A study of Adenosine-Deaminase genetic polymorphism in rheumatoid arthritis.

Recent investigations suggest that Adenosine Deaminase (ADA) could play a role in susceptibility to rheumatoid arthritis (RA). The purpose of our study is to investigate the possible role of genetic variability of ADA in the susceptibility to RA. We studied three intragenic ADA polymorphisms, ADA1, ADA2 and ADA6, in a sample of 91 subjects with RA and in 246 healthy subjects from the same Caucasian population and compared genotype and pairwise haplotype distributions between cases and controls. No statistically significant differences between RA and controls are observed for ADA genotypes. A border line difference for ADA1-ADA2 haplotype distribution is observed due to a decreased proportion of ADA1 *2/ADA2 *2 haplotype in RA compared to controls. Our data indicate a border line effect of ADA gene polymorphism on susceptibility to RA that need to be confirmed in other clinical settings.

A study of three polymorphic sites of the ADA gene in children with type 1 diabetes mellitus.

BACKGROUND: Adenosine deaminase is a polymorphic enzyme that has an important role in immune functions and in the regulation of intracellular and extracellular concentrations of adenosine and adenosine receptor activity. AIM: To search for possible association of type 1 diabetes mellitus (DM1) with three loci haplotypes (ADA1, ADA2, ADA6) of the adenosine deaminase gene. PATIENTS: One hundred and eighty-nine consecutive children with DM1 from Sassari, Sardinia, and a control sample of 239 children from the same area were studied. METHODS: ADA loci genotypes were determined by DNA analysis. RESULTS: Compared to controls, diabetic boys show a decrease of the 2(2)/6(1) haplotype while diabetic girls show an increase of the same haplotype. This association was replicated in an independent sample from Continental Italy. CONCLUSIONS: The 2(2)/6(1) haplotype may exert a protective action in males but may increase susceptibility to DM1 in females: OR = 0.398, 95% CI 0.16-0.96 for males, and OR = 2.31, 95% CI 1.32-4.06 for females.

Favism: association with erythrocyte acid phosphatase phenotype.

The frequency of carriers of the P(a)and P(c) alleles of the gene for acid phosphatase in the erythrocyte is significantly higher in male subjects deficient in glucose-6-phosphate dehydrogenase and having hemolytic clinical favism than it is in the general population. This observation seems to indicate that alleles (P(a) and P(c)) of a gene polymorphic in all human populations affect the fitness of the involved phenotypes in special genotypic and nongenotypic conditions.

Genetic polymorphism and idiopathic generalized epilepsy. Evidence of interaction between haptoglobin and ACP1 systems.

We have investigated possible interactions between ACP1 and Hp concerning their effects on the susceptibility to convulsive disorders. 129 children with idiopathic generalized epilepsy with tonic clonic seizures (IGE) and 127 controls were studied in the population of Rome. There is a significant interaction between Hp and ACP1 concerning their effects on epilepsy. The association of Hp with epilepsy depends on the ACP1 genotypes. In carriers of the *B/*B genotype of ACP1 the risk of epilepsy is much lower in Hp *1/*1 children than in other Hp types. This is not observed in carriers of other ACP1 types.The present data suggest an epistatic action of ACP1 concerning the effect of Hp on the susceptibility to convulsive disorders.

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear. METHODS: ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain- and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of activation of EGFR signalling as well as on exosome production and exosomal phospho-EGFR. RESULTS: ANXA1 was found to be downregulated in head and neck cancer tissues, both at mRNA and protein level. Its anti-proliferative effects were mediated through the intracellular form of the protein. Importantly, ANXA1 downregulation resulted in increased phosphorylation and activity of EGFR and its downstream PI3K-AKT signalling. Additionally, ANXA1 modulation affected exosome production and influenced the release of exosomal phospho-EGFR. CONCLUSIONS: ANXA1 acts as a tumour suppressor in HNSCC. It is involved in the regulation of EGFR activity and exosomal phospho-EGFR release and could be an important prognostic biomarker.

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 within human growth hormone gene region and BMI in type 2 diabetes.

Currently there is a surge of interest in the association of obesity with growth hormone (GH). Our hypothesis is that genetic variation within the hGH area could predispose to obesity in type 2 diabetes. We examined 68 Caucasian subjects with type 2 diabetes from the central area of Continental Italy. In these subjects we examined four polymorphic loci (Msp1A, Msp1B, BglIIA and BglIIB) located in the hGH gene region (chromosome 17q22-9-24). A sample of 192 adults from the population of Central Italy were studied as controls. Msp1B and Msp1A polymorphisms are associated with BMI. For both polymorphisms the proportion of overweight subjects is greater in the *1/*1 genotype than in carriers of the *2 allele (97% vs. 79% and 94% vs. 86% respectively). For both polymorphisms, the mean value of BMI is greater in the *1/*1 genotype than in carriers of the *2 allele. The mean values of age at onset of diabetes are greater in Msp1B*1/*1 and Msp1A*1/*1 genotypes than in carriers of the *2 allele. BglIIA and BglIIB polymorphisms are not associated with being overweight. The present study suggests that the structural organisation of the hGH genomic area may have an important role in being overweight associated with type 2 diabetes.

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.

Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms.

Acid phosphatase locus 1 (ACP1) is a highly polymorphic enzyme that has an important role in flavoenzyme activity and in the control of insulin receptor activity and band 3 protein phosphorylation status. Adenosine deaminase (ADA) is a polymorphic enzyme that catalyses the irreversible deamination of adenosine to inosine and has an important role in regulating adenosine concentration. Based on the hypothesis that ACP1 counteracts insulin signaling by dephosphorylating the insulin receptor and that adenosine has an anti-insulin action, we reasoned that low ACP1 activity (low dephosphorylating action on insulin receptor) when associated with high ADA activity (low adenosine concentration) would result in a cumulative effect towards an increased glucose tolerance. On the contrary, high ACP1 activity when associated with low ADA activity would result in a cumulative effect towards a decreased glucose tolerance. A total of 280 adult subjects with type 2 diabetes from the population of Penne (Italy) were studied. There was a nonsignificant trend toward an increase in the proportion of subjects with the complex type with high ACP1 activity and low ADA activity (ie, *B/*B; *A/*C; *B/*C; *C/*C//ADA*1/*2 and *2/*2) in type 2 diabetes relative to that observed in newborn infants from the same population. High ACP1 activity/low ADA activity joint genotype was positively associated with high glycemic levels and with high body mass index (BMI) values. Low ACP1 activity/high ADA activity joint genotype was also positively associated with dyslipidemia. These findings suggest that both ACP1 and ADA contribute to the clinical manifestations of type 2 diabetes and probably also have a marginal influence on susceptibility to the disease. Both additive and epistatic interactions between the 2 systems seem to be operative.

A study of human growth hormone and insulin gene regions in relation to metabolic control of non-insulin-dependent diabetes mellitus.

The possible association of human growth hormone (hGH) and insulin (INS) gene regions with metabolic control in diabetes was investigated in 98 subjects with non-insulin-dependent diabetes mellitus (NIDDM); 54 control subjects from the same population were also studied. Two polymorphic restriction sites in the region of the hGH cluster (BGLIIA and BGLIIB) show significant association with both glycemic and hemoglobin A1c (HbA1c) levels. Mean values for plasma glucose and HbA1c show a maximum in the BGLIIA *1/*1 genotype and a minimum in the BGLIIA *2/*2 genotype. Mean values for plasma glucose and HbA1c show a maximum in the BGLIIB *1/*2 genotype. The BGLIIA*2/BGLIIB*1 haplotype shows a negative correlation with plasma glucose and HbA1c levels. Since the two markers are located in the area surrounding the hGH-V locus, the expression of this gene in NIDDM warrants further investigation.

Genotypes of cytosolic low-molecular-weight protein-tyrosine-phosphatase correlate with age at onset of type 1 diabetes in a sex-specific manner.

We investigated the possible role of cytosolic low-molecular-weight protein-tyrosine-phosphatase (cLMWPTP or acid phosphatase locus 1 [ACP1]) in the mediation of age at onset of type 1 diabetes. ACP1 is an enzyme involved in signal transduction of T-cell receptors, insulin, and other growth factor receptors. We studied acid phosphatase polymorphism in 189 consecutive children with type 1 diabetes admitted to the Pediatric Clinic of Sassari University (Sardinia) and in 86 adolescent patients with recently diagnosed type 1 diabetes from continental Italy. In both populations, females with medium-high activity acid phosphatase genotypes had onset of disease significantly earlier than males. The data suggest that acid phosphatase genotype affects the age of onset and probably also the sex ratio in type 1 diabetes. Sex hormones might modulate the susceptibility to autoimmune diseases, including type 1 diabetes, through the influence of signal transduction pathways involved in immune functions. Elucidation of the molecular basis for gender differences in the course and severity of type 1 diabetes could have important implications for treatment as well, because there might be gender-specific effects in the response to immunotherapy.

Haptoglobin genotype and natural fertility in humans.

OBJECTIVE: To study the possible relation between human natural fertility and haptoglobin (Hp) genotype. DESIGN: Prospective study. SETTING: Maternity departments of local hospitals in two Italian localities. PATIENT(S): Healthy women who had just given birth in the maternity departments of two local hospitals (n = 679). INTERVENTION(S): Venous blood collection for determination of Hp genotype with the use of starch gel electrophoresis of hemoglobin-supplemented serum. MAIN OUTCOME MEASURE(S): Distribution of Hp genotypes in relation to age of puerperae. RESULT(S): In both populations, the proportion of young mothers was much higher among women who were homozygous for the Hp*1 allele (the Hp*1/*1 genotype) than among women who had other Hp genotypes. In addition, the proportion of multiparous women among the older mothers was higher among those with the Hp*1/*1 genotype than among those with other Hp genotypes. CONCLUSION(S): The data suggest that women with the Hp*1/*1 genotype reproduce at an earlier age and have higher natural fertility potential than women with other Hp genotypes.

Foetal macrosomia and erythrocyte acid phosphatase (ACP1) polymorphism in diabetic and normal pregnancy.

Both in diabetic and in normal pregnancy the proportion of macrosomic fetuses is much lower among newborns carrying Pc allele of erythrocyte acid phosphatase (ACP1) than among other ACP1 genotypes. In diabetic pregnancy the well known increased incidence of fetal macrosomia has been observed only among fetuses which do not carry this allele. ACP1 probably functions as a flavin-mononucleotide phosphatase. Since Pc allele is associated with the highest enzymatic activity it is likely that subjects carrying this gene may have a relatively lower concentration of flavin-mononucleotide cofactors and in turn a reduced rate of metabolic activities controlled by flavoenzymes. It is possible that in fetuses carrying Pc, flavo-enzyme activities are regulated at a level that does not allow a full response to stimuli (both genetic and/or environmental) aimed to maximize fetal growth.

Adenosine deaminase-acid phosphatase association and the environment: A study in a continental Italian population.

Three hundred fifty newborns from Rome and 351 from Penne were studied in continental Italy. Medium high altitude above sea level and cold winters characterize the area of Penne, while low altitude and very mild winters characterize the area of Rome. An effect of environmental conditions on the association between adenosine deaminase (ADA) and acid phosphatase (ACP1), previously shown in Sardinia, has been confirmed in continental Italy. When compared with expected independent assortment, the proportion of ACP1*A/*A carrying the ADA*2 allele is lower than expected in the lowlands and higher than expected in highlands. In continental Italy there is an interaction among ACP1-ADA genotype, season of conception, and locality. The excess of *A/*A newborns carrying the ADA*2 allele is present only among those conceived in the first half of the year (January-June). Among newborns in Penne conceived in the Spring, the proportion of those with *A/*A genotype is increased and these infants show decreased intrauterine growth. The present data suggest that ADA and ACP1 interact during intrauterine life with effects on development and survival and that such effects are dependent on local environment and season of conception. Am. J. Hum. Biol. 12:214-220, 2000. Copyright 2000 Wiley-Liss, Inc.

Health promotion and education in youth correctional facilities.

In 1997 a comprehensive perinatal/pediatric needs assessment was conducted in the two counties comprising the region. As a result, the Regional Perinatal Consortium of Monmouth and Ocean Counties, Inc. submitted both a perinatal and a pediatric plan that addressed the strengths and the needs of the region to the New Jersey Department of Health and Senior Services. One of thirteen pediatric action plans, Pediatric Health Care and Educational Services in Correctional Facilities, set the stage for the start of ongoing and wide-ranging health programs for the youth in one of the county youth detention centers. Beginning with "Alternatives to Violence," Consortium staff have met monthly with the incarcerated youth to plan and provide these much needed sessions. As expected, these sessions have produced many responses from the youth, some anticipated and many pleasantly surprising, as they have begun to recognize the helpful intent and nature of our programs. The youth are encouraged to participate in planning for upcoming programs and their input is appreciated and respected. As many of these teens are parents themselves, this program has also been able to incorporate parenting skills in some of the sessions, with a major focus on child abuse prevention. Health-education services for incarcerated youth open the door to an exciting frontier for pediatric nurses to deliver prevention in this much-needed setting. This program is a model for planning, implementing, and evaluating public health programs in the pediatric arena.

Transanal haemorrhoidal dearterialisation with mucopexy versus stapler haemorrhoidopexy: a randomised trial with long-term follow-up.

INTRODUCTION: The present study aimed to compare the long-term results of transanal haemorrhoidal dearterialisation (THD) with mucopexy and stapler haemorrhoidopexy (SH) in treatment of grade III and IV haemorrhoids. METHODS: One hundred and twenty-four patients with grade III and IV haemorrhoids were randomised to receive THD with mucopexy (n=63) or SH (n=61). A telephone interview with a structured questionnaire was performed at a median follow-up of 42 months. The primary outcome was the occurrence of recurrent prolapse. Patients, investigators and those assessing the outcomes were blinded to group assignment. RESULTS: Recurrence was present in 21 patients (16.9%). It occurred in 16 (25.4%) in the THD group and 5 (8.2%) in the SH group (p=0.021). A second surgical procedure was performed in eight patients (6.4%). Reoperation was open haemorrhoidectomy in seven cases and SH in one case. Five patients out of six in the THD group and both patients in the SH group requiring repeat surgery presented with grade IV haemorrhoids. No significant difference was found between the two groups with respect to symptom control. Patient satisfaction for the procedure was 73.0% after THD and 85.2% after SH (p=0.705). Postoperative pain, return to normal activities and complications were similar. CONCLUSIONS: The recurrence rate after THD with mucopexy is significantly higher than after SH at long-term follow-up although results are similar with respect to symptom control and patient satisfaction. A definite risk of repeat surgery is present when both procedures are performed, especially for grade IV haemorrhoids.

Adaptation to past malarial endemia and susceptibility to common diseases in modern populations: a study of adenosine deaminase and MN blood group genetic polymorphisms.

We carried out a study of adenosine deaminase (ADA) and MN blood group genetic polymorphisms in relation to past malarial morbidity in Sardinia and in relation to susceptibility to allergic asthma (a Th2 disorder) and Crohn's disease (a Th1 disorder) in the population of Rome. Eight hundred and eight schoolchildren, aged 7--14 years from 14 Sardinian villages located in the central area of the island, were considered. One hundred and twenty-two children with allergic asthma and 39 adult patients with Crohn's disease from the population of Rome were also studied. The data suggest an interaction between the two systems concerning resistance/susceptibility, both to malaria and to the diseases considered. In Sardinia, the frequency of the *L(M)/ADA*2 gametic type is negatively correlated with past malarial endemia, suggesting an increased susceptibility to malaria leading to its decrease in areas with high malarial endemia. In Rome, this gametic type is correlated negatively to allergic asthma and positively to Crohn's disease, suggesting a protective effect against allergic asthma and increased susceptibility to Crohn's disease.