The genetic history of Italians: new-insights from uniparentally-inherited markers

Genetic differences among human groups can be ascribed both to the broad-scale extents of pre-historical and historical migrations and to the fine-scale impacts of socio-cultural and geographic heterogeneity. In this thesis, the genetic information provided by uniparental markers were exploited to address different aspects of the Italian population history, by combining macro- and micro-geographic investigations at different spatial and temporal scales. To firstly assess the overall Italian variability, Y-chromosome and mtDNA markers were deeply typed in ~900 individuals from continental Italy, Sicily and Sardinia. Sex-biased patterns and contrasting demographic histories were observed for males and females. Differential European and Mediterranean contributions were invoked to explain the paternal genetic sub-structure observed in peninsular Italy, compared to the homogeneous maternal genetic landscape. If Neolithic showed to be one principal determinant of the detected paternal structure, local insights into specific Italian regional contexts highlighted the importance of Post-Neolithic contributions. Among them, migrations from the Balkans (particularly Greece) during late Metal Ages, played a relevant role in the cultural and genetic transitions occurred in Sicily and Southern Italy. On a finer geographic and temporal perspective, the more recent layers of Italian genetic history and some aspects of the gene-culture interaction were assessed by exploring the genetic variability within two “marginal populations”: Arbereshe of Southern Italy and Partecipanza in Northern Italy. The Arbereshe are Albanian-speaking communities settled in Sicily and Calabria since the end of Middle Ages. Despite sharing common genetic and cultural backgrounds, these groups revealed diverging micro-evolutionary histories, implying different founding events and different patterns of cultural isolation and local admixture. Partecipanza is an idiosyncratic institution of Medieval origin aimed at sharing and devolving collective lands. This case-study exemplified that socio-economic stratification within the same population may induce sex-biased genetic structuring and the maintenance of otherwise hidden historical genetic traces.

Natural history of very severe aortic stenosis

We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis.

A history of frequent dental care reduces the risk of tooth loss but not periodontitis in older subjects

OBJECTIVES: Information on the significance of dental care in older adults is limited. We hypothesized that regular dental visits has an effect on the number of remaining teeth and periodontal conditions in older subjects. MATERIALS AND METHODS: 1020 randomly selected individuals age 60 - 96 from the Swedish National Study on Aging and Care Blekinge received a comprehensive oral health examination. RESULTS: Dentate women and men had, on average 18.4 teeth (SD +7.6,) and 18.9 teeth (SD + 7.5) respectively (NS). In the youngest group (60 and 66 years old) with less than one dental visit per year, 37% had >20 teeth, compared with 73% among those with at least annual visits. Among the old-old, comparable figures were 1.8 % and 37% respectively. Across age groups, bleeding on probing was 23 %.When adjusting for age, and number of teeth GLM univariate analysis failed to demonstrate an effect of dental visit frequency on alveolar bone loss (p = 0.18), the number of periapical lesions (p = 0.65), or the number of endodontically treated teeth ( p = 0.41). Frequent dental visitors had more teeth than infrequent visitors (p = 0.001). CONCLUSIONS: Tooth loss and alveolar bone loss severity increase with age. Individuals with regular dental visits retained more teeth but the frequency of dental visits had no impact on plaque deposits, gingival inflammation, or alveolar bone levels.

Synthesis of 1,1'-(Hexane-1,6-Diyl)Bis(5-Oxopyrrolidine-3-Carboxylic Acid) as a Monomer for a Polyanhydride Drug Delivery System

Polyanhydrides have been given much attention in the literature recently because of their desirable properties as controlled drug delivery solutions. Drug therapies could be loaded into a polyanhydride matrix and protected from denaturation and removal from the body while being slowly eluted as the polyanhydride degraded yielding a tailorable concentration profile in the bloodstream at therapeutic levels. To that end, this report discusses the synthesis of a novel monomer for polyanhydride synthesis: 1,1'-(hexane-1,6-diyl)bis(5-oxopyrrolidine-3-carboxylic acid) henceforth known as CPyH monomer for (carboxypyrrolidone)hexane monomer.

Inhibition of IL-1, IL-6, and TNF-alpha in immune-mediated inflammatory diseases

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-alpha), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-alpha, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-alpha is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.

Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies

OBJECTIVE: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy. DESIGN: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003. METHODS: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. RESULTS: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone. CONCLUSION: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.

A de novo 1.1-1.6 Mb subtelomeric deletion of chromosome 20q13.33 in a patient with learning difficulties but without obvious dysmorphic features

We report on a de novo submicroscopic deletion of 20q13.33 identified by subtelomeric fluorescence in situ hybridization (FISH) in a 4-year-old girl with learning difficulties, hyperlaxity and strabismus, but without obvious dysmorphic features. Further investigations by array-based comparative genomic hybridization (array-CGH) and FISH analysis allowed us to delineate the smallest reported subterminal deletion of chromosome 20q, spanning a 1.1-1.6 Mb with a breakpoint localized between BAC RP5-887L7 and RP11-261N11. The genes CHRNA4 and KCNQ2 implicated in autosomal dominant epilepsy are included in the deletion interval. Subterminal 20q deletions as found in the present patient have, to our knowledge, only been reported in three patients. We review the clinical and behavioral phenotype of such "pure" subterminal 20q deletions.

Eruptive history of Maderas volcano using new 40Ar/39Ar ages and geochemical analyses

Maderas volcano is a small, andesitic stratovolcano located on the island of Ometepe, in Lake Nicaragua, Nicaragua with no record of historic activity. Twenty-one samples were collected from lava flows from Maderas in 2010. Selected samples were analyzed for whole-rock geochemical data using ICP-AES and/or were dated using the 40Ar/39Ar method. The results of these analyses were combined with previously collected data from Maderas as well as field observations to determine the eruptive history of the volcano and create a geologic map. The results of the geochemical analyses indicate that Maderas is a typical Central American andesitic volcano similar to other volcanoes in Nicaragua and Costa Rica and to its nearest neighbor, Concepción volcano. It is different from Concepción in one important way – higher incompatible elements. Determined age dates range from 176.8 ± 6.1 ka to 70.5 ± 6.1 ka. Based on these ages and the geomorphology of the volcano which is characterized by a bisecting graben, it is proposed that Maderas experienced two clear generations of development with three separate phases of volcanism: initial build-up of the older cone, pre-graben lava flows, and post-graben lava flows. The ages also indicate that Maderas is markedly older than Concepción which is historically active. Results were also analyzed regarding geologic hazards. The 40Ar/39Ar ages indicate that Maderas has likely been inactive for tens of thousands of years and the risk of future volcanic eruptions is low. However, earthquake, lahar and landslide hazards exist for the communities around the volcano. The steep slopes of the eroded older cone are the most likely source of landslide and lahar hazards.

THE FANNED FLAMES OF DISCONTENT: A SOLIDARITY-INSPIRED HISTORY OF THE IDENTITY/IDEOLOGY, CULTURAL HISTORY, AND RHETORICAL STRATEGIES OF THE WOBBLIES DURING THE 1916 MINNESOTA IRON ORE STRIKE

Rooted in critical scholarship this dissertation is an interdisciplinary study, which contends that having a history is a basic human right. Advocating a newly conceived and termed, Solidarity-inspired History framework/practice perspective, the dissertation argues for and then delivers a restorative voice to working-class historical actors during the 1916 Minnesota Iron Ore Strike. Utilizing an interdisciplinary methodological framework the dissertation combines research methods from the Humanities and the Social Sciences to form a working-class history that is a corrective to standardized studies of labor in the late 19th and early 20th centuries. Oftentimes class interests and power relationships determine the dominant perspectives or voices established in history and disregard people and organizations that run counter to, or in the face of, customary or traditional American themes of patriotism, the Protestant work ethic, adherence to capitalist dogma, or United States exceptionalism. This dissertation counteracts these traditional narratives with a unique, perhaps even revolutionary, examination of the 1916 Minnesota Iron Ore Strike. The intention of this dissertation's critical perspective is to poke, prod, and prompt academics, historians, and the general public to rethink, and then think again, about the place of those who have been dislocated from or altogether forgotten, misplaced, or underrepresented in the historical record. Thus, the purpose of the dissertation is to give voice to historical actors in the dismembered past. Historical actors who have run counter to traditional American narratives often have their body of "evidence" disjointed or completely dislocated from the story of our nation. This type of disremembering creates an artificial recollection of our collective past, which de-articulates past struggles from contemporary groups seeking solidarity and social justice in the present. Class-conscious actors, immigrants, women, the GLBTQ community, and people of color have the right to be remembered on their own terms using primary sources and resources they produced. Therefore, similar to the Wobblies industrial union and its rank-and-file, this dissertation seeks to fan the flames of discontented historical memory by offering a working-class perspective of the 1916 Strike that seeks to interpret the actions, events, people, and places of the strike anew, thus restoring the voices of these marginalized historical actors.