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A panel of experts of the Italian Society of Paediatric Endocrinology and Diabetology translated into Italian the international insulin pump therapy recommendations in children and adolescents with type 1 diabetes.After an extensive review of the literature using evidence-based recommendations, several issues were taken into account, such as patient selection, advantages and disadvantages, instrument choice, insulin type, therapy planning and follow-up, emergencies, nutrition, particular occasions (like parties, holidays, sick days, travels), exercise, continuous glucose monitoring and integrated system, neonatal diabetes. The panel evaluated the cost-effectiveness of insulin pump therapy compared to multiple daily injection therapy, analysing the cost-benefit ratio.Some tweak was needed due to the Italian dietetic singularity, meal schedule, climate and lifestyle. Insulin pump therapy in neonatal diabetes is a new issue and no guidelines have been published yet for this age-group. Moreover, legal issues according to the Italian law have been added and are peculiarity of our recommendations. An "informed therapeutic agreement" between the patient and his/her family and the diabetic team has to be signed before starting insulin pump therapy.We think that nowadays the need for clinical guidelines is important and worth the effort that all countries develop faithful adaptation into their local languages taking into account specific contexts and local peculiarities, without making substantial modifications to the original text.

MODY2 is the most prevalent monogenic form of diabetes in Italy with an estimated prevalence of about 0.5-1.5%. MODY2 is potentially indistinguishable from other forms of diabetes, however, its identification impacts on patients' quality of life and healthcare resources. Unfortunately, DNA direct sequencing as diagnostic test is not readily accessible and expensive. In addition current guidelines, aiming to establish when the test should be performed, proved a poor detection rate. Aim of this study is to propose a reliable and easy-to-use tool to identify candidate patients for MODY2 genetic testing. We designed and validated a diagnostic flowchart in the attempt to improve the detection rate and to increase the number of properly requested tests. The flowchart, called 7-iF, consists of 7 binary "yes or no" questions and its unequivocal output is an indication for whether testing or not. We tested the 7-iF to estimate its clinical utility in comparison to the clinical suspicion alone. The 7-iF, in a prospective 2-year study (921 diabetic children) showed a precision of about the 76%. Using retrospective data, the 7-iF showed a precision in identifying MODY2 patients of about 80% compared to the 40% of the clinical suspicion. On the other hand, despite a relatively high number of missing MODY2 patients, the 7-iF would not suggest the test for 90% of the non-MODY2 patients, demonstrating that a wide application of this method might 1) help less experienced clinicians in suspecting MODY2 patients and 2) reducing the number of unnecessary tests. With the 7-iF, a clinician can feel confident of identifying a potential case of MODY2 and suggest the molecular test without fear of wasting time and money. A Qaly-type analysis estimated an increase in the patients' quality of life and savings for the health care system of about 9 million euros per year.

The Milan hypertensive strain of rats (MHS) develops a genetic form of renal hypertension that, when compared to its normotensive control (MNS), shows renal dysfunction similar to that of a subset of human patients with primary hypertension. MHS and MNS were shown to be homozygous by multilocus minisatellite analysis and monolocus microsatellite markers. We show here that one point mutation in each of two genes coding for the membrane skeleton protein adducin is associated with blood pressure in the Milan strain of rats. Adducin is a heterodimer formed by alpha and beta subunits that promotes the assembly of actin with spectrin. MHS and MNS differ, respectively, by the amino acids Y and F at position 316 of the alpha subunit. In the beta-adducin locus, MHS is always homozygous for R at position 529 while in MNS either R or Q occurs in that position. The R/Q heterozygotes showed lower blood pressure than any of the homozygotes. In vitro phosphorylation studies suggest that both of these amino acid substitutions occur within protein kinase recognition sites. Analysis of an F-2 generation demonstrated that Y alleles segregated with a significant increment in blood pressure. This effect is modulated by the presence of the R allele of the beta subunit. Taken together, these findings strongly support a role for adducin polymorphisms in causing variation of blood pressure in the Milan strain of rats.

Helicobacter pylori is an accepted gastroduodenal pathogen and has recently been investigated for possible implications in non gastroenterological diseases such as growth impairment coronary heart disease and diabetes. Infection by cytotoxic, i.e., CagA or VacA positive strains seems more likely to lead to more serious gastroduodenal diseases compared to infection by non cytotoxic strains, but the possible role of CagA or VacA positive strains in non gastroenterological diseases has not been investigated. Aim of the present study was to evaluate the prevalence of Helicobacter pylori infection as well as CagA and VacA positivity in three paediatric populations auxologically normal, hyposomic and diabetic children. Sera from a total of 522 children (auxologically normal: 246, hyposomic: 164, diabetic: 112) were analyzed by a novel Recombinant ImmunoBlot Assay-Strip Immunoblot Assay--RIBA SIA--which contain individual band for whole Helicobacter pylori lysate and recombinant CagA and VacA. The overall seroprevalence of reactivities against Helicobacter pylori lysate, CagA and VacA were: 7.3%, 9.3%, 6.9% vs 11.6%, 7.9%, 8.5% vs 14.3%, 13.4%, 8% (p = NS) in auxologically normal, hyposomic and diabetic children, respectively. Summarizing, we found a similar prevalence of reactivity against both whole Helicobacter pylori lysate as well as recombinant CagA and VacA between auxologically normal, hyposomic and diabetic children. Our data do not support a possible role of Helicobacter pylori in diminished growth in children.

The aim of this study was to evaluate the age of immigrants' children at diagnosis of Type 1 diabetes (T1DM) according to their country of birth. Immigration from developing countries to a westernised area causes rapid changes in the environmental conditions, and we investigated whether the location of birth, either inside or outside Italy, is associated with age at diagnosis of diabetes. Out of a prevalent hospital-based cohort of 5718 T1DM children cared for in 2002 in 47 Italian Pediatric Diabetes Units, we recruited 195 children (M: 97) of immigrants from developing countries--119 were born in Italy and 76 outside the European Union. Children with only one immigrant parent (no. 42) were also included. Age at diagnosis of T1DM, and other variables were compared with those of Italian children. Children of immigrated families born in Italy developed T1DM at a median age of 4.0 yr (IQR 2.2-6.9), whereas those born in developing countries and that had immigrated to Italy after birth developed T1DM at a median age of 7.9 yr (IQR 5.1-10.7, p < 0.001). Among the children born in Italy, 77 had parents who were both immigrants and the children's median age at diagnosis was 3.8 yr (IQR 2.1-6.3); 42 had only one immigrant parent and, when it was the father (no. = 23), median age was even younger (2.9 yr, IQR 2.0-8.2). Ten children had immigrated in their first yr of life and their median age was 9.1 yr (IQR 5.0-10.6). The median age of the Italian children was 6.6 yr (IQR 3.6-9.5). Results show that the outbreak of T1DM is earlier in immigrants' children born in Italy than in original countries.

Many similarities in kidney-function abnormalities were found between hypertensive rats of the Milan strain (MHS) and young normotensive human subjects with hypertensive parents, compared with the appropriate controls. These similarities included an increased glomerular filtration rate, increased pressor effect of the kidney after transplantation, increased 24-h urinary output and lower plasma renin activity and urinary kallikrein. The isolated MHS kidney perfused in vitro with an artificial medium had a higher glomerular filtration rate, a higher urinary output, higher tubular sodium reabsorption and higher oxygen consumption than the kidney of control Milan normotensive rats (MNS). Further, reogenic sodium transport across brush border vesicles isolated from proximal tubular cells is faster in MHS than in MNS. Erythrocytes and proximal tubular cells of MHS have a lower volume and sodium content than those of MNS, while sodium transport is faster and the Ca2+-ATPase at Vmax is lower. This indicates that the 'genetic' cellular abnormality responsible for the renal-function abnormality and the hypertension is also present in erythrocytes. Thus these cells may be used to study the genetic cellular mechanisms of hypertension. Experiments with bone marrow transplantation and with F2 hybrids obtained by crossing the F1 (MHS X MNS) hybrids showed that the MHS erythrocyte abnormalities are genetically determined within the stem cells and are genetically associated with the hypertension. Since, in human hypertensives, there was a correlation between abnormal erythrocyte sodium transport and renal function, it is proposed that erythrocytes may be used in studying the cellular molecular mechanisms of hypertension.

A case of congenital hypopituitarism with microphallus and severe neonatal hypoglycemia is described. The results of the clinical examination and of the tests of hypothalamo-pituitary function are discussed. It is reported that with GH replacement therapy a considerable growth of the penile size was obtained. The importance of evaluating the pituitary function in patients with micropenis and neonatal hypoglycemia is emphasized.

Previous studies have shown that erythrocytes from the Milan hypertensive strain of rats (MHS) differ from erythrocytes from the control normotensive strain (MNS). These differences are determined within the stem cells, are genetically associated with the development of hypertension, and are similar to those found between the tubular cells of the two strains. Moreover they seem to be dependent upon the presence of the membrane skeleton proteins. In this paper we describe our studies aimed at identifying some precise protein difference between the membrane skeletons of the two strains, which may cause the cellular differences described above. Milan hypertensive strain and MNS rats were immunized with ghost or membrane skeleton extracts prepared from the other or their own strains. Only MHS rats immunized with MNS ghost or membrane skeleton extracts produced an antibody against a 105 KD protein in about 95% of the animals. This protein has been identified with the recently described cytoskeletal protein adducin on the following bases: the protein binds calmodulin (CaM) and protein kinase C (PKc) in a Ca2+ dependent way. It also binds phosphatidylserine, is the substrate of exogenous PKc, and finally it is purified by high salt extraction of Triton-X100 insoluble erythrocyte cytoskeletons followed by affinity chromatography on CaM-sepharose. Using this antibody the isolation from a mouse spleen library, the characterization and sequencing of a partial cDNA clone coding for this protein has been carried out. In conclusion adducin may be considered a very useful tool to test the hypothesis that the cellular differences between MHS and MNS may be caused by a difference in a membrane skeleton protein.

We examined 22,233 infants born in Emilia-Romagna (Italy). Capillary blood samples for 17-OH-progesterone assay were collected on the 3rd, 4th, 5th, 6th or 7th day of life on filter paper of the same type used for the screening of aminoacidopathy and hypothyroidism. 17-OH-progesterone values were determined using a micromethod modified from that of Pang and co-workers. 20 pg/disk was considered as a threshold value and called for a second assay, which was performed in 0.18% of the cases. Pathologic values of 17-OH-progesterone were confirmed in the serum of 4 neonates. In our population the incidence of 21-hydroxylase deficiency was found to be 1 out of 5,558 cases.

Since it has become possible to “read the book of life”, different approaches to the universe, revealed by genetic scientific advances, have come into being. On the one hand, the Human Genome Project (HGP) has opened the medical field to new treatments – or at least to the hope of new therapies – through, for instance, gene therapy. On the other hand, developments in genetics have allowed reductionism or genetic essentialism to make its way into the public and institutional perception of genetic advances. This paper will argue that the essentialist approach to genetics is inspired by the constant craving of humans to find, once and for all, those features and determinants that constitute identity: the human nature. I will argue against this trend by testing a particular field in which the concept of human nature could be the source of discrimination and inequalities, that being genetic human nature based law.

The paper deals with the use of predictive genetic tests in medical research. I limit my discussion to those advances in genetics which try to overcome the limits represented by our genetic make-up, in particular by gene mutations that lead, or could lead, to the development of genetic diseases. Besides the ethical issues concerning the topic of the current discussion, the reader will also find an evaluation of the legal provisions elaborated at the different levels of the legal order (international, European, and national). The aim of this evaluation is to find out which model of Law is being adopted in bioethical issues like the one discussed in this paper. The paper underlines and argues how Law can contribute (and has already contributed at the different levels: International, European, and national) to value and to spread an ethics of responsibility.

Nardi L, Zucchini S, D’Alberton F, Salardi S, Maltoni G, Bisacchi N,Elleri D, Cicognani A. Quality of life, psychological adjustment andmetabolic control in youths with type 1 diabetes: a study with self- andparent-report questionnaires.Pediatric Diabetes 2008: 9: 496–503.Objective: To evaluate self and parent reports on quality of life (QoL)and psychological adjustment of youths with type 1 diabetes, incomparison to a general paediatric population, and identify relationshipsbetween disease duration, metabolic control and psychologicalparameters.Research design and methods: Participants included 70 youths with type1 diabetes and their parents. They were compared with 70 non-diabeticsubjects. Data were analyzed in the whole group and in subgroups aged6–10, 11–13 and 14–18 yr. All cases performed pediatric QoL, ChildBehaviour Checklist, filled in by parents, and Youth Self-Report, filled inby youths. Data were compared with haemoglobin A1c (HbA1c) valuesand disease duration.Results: Self-reports showed a psychological adjustment of youths withtype 1 diabetes similar to that of controls. Parent reports showed thatparents of children with type 1 diabetes were more worried than those ofcontrols (p , 0.01). Adolescents showed a worse QoL and more frequentpsychological disturbances. In this group, for youth and parent reports,HbA1c levels correlated positively with psychological problems(p , 0.05) and negatively with QoL (p , 0.05). Only for parent reports,in the whole group and in subgroups aged 6–10 and 11–13 yr, diseaseduration correlated positively with psychological adjustment (p , 0.05).Conclusions: Before adolescence, youths with type 1 diabetes showedonly slight problems in psychological adjustment and QoL, with anassociation with disease duration reported by parents. In adolescence,both youths and their parents reported more emotional and behaviouralproblems, independent of disease duration. Better metabolic control andpsychological well-being seemed directly related.

A cross-sectional study design was undertaken to assess pulmonary function in children with insulin-dependent diabetes mellitus (IDDM), and to establish if there is any relationship with diabetic factors and complications. Thirty-eight children (10 +/- 1.8 years) with IDDM and without clinical or radiological evidence of lung involvement, and 41 healthy age-matched reference subjects, underwent a pulmonary function study. Thirteen (34%) of 38 subjects with IDDM were studied at the onset of their disease. Adjusted values expressed as SD score of forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and the transfer factor for carbon monoxide (TLCO) were found to be significantly lower than in controls (-0.54 +/- 0.87 vs. 0.40 +/- 1.10, P = 0.0008; -0.11 +/- 0.96 vs. 0.52 +/- 1.07, P = 0.01; -1.60 +/- 1.07 vs. -0.57 +/- 1.28, P = 0.001, respectively). These differences also existed in the group investigated at onset of diabetes. Residual volume (RV) and RV/total lung capacity ratio (RV/TLC) were significantly higher in the whole group of patients with IDDM than in controls (-0.20 +/- 0.83 vs. -0.80 +/- 0.88, P = 0.003; and 26 +/- 6.2 vs. 21 +/- 5.0, P = 0.0002, respectively). Seventeen patients (45%) had abnormal pulmonary function (SD score, less than -1.64): 16 subjects had reduced TLCO, 4 had reduced FVC, and in 3 of the 17, both functional indices were abnormal. There was no significant relationship between pulmonary function indices and diabetic factors or complications. The only significant association was between abnormal TLCO and females (P = 0.03), suggesting that sex may be a predisposing factor for the development of pulmonary complications. This study supports the view that the lung is functionally involved in children with IDDM early on in the course of the disease. Copyright 2004 Wiley-Liss, Inc.

Milan hypertensive rats (MHS) develop hypertension because of a primary renal alteration. Both apical and basolateral sodium transport are faster in membrane vesicles derived from renal tubules of MHS than in those of Milan normotensive control rats (MNS). These findings suggest that the increased renal sodium retention and concomitant development of hypertension in MHS may be linked to an altered transepithelial sodium transport. Since this transport is mainly under the control of the Na-K pump, we investigated whether an alteration of the enzymatic activity and/or protein expression of the renal Na,K-ATPase is detectable in prehypertensive MHS. We measured the Na,K-ATPase activity, Rb + occlusion, turnover number, α 1 - and β 1 -subunit protein abundance, and α 1 and β 1 mRNA levels in microsomes from renal outer medulla of young (prehypertensive) and adult (hypertensive) MHS and in age-matched MNS. In both young and adult MHS, the Na,K-ATPase activity was significantly higher because of an enhanced number of active pump sites, as determined by Rb + occlusion maximal binding. The higher number of pump sites was associated with a significant pretranslational increase of α 1 and β 1 mRNA levels that preceded the development of hypertension in MHS. Since a molecular alteration of the cytoskeletal protein adducin is genetically associated with hypertension in MHS and is able to affect the actin-cytoskeleton and Na-K pump activity in transfected renal cells, we propose that the in vivo upregulation of Na-K pump in MHS is primary and linked to a genetic alteration of adducin.

Rats of the Milan Hypertensive Strain (MHS) may be considered a useful model for understanding the genetic molecular mechanism underlying a primary form of hypertension in at least a subgroup of patients. Many differences between MHS and its normotensive control strain (MNS) were found at the organ, cellular and biochemical level. In the present investigation renal cell membrane proteins (BBMV) were analysed by two-dimensional electrophoresis and a difference between MHS and MNS was shown in a polypeptide of 32 kDa, subsequently identified as the C-terminal fragment of aminopeptidase M (APM). The activity of the enzyme was higher in MHS. Genetic relationships between this enzyme and the other biochemical cellular abnormalities of MHS, namely sodium transport in BBMV and renin activity in kidney cortex were investigated in MHS, MNS and in two inbred recombinant strains. This analysis showed that faster sodium transport, low kidney levels of renin and hypertension, but not differences in two-dimensional electrophoretic pattern and in aminopeptidase M activity, cosegregated in recombinant strains. These results are consistent with the hypothesis that the faster sodium transport can be considered a primary cellular abnormality responsible for hypertension in MHS and that the aminopeptidase difference is not involved in the cellular abnormalities.

This paper describes experiments to examine Rb + fluxes via the Na + /K + /Cl − cotransporter in membrane vesicles from renal outer medulla of three strains of rat: (A) Wistar (B) Milan hypertensive (MHS) and normotensive (MNS), and (C) Sabra salt-sensitive hypertensive (SBH) and salt-resistant (SBN). Initially, Na + -dependent furosemide- or bumetanide-inhibited 86 Rb + fluxes were characterised using Wistar rat microsomes. The latter were partially purified on a metrizamide cushion, and assay conditions were optimized for use with microsomes from the other rats. The major result is that in microsomes from adult Milan hypetensive (MHS) rats the rate of the Na + /K + /Cl − -cotransporter mediated 86 Rb flux at sub-saturating concentrations of Rb, appears to be significantly greater than in the normotensive (MNS) controls. The effect reflects an increased apparent Rb affinity of the cotransporter in MHS microsomes. There is no difference in maximal rate or in the apparent Na + activation affinity of the 86 Rb + flux. In addition bumetanide appears to be a somewhat more effective inhibitor in MHS compared to MNS microsomes. The 86 Rb + flux result is compatible with a previous finding that in red cells, Na + /K + -cotransporter mediated fluxes are increased in MHS compared to MNS. It supports the notion that the Na + /K + /Cl − -cotransporter in both red cells and kidney is a genetic marker for hypertension. It is of interest that apparetly more than one Na + transport system is affected in MHS hypertensive kidneys (a) the Na + /K + /Cl − cotransporter i nthe thick ascending limb of Henle and (b) the Na + /H + exchanger and/or a conductive Na + -pathway in brush-border membranes from proximal tubule. It is conceivable that in the hypertensive animals a common regulatory pathway (e.g., phosphorylation) or protein (e.g., cytoskeleton) is affected along the length of the nephron. In Sabra SBH and SBN rat microsomes, no difference was found for the 86 Rb + flux via the Na + /K + /Cl − cotransporter (or via a K + channel).

We studied the activity of plasma membrane (Ca+Mg)ATPase from erythrocytes of Milan hypertensive rat strain (MHS) and Milan low calpastatin rat strain (MLCS), that show an activity level of the specific calpain inhibitor, calpastatin, about five fold reduced in comparison with the Milan normotensive rat strain (MNS), while the protease activity level is similar. This imbalance of calpain:calpastatin ratio leads to a decrease of the erythrocyte plasma membrane (Ca+Mg)ATPase activity and to the appearance of 124 kDa fragments, which are the typical products of proteolytic calpain action on the 136 kDa (Ca+Mg)ATPase native form.