forms as a particular subgroup of not determined leucoencephalopathies (NDLE), with both MRI and histological pattern dominated by inflammation as distinctive feature.

HLA-DRB1 polymorphisms distribution in chronic dysimmune polyneuropathy.

The frequency of HLA-DRB1*15 polymorphism, which is strongly associated to multiple sclerosis, was investigated in 84 adult patients with chronic dysimmune polyneuropathy and 272 healthy controls. No significant differences were detected between cases and controls and, among patients, according to gender, peripheral nerve antigen antibody seropositivity, and electrophysiological features. A trend towards an increase of HLA-DRB1*11 in anti-MAG neuropathy was detected.

Magnitude of asbestos-related lung cancer mortality in Italy.

An ecological study, based on a data set containing all lung and pleural cancer deaths in each Italian municipality in the period 1980-2001, was performed. The pleural to lung cancer ratio was estimated to be 1 : 1 and 3% (around 700) of all male lung cancer deaths were found to be asbestos-related.

Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema?

AIM: A retrospective comparative case series was studied to determine whether the use of prostaglandin (PG) analogues to treat raised intraocular pressure (IOP) in patients with uveitis resulted in an increase in the frequency of anterior uveitis or cystoid macular oedema (CMO). METHODS: 163 eyes of 84 consecutive patients with uveitis and raised IOP treated with a PG analogue at two tertiary referral uveitis clinics were identified over a 3-month period. Control eyes were selected as those uveitic eyes of the same patients, which were treated with topical IOP-lowering agent(s) other than a PG analogue. Pretreatment IOP was compared with the mean IOP during PG analogue treatment. The frequency of anterior uveitis and CMO during PG analogue treatment was compared with the frequency of these complications in the control eyes during non-PG IOP-lowering treatment. RESULTS: Significant IOP reductions were observed during PG analogue treatment. There was no significant difference in the frequency of anterior uveitis in those eyes treated with PG analogues and those treated with non-PG agents (p = 0.87, Fisher exact test). None of the 69 uveitic eyes without a previous history of CMO developed this complication. There was no increase in the frequency of visually significant CMO during PG treatment compared with that during non-PG treatment (p = 0.19, Fisher exact test). CONCLUSION: This study demonstrates that PG analogues are potent topical medications for lowering raised IOP in patients with uveitis and are not associated with increased risk of CMO or anterior uveitis.

Occupational exposure levels to wood dust in Italy, 1996-2006.

BACKGROUND: Wood dust has been classified as carcinogenic to humans and the association with nasal cancer risk has been observed in a large number of epidemiological studies. OBJECTIVES: The aim of this study is to summarise data about occupational exposure levels to wood dust in Italy and to examine some exposure determinants. METHODS: Exposure measurements on wood dust were extracted from the SIREP (Italian Information System on Occupational Exposure to Carcinogens) database between 1996-2006. Descriptive statistics were calculated for exposure-related variables using univariate analyses. The prevalence of elevated exposure levels was estimated overall and for some industrial sectors. A multifactorial analysis of variance was performed to determine which factors influenced exposure levels to wood dust. RESULTS: The total number of exposure measurements (n) reported is 10,837, which refer to 10,528 workers and 1181 companies. The overall arithmetic mean is 1.44 mg/m(3) and the geometric mean is 0.97 mg/m(3). Industrial sectors at high risk are "manufacture of wood and wood products" (n = 5539) as well as "manufacture of furniture" (n = 4347). About 74% of exposure measurements report a value <2 mg/m(3). In the multifactorial analysis, it has been found that job category, industrial sector, company size and geographical location of the company influence the exposure levels. CONCLUSIONS: This study confirms the previous findings about occupational exposure to wood dust (mainly in wood industry and among woodworking machine operators) and suggests further investigations on other risk sectors (building and repairing of ships and boats). The potential of the occupational exposure database as a source of data for exposure assessment and surveillance is also confirmed.

[Viral infections of the fetus and newborn infant]. / Infezioni virali congenite, perinatali e neonatali.

Viral infections may be vertically transmitted from mother to child at different times, ranging from in utero transmission, which occurs during pregnancy, perinatal transmission, which takes place during delivery and postnatal transmission, which is usually the consequence of breastfeeding. Mother-to-child transmission, which may occur after primary, recurrent or chronic maternal infection, is potentially harmful to the fetus or the newborn since it may result in miscarriage, fetal death, congenital anomalies, intrauterine growth restriction, or severe neonatal disease. Some risk factors are thought to affect the rate of mother-to-child transmission, such as the presence of other viral infections, maternal viral load, type of infection (primary versus recurrent), obstetrical procedures (prolonged rupture of membranes, mode of delivery), social-economical conditions and breastfeeding. For some of the vertically transmitted viruses, interventions are nowadays available to prevent mother-to-child transmission, such as vaccines, passive immunization, antiviral drugs. Moreover, perinatal and postnatal infections may be prevented by the use of elective caesarean delivery and avoidance of breastfeeding.

A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy.

Several studies suggest that the histocompatibility complex (HLA) class I region harbours genes modulating multiple sclerosis (MS) susceptibility independently from the effect of class II alleles. A candidate gene in this region is MOG, encoding the myelin oligodendrocyte glycoprotein. A significant association with the missense variation V142L (rs2857766) was previously reported in a small sample of 50 Italian MS patients. We confirmed this result in two independent Italian sample sets consisting of 878 MS patients and 890 matched controls (P=6.6 x 10(-4)) and 246 trio families (P=1.5 x 10(-3)). The comparison of genotype frequencies suggested a dominant-protective effect of L142. In the combined sample sets L142 conferred an odds ratio (OR)=0.70 (95% confidence interval (CI): 0.60-0.82) that remained similar after accounting for HLA-DRB1(*)15 carrier status. The association with MOG V142L was still significant after conditioning for all DRB1 alleles (P=0.035). Eleven additional single nucleotide polymorphisms in the MOG gene (namely -1077T/C, -910T/C, -875A/G, -93T/C, S5S, Indel L22, V145I, +814C/T, +900A/G, +1024A/T, +1059C/T), two microsatellites in the MOG 5' flanking (MOGCA) and 3' untranslated (MOGTAAA) regions and four microsatellites in the HLA-class I region, from HLA-B to HFE, (namely MIB, D6S265, D6S1683 and D6S2239) were tested by transmission disequilibrium test in 199 trio families. None of these polymorphisms or of their haplotypic combinations showed a significant transmission distortion, in the absence of V142L. In conclusion, MOG V142L, or an untested variant in tight-linkage disequilibrium with it, is an independent MS susceptibility-modulating factor in the HLA class I region.

Reactivation of JC virus and development of PML in patients with multiple sclerosis.

The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years. PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS. In this review, we examine the current status of knowledge of the virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue. Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.