Seroepidemiology of HEV and HAV in two populations with different socio-economic levels and hygienic/sanitary conditions.

The epidemiological scenarios of hepatitis E virus (HEV) and hepatitis A virus (HAV) infections have changed in the last few decades, but precise epidemiological data on the prevalence of anti-HEV and anti-HAV, alone or in combination, in the general population are scanty. We investigated HEV and HAV seroprevalence comparing two population samples living in Northern (Abbiategrasso, Milan) and Southern Italy (Cittanova, Reggio Calabria), the latter being characterized by a poorer socio-economic level and hygienic/sanitary conditions. Based on census records, we randomly enrolled and tested 3,365 subjects (Abbiategrasso, n = 2,489; Cittanova, n = 876) aged 18-75 years for anti-HAV and anti-HEV. Anti-HAV (71.3 % vs 52.5 %) and anti-HEV (17.8 % vs 9.0 %) prevalence rates were higher in Southern Italy (both p < 0.001). Most anti-HEV-positive subjects also had anti-HAV. Subjects testing positive for anti-HAV, alone or with anti-HEV, were older (p < 0.001 in both populations) and showed a trend toward declining prevalence in the youngest birth cohorts. The prevalence of subjects with a positive result for anti-HEV alone did not change in birth cohorts in the two towns. Detection of anti-HEV was independently associated with anti-HAV, town, birth cohort, and education level in multivariate analysis. Low socio-economic level and hygienic/sanitary conditions are associated with high HAV and HEV seroprevalence rates in Italy. Recent improvements, especially in the South, have led to a declining prevalence of anti-HAV, alone or with anti-HEV. Seroprevalence of HEV alone is uniformly low and does not change in birth cohorts born between 1938 and 1993.

ABH secretor genetic polymorphism: evidence of intrauterine selection.

OBJECTIVE: Fucosyltransferase locus 2 (FUT2) controls the presence or absence of blood group substances (A, B, H) in the saliva and other body secretions. Secretor/non-secretor phenotypes are associated with some metabolic and infectious diseases. ABO and FUT2 contribute to build up oligosaccharide structures of the cell surface that are important for blastocyst adhesion and resistance to microbial invasion. We investigated a possible selection on ABH secretor phenotypes during intrauterine life. STUDY DESIGN: Three hundred and fifty-six consecutive healthy puerperae and their newborn infants from the caucasian population of Rome were studied. Informed consent for study participation was obtained from the mothers to participate and the study was approved by the Institutional Review Board. ABH secretor Se phenotype was determined on saliva by standard laboratory procedure. RESULTS: Symmetry analysis of mother infant Se phenotype revealed a deficit of mother Se+/newborn Se- with respect to expected values. The asymmetry is present only in infants carrying the A blood group antigen. The asymmetry was dependent on several maternal and neonatal parameters including maternal age, smoke, parity and gestational duration. CONCLUSIONS: The data suggest intrauterine selection against Se- of the embryo carried by a Se+ mother. Such selection is dependent on factors influencing the maternal environment. The study could have practical importance in assessing the risk of infertility and success of artificial insemination.

Coronary artery disease: evidence of interaction between PTPN22 and p53 genetic polymorphisms.

OBJECTIVES: We recently reported an association between the PTPN22 genetic polymorphism and coronary artery disease (CAD) in nondiabetic subjects. Since recent studies suggest that p53 may be involved in coronary atherosclerosis, we have investigated a possible interaction between PTPN22 and p53 codon 72 genetic polymorphisms regarding their effects on susceptibility to CAD in nondiabetic subjects. METHODS: The genotypes of p53 codon 72 and PTPN22 were determined by DNA analysis in 128 nondiabetic subjects with CAD, 122 healthy blood donors and 117 nondiabetic subjects with cardiovascular diseases without CAD. RESULTS: In subjects with the *Arg/*Arg genotype of p53 codon 72, no association was observed between CAD and PTPN22. However, this association was very strong in subjects carrying the *Pro allele of p53 codon 72. Subjects carrying both the *T allele of PTPN22 and the *Pro allele of p53 were overrepresented in CAD nondiabetic cases relative to the other two groups (p = 0.001). CONCLUSIONS: Since both p53 and PTPN22 are involved in autoimmune inflammation, an interaction between the two systems appears biologically plausible. In the analysis of multifactorial disorders, the simultaneous analysis of multiple genes functionally related to diseases will provide a more productive approach than studies of single genetic factors performed from a Mendelian perspective.

Haptoglobin phenotype and reproductive success in repeated spontaneous abortion.

OBJECTIVE: To study the reproductive success of couples with a history of repeated spontaneous abortion (RSA) with respect to the haptoglobin (Hp) phenotypes of both the wife and husband. STUDY DESIGN: This study examined maternal and paternal Hp in 194 couples with primary and secondary RSA recruited from the Center for Reproductive Disorders of the Institute of Obstetrics and Gynaecology at the University of Rome, La Sapienza. Reproductive success was indicated by the presence of at least one live-born infant after more than 5 years of follow-up. RESULTS: The proportion of wives carrying Hp2/1 phenotype and with at least one live-born infant is significantly lower than that of wives without a live-born infant. Moreover, the proportion of couples in which both wife and husband possess the Hp2/1 phenotype is much lower in those with at least a live-born infant than in those without a live-born infant. Both maternal and paternal Hp contribute to reproductive success. However, the contribution of maternal Hp appears stronger than that of paternal Hp. CONCLUSIONS: Hp may play an important role in implantation and/or embryo survival. Couples in which both partners carry the Hp2/1 phenotype have a low probability of producing a live-born infant.

Antiviral treatment for hepatitis C virus infection: effectiveness at general population level in a highly endemic area.

BACKGROUND: Peginterferon plus ribavirin treatment induced a sustained virological response in >50% of HCV-RNA-positive individuals enrolled in published clinical trials. AIM: To determine anti-HCV treatment effectiveness at a general population level. PATIENTS AND METHODS: In 2002, a 1:5 random sample of >11 years old inhabitants of a small Italian town (Cittanova) was invited for HCV screening. HCV-RNA-positive individuals were evaluated for antiviral treatment. RESULTS: 1645 of 1924 invited individuals (85.5%) participated in the screening. 84 HCV-RNA-positive individuals were detected: median age was 65 years (range: 32-87); 67% was infected with genotype 1 or 4. Antiviral treatment was judged unnecessary for 43 (51.2%), due to persistently normal alanine aminotransferases, mild disease at liver biopsy or age >70 years without cirrhosis. Twenty-eight of the remaining 41 patients (68.3%) were ineligible for treatment, because of medical/psychiatric contraindications (42.9%), alcohol/drug abuse (17.9%), decompensated cirrhosis/hepatocellular carcinoma (17.9%), not attending official appointments (10.7%), previous intolerance/non-response to interferon plus ribavirin (10.7%). 5 of 13 eligible patients (38.5%) did not receive treatment (4 refused and 1 accidental death). 3 of 8 treated patients (37.5%) reached a sustained virological response. CONCLUSIONS: Although efficacy of anti-HCV therapy improved in recent years, we found that low eligibility to treatment still limited its effectiveness at general population level in a highly endemic town.

Management of highly sensitized patients: capitol medical center experience.

Highly sensitized patients with elevated anti-HLA antibodies have difficulty to get a living donor due to cross-match positivity and longer waiting times for cadaveric donor transplantation. In this regard, several studies have been made to abrogate cross-match positivity for a possible successful kidney transplantation. In this article, we report our experience, using a desensitization protocol with Rituximab monoclonal antibody complemented with intravenous immunoglubulin and/or plasmapheresis, to prepare highly sensitized patients for successful kidney transplantation.

The correlation of renal allograft weight to metabolic index ratios and glomerular filtration rate among living-unrelated kidney transplant patients: a cross-sectional study.

OBJECTIVE: This study sought to determine whether there was a relationship between the ratios of renal allograft weight (RAW) and metabolic indices: specifically, recipient body weight (RBW), recipient body mass index (RBMI), and recipient body surface area (RBSA), and posttransplant renal function as measured by glomerular filtration rate (GFR). It also sought to determine which of the 3 ratios, and the minimum ratio, that was predictive of a good GFR as well as to ascertain which computational formula (Cockroft-Gault [C&G] vs abbreviated Modification of Diet in Renal Disease [aMDRD]) better predicts renal function. METHODS: This cross-sectional study was performed among living unrelated kidney transplant patients who did not manifest rejection, ischemic injury, or postoperative morbidity and mortality from January to December 2006. Donor/recipient matching was based on conventional immunologic parameters. The harvested kidney was weighed after a cold bath and then transplanted by a single surgical team. The 3 ratios, RAW/RBW, RAW/RBMI, and RAW/RBMI were correlated with GFR, which was computed using C&G and aMDRD formulae based on serum creatinine at discharge and at 6 months follow-up. Statistical analysis used STATA 7 and the Pearson correlation using linear regression analysis. RESULTS: The 53 kidney transplant patients has a mean age of 39.8 years +/- 19 SD (range, 6-74), and slight male predominance (58% vs 42%). RAW/RBW was most positively correlated with GFR estimated by aMDRD (r = .89; P < .001) but negatively correlated with GFR estimated by the C&G formula both at discharge and at 6 months follow-up. A similar trend was observed with RAW/RBMI (r = .79; P < .001), whereas RAW/BSA was related to neither GFR formula. Of the 3 ratios, RAW/RBW best predicted GFR using the aMDRD formula. The minimum RAW/RBW ratio that predicted good GFR (>90 mL/min) at 6 month follow-up was 8.2 (accuracy 88.6%; P = .004). CONCLUSION: The RAW/RBW and RAW/RBMI correlated with GFR measures by the aMDRD method. Of the 3 ratios, only RAW/RBW was useful to predict GFR, best estimated by the aMDRD formula. A minimum RAW/RBW ratio of 8.2 predicted a good GFR at 6 months posttransplant. The findings suggested that transplanting a small kidney into a heavy patient may be a risk factor for allograft failure and that having a high initial ratio (> or =8.2) of renal allograft weight to initial recipient body weight was an advantage.

Repeated spontaneous abortion. Cooperative effects of ADA and ACP1 genetic polymorphisms.

PROBLEM: In consideration of the effect of adenosine deaminase (ADA) and ACP1 (a low-molecular-weight protein tyrosine phosphatase) on T-cell receptor activity, we have analysed the joint distribution of these polymorphisms in a sample of women with primary repeated spontaneous abortion (RSA) to search for possible interactive effects on susceptibility to RSA. METHOD OF STUDY: ACP1 and ADA phenotypes were determined in 170 women with primary RSA in 79 healthy consecutive puerperae and in 160 female newborns from the Caucasian population of Rome and in 357 healthy consecutive puerperae from the Caucasian population of Penne. Chi-square test of independence and three way contingency table analysis by a log-linear model were performed. RESULTS: Women with low-ADA activity and high-ACP1 activity show the lowest susceptibility to RSA. Women with high-ADA activity and low-ACP1 activity, on the contrary, show the highest susceptibility to RSA and also the highest incidence of auto antibodies and of A blood group incompatibility. CONCLUSION: The data are in agreement with those expected on the basis of the effects of ACP1 and ADA genetic variability on T-cell receptor activity and suggest a cooperative effect of the two polymorphic systems in the susceptibility/resistance to repeated spontaneous abortion.

Functional aspects of genetic variability in the GH genomic region.

Because of the small differences among genotypes, it would be difficult in basal conditions to detect the effect of genetic polymorphism in endocrine function, but this could emerge during provocative tests. We have studied four polymorphic sites of the GH gene region (17q24.2), MSPIA, MSPIB, BGLIIA, and BGLIIB. Gene and haplotype distributions in classes of growth retardation have been studied. The outcome of GH diagnostic test in relation to GH region genotypes has been evaluated by the analysis of area under the GH secretory curve. Ninety-eight growth retarded children have been studied. On the basis of provocative GH test these children were classified as total GH deficit (TD), partial GH deficit (PD), and familial short stature (FSS) with no deficit of GH. Sixty-three healthy controls were also considered. An increased frequency of MSPIA*2 allele in PD and TD as compared with FSS children and controls has been observed suggesting that this allele is associated with a decreased GH release. BGLIIA*2 allele appears decreased in PD and TD as compared with FSS and controls, suggesting that this allele is associated with an increased release of GH. Carriers of MSPIA*2 allele show a lower GH release as compared with MSPIA *1/*1 subjects on the provocative test by insulin, while carriers of BGLIIA*2 allele show a higher GH release as compared with BGLIIA *1/*1 subjects on the provocative test by clonidine. The functional aspects of genetic variability within the GH genomic area parallel the genetic differences observed between TD and PD versus FSS and control children.

Genetic polymorphism and TH1/TH2 orientation.

BACKGROUND: It is likely that besides developmental and environmental factors, genetic factors also play an important role in Th1/Th2 orientation and susceptibility to related disorders. Thus, for each genetic factor involved one would expect an opposite pattern of susceptibility towards Th1- and Th2-associated diseases. METHODS: We report a comparative analysis of the pattern of association of four genetic polymorphisms with bronchial asthma (Th2 disease) and Crohn's disease (CD; Th1 disease). The study population included 291 Roman children with bronchial asthma and 72 adult Romans with CD, and haptoglobin, adenosine deaminase (ADA), acid phosphatase locus 1 (ACP1) and MN phenotypes were determined. RESULTS: Compared with controls from the same population, the pattern of phenotype association observed in bronchial asthma is exactly opposite to that observed in CD. The analysis of pairwise gametic type distribution for ACP1, ADA and MN polymorphisms has shown that the pattern of differences between bronchial asthma and controls is opposite to that observed between CD and controls. CONCLUSIONS: The pattern of differences between bronchial asthma versus CD is compatible with the hypothesis that some of the genetic systems considered contribute to Th1/Th2 orientation.

Risk of type 1 diabetes in childhood and maternal age at delivery, interaction with ACP1 and sex.

BACKGROUND: We have investigated the possible role of ACP1 (also known as cLMWPTP: cytosolic low molecular weight phosphotyrosine phosphatase), a highly polymorphic enzyme involved in signal transduction of T-cell receptor, insulin receptor and other growth factors in the relationship between maternal age at delivery and risk of type 1 diabetes in the offspring. METHODS: One hundred and eighty-nine consecutive children with type 1 diabetes (TIDM) diagnosed at the Department of Pediatrics of the University of Sassari (Sardinia) were studied. A control sample of 5460 consecutive newborns from the same population was also studied. RESULTS: Maternal age at birth of children with type 1 diabetes has shifted towards high values. There is also an effect of birth order on the susceptibility to type 1 diabetes, which is independent of that due to maternal age. The proportion of low activity ACPl genotypes is much higher among children born from older mothers than among diabetic children born from relatively young mothers. There is a significant effect of sex, maternal age, sex-ACPl two-way interaction and sex-ACP1-maternal age three-way interaction on the age at diagnosis of diabetes. CONCLUSIONS: The present data confirm the strong association between maternal age at delivery and risk of type 1 diabetes in the child. In addition, our analysis suggests a complex interaction among maternal age, sex of infant and ACP1 concerning age at diagnosis of diabetes. Thus, risk and clinical course of type 1 diabetes seem to be dependent on both maternal environment during intrauterine development and foetal genetic factors.

Intrauterine development and MNSs blood groups in repeated spontaneous abortion.

OBJECTIVES: To determine whether the maternal MNSs genotype has an effect on the birth weight and gestation duration of the live offspring of women with repeated primary spontaneous abortion (RSA). METHODS: The study sample consisted of 239 healthy white women who had been delivered of a live infant, and 137 women with a history of primary RSA-54 of whom had recently been delivered of a live infant and 83 who had had a spontaneous abortion. Maternal MNSs phenotypes were determined by standard serological methods, and the results were analyzed for relationships between these phenotypes and the mothers' reproductive status and the infants' birth weight and gestational age. Analysis of variance, the chi(2)-test of independence, and the Mantel-Haenszel test for linear association were performed for data analysis. RESULTS: Infants born to mothers with the Ss genotype showed significantly lower birth weight and gestational duration compared with the infants of mothers with other genotypes. Additionally, the MNSs haplotype was found to be associated with birth weight. CONCLUSIONS: Previous studies have shown that the MNSs system influences the gestational age of aborted fetuses in cases of RSA. The present study supports the hypothesis that this genetic factor influences intrauterine growth and development in women experiencing RSA.

Preliminary report: BGLIIA-BGLIIB haplotype of growth hormone cluster is associated with glucose intolerance in non-insulin-dependent diabetes mellitus and with growth hormone deficit in growth retardation.

We studied 101 growth-retarded children from the population of Ancona (Italy). Plasma growth hormone (GH) levels at the end of insulin and clonidine tests were considered for classification of children into 3 categories according to severity of GH deficit: total deficit of GH (TD), partial deficit (PD, and familiar short stature (FSS; no deficit of GH). The BGLIIA*2/BGLIIB*1 haplotype of GH cluster that was previously found to be negatively associated with severe glucose intolerance in non-insulin-dependent diabetes mellitus (NIDDM) is negatively associated with GH deficit in growth-retarded children. The hypothesis that intrauterine growth retardation and glucose intolerance in adult life could be phenotypes of the same underlying genotype has been recently put forward. The present observation suggests that genes influencing both growth and glucose tolerance are encoded in the GH cluster.

The genetics of signal transduction and the outcome of diagnostic tests in growth retardation.

The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0.02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0.005) and to react more promptly than the genotypes with high S isoform concentrations (P<0.05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.

Maternal-fetal interaction in the ABO system: a comparative analysis of healthy mothers and couples with recurrent spontaneous abortion suggests a protective effect of B incompatibility.

We investigated the possible differential effects of A and B blood group materno-fetal incompatibility on human fertility through a comparative analysis of couples with recurrent spontaneous abortion (RSA) and healthy mothers. ABO phenotype was determined in 5180 healthy mothers and their newborn babies from the population of Sassari (Sardinia) and in 1359 healthy puerperae (women who have just given birth) from the population of Rome. Mother-newborn joint ABO distribution in healthy mothers was compared with wife-husband joint ABO distribution in RSA couples. Distortions from expected distribution were evaluated by symmetry analysis. In both RSA couples and healthy mothers significant deviation from expected symmetry patterns were observed. Deviations in RSA are in the opposite direction to those observed in healthy puerperae. The most important difference observed concerned the symmetric joint phenotypes mother (women) A/infant (husband) B (B incompatible) and mother (women) B/infant (husband) A (A incompatible). A low number of B incompatible in RSA couples and a high number of B incompatible in healthy mothers was observed. The phenomenon is much more evident in women aged 24-28 years, a period of maximum fecundity. It is possible that the presence of anti-B immunoglobulin in the mother might have a protective effect against fetal loss in some cases of mother-infant ABO incompatibility.

Rh system and intrauterine growth. Interaction with season of birth.

Based on the hypothesis that maternal-fetal genetic differences in membrane transport and signal transduction may influence intrauterine development, the recent acquisition on transport function of Rh protein prompted us to study the relationship between joint maternal-fetal Rh phenotype and birth weight. Considering that metabolic effect of maternal-fetal competition could be amplified by environmental conditions, we have investigated possible seasonal effects on such relationship. We have studied 5291 infants born in Sardinia in the period January 1993--December 1996 and 984 infants born in Rome during 1996. In Rh(-) mothers there is a significant association between season of birth and birth weight that shows the highest mean value in infants born in autumn (i.e. conceived in winter). The association is much more evident in male than in female infants. In male infants from Rh(-) mothers, the association between birth weight and season is significant in Rh(+) male newborns only. Recent observations by our group in NIDDM suggest that glucose transport in RBC may be related to D protein, thus we propose an interpretation of the present observation in terms of transport function. When the density of D protein in the infant is greater than in the mother, the balance is in favour of the infant who may attain a significant developmental advantage when conceived in the cold season.

ACP1 and human adaptability. 2. Association with season of conception.

We have studied the pattern of association between the season of conception and cytosolic low molecular weight phosphotyrosine phosphatase (ACP1) genetic polymorphism in 329 consecutively newborn infants from the population of Penne and 361 consecutively newborn infants from the population of Rome. In addition, 329 mothers were studied in the population of Penne. A concordant, highly significant association was observed in the two populations between ACP1 parameters and the season of conception of newborn infants. The total activity of ACP1 shows a minimum in infants conceived in January-February and a maximum in those conceived at the end of the solar year. Analysis of the joint mother-newborn ACP1 distribution in relation to the season of fertilisation has shown that among mothers carrying ACP1*A (the allele showing the lowest activity), the proportion of newborns carrying this allele is higher in those conceived in the first months of the year than in those conceived subsequently. Since ACP1 probably functions as a phosphotyrosine phosphatase and as a flavin mononucleotide phosphatase, low activity could enhance the metabolic rate and would be advantageous in a cold environment. The cycle of variation of ACP1 in infants follows the cycle of solar illumination. It is possible that individuals who have a genetic background allowing them to adapt easily and readily to seasonal demand are more successful in reproducing themselves. The population of zygotes conceived in a given season would therefore reproduce the pattern of gene combination more fit for that season.

Malignant fibrous histiocytoma of the maxilla: a case report.

Malignant fibrous histiocytoma is one of the most common sarcomas of soft tissues in late adult life. However, this neoplasm rarely arises in the oral and maxillofacial region with the maxilla presenting as an unusual site. A case report of a 40-year old woman with malignant fibrous histiocytoma involving the maxilla is discussed with relevant literature reviewed. The treatment chosen was partial maxillectomy. The patient was referred for cobalt therapy after surgery. Eight months after diagnosis, the patient died of the illness.

A pharmacokinetic comparison of the corn oil versus microemulsion gelcap formulation of cyclosporin used de novo after renal transplantation.

The initial poor absorption of the corn oil-based, gel capsule oral formulation of cyclosporin (CyA) greatly limits its use for inception of immunosuppressive therapy. Insufficient drug concentrations during the early post-transplant period predispose to renal allograft rejection. The present study served to compare the time required to achieve the therapeutic CyA concentrations after de novo administration of the corn oil-based gel capsule (CyA-GC; n = 11) versus the microemulsion (CyA-ME; n = 11) formulation of CyA. During the 1st month after renal transplantation, patients underwent serial pharmacokinetic profiling from which we obtained observed and dose-corrected values of several parameters. Although patients in neither the CyA-GC nor the CyA-ME group adequately absorbed the drug during days 0-2, from day 3 to 4 patients in the CyA-ME group showed significantly greater absorption than those in the CyA-GC group (P = 0.041). Patients in the CyA-ME group reached the 1st month target average concentration (Cav) values (> or = 550 ng/ml) earlier than those in the CyA-GC group and required significantly lower daily CyA doses (P = 0.018). We conclude that therapeutic CyA levels can be achieved more rapidly and with lower doses of the drug after de novo administration of CyA-ME than with CyA-GC.