Southern Mediterranean Population Research Articles

Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients.

Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;-163C>A), CYP1A2*1C (rs2069514;-3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (CYP1A2*1F) was the most frequently detected (58.8%). For CYP1A2*1F, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL-1 per mg day-1 in AA group (p < 0.001). The influence of genetic (CYP1A2*1F, CYP1A2*1C and CYP2C19*2) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the CYP1A2*1 F polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 -163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.

Modified Mediterranean diet score adapted to a southern Mediterranean population and its relation to overweight and obesity risk.

The current study aimed to develop a modified Mediterranean diet (MMD) score adjusted to the southern Mediterranean countries' cultural specificities and to evaluate associations between adherence to this modified score and overweight/obesity risk in Moroccan adults. Population-based cross-sectional study. Rural and urban areas of the five greatest provinces of Morocco. In total, 1516 participants were recruited between September 2009 and February 2017. Dietary assessment was obtained using a validated Moroccan FFQ. We constructed a MMD score focusing on twelve components. The MMD score ranged from 0 (no adherence to the traditional southern Mediterranean diet (MD)) to 12 (maximal adherence) and was categorised as low (scores 0-4), moderate (scores 5-7) and high (scores 8-12). Among the whole population, 754 (50·5 %) were women and 738 (49·5 %) were men, and the mean age was about 55·60 ± 13·70. In total, 58 % of participants were moderately active. Regarding educational level, 50·7 % were illiterate. The prevalence of overweight and obesity was 43·3 and 8·6 %, respectively. In multivariate analyses, close adherence to MMD (scores 8-12) was associated with reduced overweight/obesity risk (OR 0·61, 95 % CI 0·44, 0·84). The prevalence of overweight and obesity was very high among Moroccan adults. Adherence to the traditional southern MD may help prevent overweight and obesity.

Mediterranean and Northern Iberian gene pools of wild Castanea sativa Mill. are two differentiated ecotypes originated under natural divergent selection.

Nine wild Iberian provenances of Castanea sativa Mill. grouped in two gene pools, North Iberian Peninsula and Mediterranean, were evaluated for several adaptive traits in two provenance–progeny trials with the aim of evaluating the role of natural selection in shaping adaptive variation and increasing our understanding of the genetic structure of this species, as well as reporting complete information on the genetic variation among and within the studied populations. An annual growth rhythm experiment was evaluated during the first 3 years after establishment for phenology, growth, stem form and survival, and a periodic drought-stress experiment was evaluated for dry weight, growth, survival and other related drought traits in both well-watered and drought-stress treatments. The high genetic variability reported in both trials is largely due to the genetic variation among populations. The significant differences reported between quantitative genetic and neutral marker differentiation indicated the local adaptation of these populations through directional selection, mainly for phenology, growth and biomass allocation. A clinal variation among populations was determined through correlations of phenology with latitude and xerothermic index of the provenances, showing that central and southern Mediterranean populations had earlier phenology than northern populations and that drought played a relevant role in this differentiation. The significant correlation between phenological traits and the ancestry values in the Mediterranean gene pool supported the different pattern of behavior between both gene pools and also indicated the existence of two ecotypes: xeric and mesophytic ecotypes, corresponding to Mediterranean and North Iberian gene pools, respectively. The results obtained in the drought-stress experiment confirmed that, in general terms, xeric populations showed a greater adaptability to drought, with more developed root systems and higher survival than northern populations. Moreover, the genetic variability observed within populations indicated the potential response capacity of Iberian C. sativa populations to undergo fast adaptive evolution.

BRCA1/BRCA2 Mutations Shaped by Ancient Consanguinity Practice in Southern Mediterranean Populations

The aim of this study is to investigate the involvement of consanguinity on BRCA1/2 mutation incidence in Southern Mediterranean populations and to confirm their low penetrance by comparison of their recurrence in sporadic and familial breast cancer in a context of ancient consanguinity practice. Our study comprises of two parts: First, a comparison of the consanguinity rates of the South Mediterranean countries in a relationship with the frequency of BRCA1 deleterious mutations in breast cancer families and the recurrence of these mutations. Second, we investigated 23patients with a family history of breast cancer, 51 patients without a family history of breast cancer using next-generation sequencing of BRCA2 and then confirmed by Sanger sequencing for the novel mutation. As results, we clearly show a strong relationship between the frequency of BRCA1 deleterious mutations in breast cancer families and rate of consanguinity, since they are significantly inversely correlated. Four deleterious mutations were found in BRCA2 gene including a novel frame-shift mutationc.9382_9383dup in a patient with familial breast cancer and three other frame-shift mutations c.6591_6592del, c.1310_1313del and c.7654dup in patients with sporadic breast cancer.These results are discussed in a context of selective pressure of ancient consanguinity practice. In conclusion, the study of BRCA1/2 gene in Southern Mediterranean countries revealed low penetrance recurrent mutations in sporadic and familial breast cancer. These mutations have been selected in a context of ancient consanguinity practice along with protective genetic and environmental factors.

Morphological response of the larvae of Arbacia lixula to near-future ocean warming and acidification

The distribution of the sea urchin Arbacia lixula, a warm affinity species, has been expanding in the Mediterranean Sea. To address questions on potential for future success of this species in the region, the thermotolerance of larval development was investigated in context of regional warming. The larvae were reared in present day spawning period (20 °C) and warming conditions (+4 = 24 and +6 = 26 °C). As the calcifying larvae of sea urchins are vulnerable to stunted growth caused by ocean acidification, the impact of lower pH (−0.3 pH units) on larval development was also investigated in combination with warming. Morphological traits of the larvae, post-oral length arms, overall length of larvae and body length, were affected by increased temperature across pH treatments, indicating that for the larvae of southern Mediterranean population here, 24 °C appears to approximate the optimal temperature for development. A slightly negative effect of pH was evident. Increased temperature ameliorated the stunting effect of acidification on growth. The thermal tolerance of A. lixula development overlaps with projections for warming in the region by 2100 and also indicates that this species has acclimatized or adapted its reproductive biology to the broad environmental conditions of the Mediterranean Sea. Due to the broad thermal range (∼10 °C) of development of A. lixula across its distribution, this species is likely to be a winner in the climate change stakes. The broad thermal tolerance of the larvae is likely to assure population connectivity between Mediterranean sub-basins populations. The continued success of A. lixula can have a strong consequences for the ecological structure of Mediterranean rocky habitat.

Origin and expansion of the allotetraploid Aegilops geniculata, a wild relative of wheat

*This study reconstructs the phylogeography of Aegilops geniculata, an allotetraploid relative of wheat, to discuss the impact of past climate changes and recent human activities (e.g. the early expansion of agriculture) on the genetic diversity of ruderal plant species. *We combined chloroplast DNA (cpDNA) sequencing, analysed using statistical parsimony network, with nonhierarchical K-means clustering of amplified fragment length polymorphism (AFLP) genotyping, to unravel patterns of genetic structure across the native range of Ae. geniculata. The AFLP dataset was further explored by measurement of the regional genetic diversity and the detection of isolation by distance patterns. *Both cpDNA and AFLP suggest an eastern Mediterranean origin of Ae. geniculata. Two lineages have spread independently over northern and southern Mediterranean areas. Northern populations show low genetic diversity but strong phylogeographical structure among the main peninsulas, indicating a major influence of glacial cycles. By contrast, low genetic structuring and a high genetic diversity are detected in southern Mediterranean populations. Finally, we highlight human-mediated dispersal resulting in substantial introgression between resident and migrant populations. *We have shown that the evolutionary trajectories of ruderal plants can be similar to those of wild species, but are interfered by human activities, promoting range expansions through increased long-distance dispersal and the creation of suitable habitats.

Population health and Mediterranean diet in southern Mediterranean countries

In recent decades, the prevalence of non-communicable diseases (NCDs), such as obesity, diabetes and cardiovascular disorders has increased worldwide; the objective here is to describe the situation in southern Mediterranean countries. Data derived from surveys in the region countries showed that in 2002 more than 60% of all deaths in the southern Mediterranean region are attributed to NCDs. Cardiovascular diseases (CVD) caused from about 34.3 to 52% of all deaths, making it the major killer among NCDs. In almost all of the southern Mediterranean countries, CVD risk factors increased with age, affected more women and urban area and were significantly associated with obesity. The Mediterranean dietary pattern, generally recognised, as a healthy diet is still the model for southern Mediterranean population; however, following the rapid process of urbanisation, southern Mediterranean populations have changed their lifestyle and food habits and tend to shift from traditional food habit. Indeed, intake trends illustrate the fall in whole-grain intake with a rise in animal sources and vegetable oils. Dietary energy has been steadily increasing by approximately 1000 kcal per capita per day between 1965 and 2000, exceeding per caput energy requirements. Protein and carbohydrate contribution to the energy intake show only small deviations and fat contribution to the energy intake is low, whereas fibre intake is generally low and that of SFA is high. Also, sedentarity appears to play a critical role in the development of body fat and may be a risk indicator for features of metabolic syndrome. The major goal to prevent CVD should begin by preventing obesity through physical exercise and healthy nutrition. The nutritional prevention policy required should encourage population to adhere to the Mediterranean model.

Diet, serum homocysteine levels and ischaemic heart disease in a Mediterranean population.

Homocysteine (Hcy) is recognised as a risk factor for IHD. Serum Hcy is negatively correlated with serum folate levels, the main sources of which are fruits, vegetables and legumes. The present case-control study was designed to examine the relationship between serum Hcy levels and IHD and to assess the role of dietary factors in the southern Mediterranean population of Crete, Greece. Serum Hcy, folate, vitamin B12, creatinine and glucose levels and a full lipid profile were measured in 152 patients with established IHD, median age 64 (range 33-77) years, and 152 healthy control subjects, age- and sex-matched. Dietary data were assessed using a 3 d food intake record. Compared with controls, patients with IHD had significantly higher daily intakes of vitamin B12 and MUFA and significantly lower intakes of carbohydrate, fibre, folate, cholesterol, n-3 fatty acids and total trans unsaturated fatty acids. Moreover, patients had significantly higher serum Hcy, vitamin B12 and creatinine levels, but significantly lower folate. Serum folate concentrations in both groups had a significant positive correlation with dietary fibre consumption and a significant inverse correlation with vitamin B12 intake. IHD patients should be encouraged to increase their daily dietary intake of fibre, folate and n-3 fatty acids, which are significant components of the traditional Cretan Mediterranean diet. Where dietary folate intake is inadequate, folate supplements are recommended to reduce elevated Hcy levels.

Polyploidy, phylogeography and Pleistocene refugia of the rockfern Asplenium ceterach: evidence from chloroplast DNA.

Chloroplast DNA sequences were obtained from 331 Asplenium ceterach plants representing 143 populations from throughout the range of the complex in Europe, plus outlying sites in North Africa and the near East. We identified nine distinct haplotypes from a 900 bp fragment of trnL-trnF gene. Tetraploid populations were encountered throughout Europe and further afield, whereas diploid populations were scarcer and predominated in the Pannonian-Balkan region. Hexaploids were encountered only in southern Mediterranean populations. Four haplotypes were found among diploid populations of the Pannonian-Balkans indicating that this region formed a northern Pleistocene refugium. A separate polyploid complex centred on Greece, comprises diploid, tetraploid and hexaploid populations with two endemic haplotypes and suggests long-term persistence of populations in the southern Mediterranean. Three chloroplast DNA (cpDNA) haplotypes were common among tetraploids in Spain and Italy, with diversity reducing northwards suggesting expansion from the south after the Pleistocene. Our cpDNA and ploidy data indicate at least six independent origins of polyploids.

Melanocytic nevi and risk of cutaneous malignant melanoma in southern Spain.

The main objective of this study was to assess whether cutaneous malignant melanoma (CMM) shows a stronger relation with the melanocytic nevi count at the site where CMM was diagnosed than with the melanocytic nevi count at other sites, stratifying by histologic CMM type, in a southern Mediterranean population. Cases and controls were selected from a population in southern Spain in 1988-1993. The study population included 116 incident cases with non-familial CMM (International Classification of Diseases 9th Revision (ICD-9) code 172), and 116 controls matched 1:1 for sex and age (+/- 4 years). Data were collected by personal interview, and melanocytic nevi were counted over the entire body surface by clinical skin examination performed by a dermatologist. Crude and multiple risk factor-adjusted odds ratios and 95% confidence intervals were computed by conditional logistic regression analysis. After adjustment by skin type, unexposed skin color, and sun exposure, CMM was found to occur significantly more frequently in individuals with a high number of melanocytic nevi at the same site where CMM originated (odds ratio (OR) for >8 nevi = 12.0, 95% confidence interval (CI) 1.3-108.2). The ability to predict the number of melanocytic nevi on different anatomic sites on CMM, but excluding the CMM cases on each corresponding site, was also examined. A significant trend with the number of nevi on the anterior surface of thighs was found (OR for >4 nevi = 4.5, 95% CI 1.4-14.9). Melanocytic nevi count on the melanoma site was the variable most closely related to superficial spreading melanoma subtype (SSM) (OR for >8 nevi = 82.19, 95% CI 2.72-2,454). On the other hand, the number of melanocytic nevi on the melanoma site was unrelated to risk of CMM subtypes other than SSM. These results support the hypothesis that nevi are an important risk factor for melanoma, especially SSM, in populations with a darker ethnic background.

Immunogenetics of Systemic Lupus Erythematosus in Spanish Patients: Differential HLA Markers

HLA-DR3 antigen included in the compound phenotype B18BfF1 (but not the one linked to the B8BfS compound phenotype) was found to be significantly increased in our SLE patients. It is remarkable that in our Southern-Mediterranean population, B18BfF1DR3 individuals (but not B8BfSDR3) are prone to SLE with renal disease, in contrast with other Northern European and Caucasoid populations. Also, patients with autoantibodies to Ro/La have a significant increase of the B8DR3 compound phenotype. Production of autoantibodies against Ro alone was associated to DR2 and production of anti-Sm/nRNP to DR3 (either B18BfF1 or B8BfS associated) only in the subgroup without renal disease. The distinctive HLA and autoimmune associations to SLE with and without renal disease suggests that both clinical forms may not share a common identical pathogenesis.

Reproductive activity inAsellus aquaticusL. (Crustacea, Isopoda) from southern Italy

Asellus aquaticus is a freshwater species occurring throughout the entire paleoarctic continent. In winter, southern Mediterranean population prolongs the duration of amplexus, at the end of which fertilization occurs, and also embryonic/larval development, whilst northern populations show a typical reproductive diapause. Reproductive activity therefore shows a geographical variability, larviposition taking place only when conditions are favourable.