Densità di popolazione e SARS-CoV-2: uno studio epidemiologico di urban health.

Despite SARS-CoV-2 transmission being a complex phenomenon, greater population density seems to be a risk factor. The aim of this study was to analyze through an epidemiologic urban health approach the relationship between population density and SARS-CoV-2 incidence using data which are comparable with regard to testing strategies. All 10,300 SARS-CoV-2 confirmed cases between October and December 2020 were included. We conducted separate analysis by gender standardizing and stratifying by age and month. In the Province Capital (p.d.=765 inhabitants/km2), standardized SARS-CoV-2 incidence rate was higher than the expected, both in men (SIR=1.17, 95%CI=1.12;1.22, p<0.0001) and women (SIR=1.20, 95%CI=1.15;1.25, p<0.0001). In municipalities with p.d. >200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was similar to the expected (p>0.05). In municipalities with p.d. <200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was lower than the expected, both in men (SIR=0.85, 95%CI=0.81;0.90, p<0.0001) and women (SIR=0.84, 95%CI=0.80;0.88, p<0.0001). Stratified analysis by months with likelihood ratio test showed heterogeneity of the p.d. effect in men and women (p<0.05). SARS-CoV-2 incidence rate seemed to be higher in most densely populated areas, both in men and women. Our results confirmed the great importance of restrictive measures as well as the importance of limiting the epidemic wave in the initial stages and could help guide pandemic management strategies according to urban context and population density.

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients.

Cystinuria is a rare autosomal inherited disorder characterized by impaired transport of cystine and dibasic aminoacids in the proximal renal tubule. Classically, cystinuria is classified as type I (silent heterozygotes) and non-type I (heterozygotes with urinary hyperexcretion of cystine). Molecularly, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). The goal of this study is to provide a comprehensive clinical, biochemical and molecular characterization of a cohort of 12 Portuguese patients affected with cystinuria in order to provide insight into genotype-phenotype correlations. We describe seven type I and five non-type I patients. Regarding the molecular classification, seven patients were type A and five were type B. In SLC3A1 gene, two large genomic rearrangements and 13 sequence variants, including four new variants c.611-2A>C; c.1136+44G>A; c.1597T (p.Y533N); c.*70A>G, were found. One large genomic rearrangement was found in SLC7A9 gene as well as 24 sequence variants including 3 novel variants: c.216C>T (p.C72C), c.1119G>A (p.S373S) and c.*82C>T. In our cohort the most frequent pathogenic mutations were: large rearrangements (33.3% of mutant alleles) and a missense mutation c.1400T>C (p.M467T) (11.1%). This report expands the spectrum of SLC3A1 and SLC7A9 mutations and provides guidance in the clinical implementation of molecular assays in routine genetic counseling of Portuguese patients affected with cystinuria.

[Environmental and biological monitoring of exposure to PAHs in Taranto coke-oven workers and in two groups of the general population from Apulia]. / Monitoraggio ambientale e biologico dell'esposizione a IPA nei lavoratori della cokeria di Taranto e confronto con due gruppi della popolazione generale pugliese.

The exposure to PAHs was assessed by personal air sampling and urinary 1-hydroxypyrene (1-OHP) in 100 coke-oven workers (CW) of the Taranto plant and in subjects from the general population living close (NC, 18) and far away (FC, 15) from the plant. Median airborne benzo[a]pyrene (BaP) and 1-OHP levels were 152, 1.5, and 3.6 ng/m3 and 2.0, 0.5 and 0.6 microg/g creatinine in CW, NC, and FC, respectively. BaP exposure exceeded the German acceptable (70 ng/m3) and tolerable (700 ng/m3) limit risk based values in 82 and 11% of CW and the European target value for ambient air (1 ng/m3) in about 65% of NC and FC. 1-OHP levels exceed the proposed biological limit value for the coke-oven industry (4.4 microg/g crt) in 21% of CW and the Italian reference value (0.3 microg/g crt) in about 90% of NC and FC. The exposure resulted lower than in the past, but this study highlights that PAHs exposure from the coke plant still poses a health risk for workers and the general population.

[Source apportionment of benzo(a)pyrene in Taranto and carcinogenic risk estimate in general population]. / Individuazione e caratterizzazione delle sorgenti di benzo(a)pirene nel comune di Taranto e stima del rischio cancerogeno associato all'esposizione della popolazione generale.

INTRODUCTION: In 2009 the limit value of benzo(a)pyrene (BaP) in ambient air of 1.0 ng/m3 has been exceeded in the urban district of Taranto near to the industrial area, where a several large plants are located, including an integrated cycle steel plant. OBJECTIVE: To identify emission sources and quantify relative contribution to the PAHs levels; to estimate health impact associated to PAHs exposure in general population. METHODS: Multivariate receptor models have been used. Concentration of PAHs measured in 4 location in Taranto in 2008-2009 have been analyzed. 5 different models estimated profiles of unknown sources and identified significant chemical species. To compute the lung cancer risk the WHO unit risk estimate for BaP (8.7 x 10(5) ng/m3) has been adopted. RESULTS: Models employed identify 3 to 4 emission sources. Estimated profiles have been compared with measured ones. Based on the average annual BaP level measured (1.3 ng/m3), 2 attributable cancer cases in the district Taranto population are estimated to result from a life-time exposure. CONCLUSIONS: Among different emissive sources, the analysis identifies theoretical sources whose profiles, compared with observed data, allow to identify dominant contributions to PAHs pollution and to design corrective actions to reduce environmental and health impact.

[Biological monitoring in workers exposed to inorganic arsenic in a disused industrial plant in the area of Manfredonia]. / Monitoraggio biologico dell'esposizione professionale ad As inorganico in lavoratori di un impianto industriale dismesso nell'area di Manfredonia.

Inorganic arsenic and its methylated metabolities were measured in 108 spot urine samples obtained from the medical surveillance programme of workers exposed to inorganic Arsenic in July 2006. 15% of the samples showed levels higher than limit value of 35 microg/L (mean value 23,9 microg/L). After the improvement of the working conditions, in August-October 2006, we collected a urinary sample from each of the 108 workers enrolled. A questionnaire was also administrated, in order to investigate the influence of occupational and non occupational factors on the urinary arsenic excretion. The median value of urinary arsenic was 15,12 microg/L; among the 108 samples, 5% showed levels higher than limit value. A significant difference was observed in relation with sea-food consumption and aging stratification. In conclusion, we have described a significant reduction of urinary arsenic excretion between the two phases of biological monitoring, likely due to a proper hygienic work-related intervention.

Biological monitoring and allergic sensitization in traffic police officers exposed to urban air pollution.

Urban air pollution is associated with an increased incidence of allergic respiratory diseases. The aim of this study is to assess the occupational exposure to urban pollution through biological monitoring of PAHs and CO airborne levels in 122 traffic wardens in Bari, Italy and to investigate sensitization to inhaled allergens in a subgroup of workers. After filling in a questionnaire on lifestyle habits and occupational history, a medical examination, spirometry were carried out and blood samples were taken; the measurement of exhaled CO and urinary 1-hydroxypyrene (1-HOP) was performed and data on the air quality of Bari Municipality were obtained. Specific IgE dosage and skin prick tests were done on 18 workers giving altered values of spirometry or anamnestic allergic symptoms. Urinary 1-HOP showed median levels of 0.1 microMol/Mol(creat) (range 0.02-6.68) and was not influenced by smoking habits, work tasks, area of the city and environmental levels of PM10. Exhaled CO, with median value of 1 ppm (range 0-27), was significantly higher in smokers than in non-smokers, while no other variable seemed to play a role in modifying the levels. Specific IgE production versus inhalant allergens was found in 6 cases. Positive skin prick test results were observed in 11 cases. Allergic rhinitis was diagnosed in 6 cases. At least one of the allergometric tests performed was positive in 61 percent of the subjects. In conclusion, our results suggest the importance of introducing allergic status evaluation in this class of workers, exposed to several urban air pollutants.

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype.

OBJECTIVE: To clarify the genotype-phenotype correlation and elucidate the role of digenic inheritance in cystinuria. METHODS: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 (type A) and SLC7A9 (type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I (silent heterozygotes), 46 type non-I (hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands. RESULTS: Mutations were identified in 97% of the probands, representing 282 alleles (86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5-E9 showed phenotype non-I in some heterozygotes. Type B heterozygotes showed phenotype non-I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non-I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes (type AB) had greater aminoaciduria than single heterozygotes in their family. CONCLUSIONS: Digenic inheritance is an exception (two of 164 families), with a limited contribution to the aminoaciduria values (partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes (SLC3A1 preferentially for type I and SLC7A9 for type non-I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.

A YAC contig spanning the blepharophimosis-ptosis-epicanthus inversus syndrome and propionic acidemia loci.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant condition consisting of congenital dysplasia of the eyelids with a reduced horizontal diameter of the palpebral fissures, droopy eyelids and epicanthus inversus. Two clinical entities have been described: type I and type II. The former is distinguished by female infertility, whereas the latter presents without other symptoms. Both type I and type II were recently mapped on the long arm of chromosome 3 (3q22-q23), suggesting a common gene may be affected. The centromeric and the telomeric limits of this region are well defined between loci D3S1316 and D3S1615, which reside approximately 5 cM apart. Here, we present the construction of a YAC contig spanning the entire BPES locus using 17 polymorphic markers, 2 STS and 28 ESTs. This region of approximately 5 Mb was covered by 31 YACs, and was supported by detailed FISH analysis. In addition, we have precisely mapped the propionyl-CoA carboxylase beta polypeptide (PCCB), the gene mutated in propionic acidemia, within this contig. Apart from providing a framework for the identification of the BPES gene, this contig will also be useful for the future identification of defects and genes mapped to this region, and for developing template resources for genomic sequencing.

C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers?

Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C-->T mutation (C677T), converting an alanine to a valine residue in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR's involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30-5.57) and 2.51 (1.00-6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo's genotype.

Cystinuria phenotyping by oral lysine and arginine loading.

BACKGROUND: Cystinuria is an inherited disorder of cystine and dibasic amino acids transport that results in urolithiasis because of poor cystine solubility. Three cystinuria phenotypes, differentiated according to urinary amino acid excretion in obligate heterozygotes, were regarded as allelic variants of a monogenic disease. Two mutated amino acid transporter genes, however, have been recently identified as responsible for cystinuria. Mutations in the SLC3A1 gene. encoding for the heavy subunit of the transporter protein rBAT, were associated with type I cystinuria, whereas type II and III cystinuria were associated with mutations in the SLC7A9 gene, encoding for a light subunit of rBAT. Lysine and arginine metabolism have, therefore, been evaluated in cystinuria homozygotes and heterozygotes to better define the cystinuria phenotypes and their correlations with these emerging genotypes. PATIENTS AND METHODS: Lysine and arginine intestinal absorption and renal excretion were assessed by oral loading and compared to normal controls. Seven cystinuria homozygotes and 7 obligate heterozygotes belonging to the different types received alternately an oral dose of 0.5 mmol/kg body weight lysine or arginine. Plasma concentrations of lysine, arginine, ornithine (derived from rapid arginine conversion) were measured 0, 1, 2, and 3 hours after loading. Their urinary concentrations were measured in morning urine and in urine collected 0-6 hours after loading. RESULTS: Gut lysine absorption was deficient in type II and III, and normal in type I cystinuria homozygotes. Impaired arginine intestinal absorption, as well as massive lysine, arginine, and ornithine hyperexcretion were shared by all homozygotes, irrespective of the type. All heterozygotes shared normal lysine absorption, whereas arginine absorption was slightly impaired in type II and III heterozygotes, which also displayed high lysine, arginine, and ornithine urinary excretion after loading. CONCLUSIONS: Two cystinuria phenotypes, type I and non-type I, can be identified in both homozygous and heterozygous cystinuric subjects by oral loading tests with lysine and arginine. In agreement with recent molecular findings, non-type I cystinuria comprises mentioned type II and type III, which constitute allelic variants of a cystine and dibasic amino acid transport disorder distinct from type I cystinuria.

[Role of biological monitoring in health and epidemiological surveillance: a proposal]. / Ruolo del monitoraggio biologico nella sorveglianza sanitaria ed epidemiologica: proposte operative per la SIMLII.

Biological markers can be used at an individual level for medical surveillance or at group level within the context of epidemiological surveillance. However, the use of biological monitoring for medical and epidemiological surveillance is heavily conditioned by the critical issue of biomarker validation. One effective means for combining biological monitoring with medical and epidemiological surveillance is the mandatory annual report on anonymous and collective data; this will be made possible after providing adequate training schemes for the occupational physicians involved and the definition of appropriate guidelines, aimed at improving the quality of occupational health services. It will then be possible to design multicentric surveys to assess the quality of occupational health services using validated indicators.

[Occupational epidemiology in Italy]. / L'epidemiologia occupazionale in Italia.

The development of Occupational Epidemiology in Italy is closely correlated with the political and social awareness of the needs of preventive strategies in the workplace. In the late '60s the Trade Unions supported a model of intervention based on the involvement of the so-called "Homogeneous group of workers" in the validation of the preventive measures taken on the workplace. In spite of the shortcomings of the model, it was extremely effective resulting in enhanced perception of the priority of preventive strategies and in the formation within the National Health Service of the Occupational Health Services. In Italy over the period 1973-2002 there has been an impressive trend of research in field of occupational epidemiology (a search on Medline shows an increasing trend over the years and, in terms of international comparison, higher figures than in Germany, France and Spain). Occupational Epidemiology is now present in the activities of the local Occupational Health Services and in the teaching activities of the Medical Schools throughout the country.

[A genetic viewpoint of focal glomerular sclerosis: fom genes to glomerular pathophysiology [corrected]]. / La genetica della glomerulosclerosi focale: dai geni alla fisiopatologia del glomerulo.

Recent studies of Mendelian disease have begun to clarify the clinical spectrum of the group of disorders that make up familial, focal segmental glomerulosclerosis (FSGS) and nephrotic syndromes. In familial forms of focal segmental glomerulosclerosis (FSGS), both autosomal recessive and dominant inheritance patterns have been reported. At least three genes have been identified which, when defective, cause familial FSGS or nephrosis: the NPHS1 gene, encoding nephrin; the NPHS2 gene, encoding podocin; and the ACTN4 gene, encoding a-actinin-4. Because the majority of FSGS cases occur as sporadic disease, the recently described mutations in the NPHS2 gene "in approximately 25 percent of cases of apparently sporadic, steroid-resistant FSGS in children" have claimed great interest. The applicability of these observations to adults, including the possible importance of the nephrin and alpha-actinin-4 genes in the sporadic disease, remain to be determined. Finally, the mechanisms of podocyte damage and the molecular basis of glomerulosclerosis are reviewed.

[Environmental pollution and short-term effects on human health in industrialized urban areas]. / Inquinamento ambientale ed effetti a breve termine sulla salute umana in aree urbane industrializzate.

Several studies investigating the adverse short-term effects of air pollution indicate that even concentrations of air pollutants close to or lower than air quality standards could negatively affect respiratory and cardiovascular health. Therefore, it seems crucial to develop knowledge about health adverse effects in industrialized urban areas. A time-series study on the association between air pollution levels and daily mortality and hospital admissions for respiratory and cardiovascular diseases is currently carried out in the town of Taranto, "area at high environmental risk" according to WHO because of the presence of several heavy industries and elevated rates for all-causes and all cancer mortality, higher than regional mortality rates, especially for lung cancer.

[Mortality among workers employed in the production of pulp and paper in Apulia]. / Studio di mortalità di lavoratori addetti alla produzione di cellulosa e carta in Puglia.

The authors studied a cohort of 2660 pulp and paper workers in Capitanata, Apulia (Italy). All workers with at least 1 year of employment on January 1 1965 or thereafter until march 30, 2000 where studied. Standardized Mortality Ratios (SMRs) were used to compare the mortality rates of the cohort with those of Apulian population. Ninetyfive percent confidence intervals (CIs) for SMRs were obtained. Cancer risks significantly associated with work where observed: all causes for males (SMR 112.09, 95% CI 104.91-119.77), brain cancer for males (SMR 206.04, 95% CI 103.04-412.01), digestive tract for males (SMR 126.78, CI 100.63-159.73). Association with other malignancies are suggested in this study for Laryngeal and Kidney. These malignancies have been associated with different exposures in the production cycle: biocides (Kidney), Formaldehyde (Kidney, Brain). Unclear is the risk factor for the excess showed in digestive tract cancer.

[Semiautomatic defibrillators at the workplace health service]. / I defibrillatori semiautomatici nel servizio sanitario aziendale.

Implementation of automated external defibrillators (AEDs) in workplace can help to revive victims of sudden cardiac arrest. The American College of Occupational and Environmental Medicine, the American Heart Association have all issued guidelines for medical management of AED programs. The School of Occupational Health-University of Bari--is currently involved in a programme to be developed with the regional 118 emergency team and the Health Department of Region Apulia aiming at establishing a well controlled use of AED in the workplace.

Lattice Corneal Dystrophy-Variant: a report of three new cases due to p.V631D mutation in the TGFBI gene.

PURPOSE: To report clinical findings and molecular defect in three subjects affected by Biber-Haab-Dimmer dystrophy or Lattice Corneal Dystrophy Type I (LCD1), a corneal dystrophy transmitted as an autosomal dominant tract. MATERIALS AND METHODS: Three subjects underwent a complete ophthalmic examination and confocal microscopy study. Following the collection of DNA from the patients, the TGFBI gene was screened for mutations by direct sequencing. RESULTS: Confocal microscopy study revealed that the opacity typical of the disease was assembled in the axial region of the cornea. The causative TGFBI mutation p.Val631Asp was identified in all subjects. CONCLUSIONS: The finding of the p.Val631Asp mutation responsible for this form of LCD-Variant highlights the utility of molecular genetic analysis of the TGFBI gene in order to offer early diagnosis. These results provide more data for molecular diagnosis and prognosis of this clinical and genetic heterogeneous disease.