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Biomedical subjects

Renata Lorini

Publications and source records attributed to Renata Lorini.

At least 19 recordsLinked to original sources
PubMed2006

Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities.

CONTEXT: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and/or optic nerve abnormalities. OBJECTIVE: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome. MAIN OUTCOME MEASURES: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured. RESULTS: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2Tb > C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity. CONCLUSIONS: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.

Cells, Cultured↗
PubMed2006

Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies.

CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.

Body Height↗
PubMed2006

Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity.

OBJECTIVES: Autoimmune targeting of hypothalamic-neurohypophyseal structures in children and young adults with posterior pituitary and anterior pituitary dysfunction, as well as pituitary stalk involvement, are not yet completely understood. DESIGN: We aimed to (1) evaluate the presence of circulating vasopressin-cell autoantibodies (AVPc-Abs) in young patients with central diabetes insipidus (CDI), (2) detect organ-specific autoantibodies as markers of autoimmunity, and (3) define the relationship between immune markers and neuroimaging findings. PATIENTS: Twenty patients were evaluated at a median age of 16.3 years. Twelve patients had idiopathic CDI, six had Langerhans cell histiocytosis (LCH) and two had germinoma. AVPc-Abs were evaluated in 40 healthy children. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was performed longitudinally in all subjects. MEASUREMENTS: Circulating arginine vasopressin (AVP), protein tyrosine phosphatase (IA2), glutamic acid decarboxylase (GAD), 21-hydroxylase (21-OH), endomysium antibodies (EMA), parietal cell (PCA), thyroid peroxidase (TPO), thyroglobulin (TG) and TSH-receptor (TSHr) autoantibodies were evaluated. RESULTS: Circulating AVPc-Abs were found in 15 patients (75%), nine with idiopathic CDI, four with LCH and two with germinoma; the pituitary stalk was involved in most of them. Five patients with idiopathic CDI showed a persistence of AVPc-Abs during follow-up and one became positive subsequently. Serum IA2 autoantibodies were demonstrated in 14 patients (70%) and 21-OH autoantibodies in three of them. CONCLUSION: In idiopathic CDI, circulating AVPc-Abs suggest an autoimmune involvement of the neurohypophyseal system. The identification of AVPc-Abs in subjects who could have either idiopathic CDI or LCH or germinoma, however, indicates that AVPc-Abs cannot be considered a completely reliable marker of autoimmune CDI. Thus, close clinical and MRI follow-up are needed because AVPc-Abs may mask germinoma or LCH.

Adolescent↗
PubMed2006

Blood ketone bodies in patients with recent-onset type 1 diabetes (a multicenter study).

BACKGROUND: Insulin deficiency with glucagon excess leads to the release of ketone bodies (KBs) by the liver and excretion in the urine. So far, only KB monitoring in urine has been used during assessment of children with diabetes. Currently used nitroprusside strips for urine KB detection react only with acetoacetate (AcAc) and not with the most prevalent KB moiety - 3beta-hydroxybutyrate (3HB) - that is in equilibrium with AcAc (up to 10:1 ratio). AIM: To verify the significance of 3HB in the blood compared to that of AcAc in the urine in recently diagnosed type 1 diabetic subjects independent of the presence of diabetic ketoacidosis (DKA). METHODS: A total of 118 consecutive newly diagnosed subjects with type 1 diabetes from different centers in Italy underwent intensive insulin therapy and hydration when necessary (38/118 = 32% with DKA). Hourly urine and capillary blood samples were used to monitor KBs until metabolic control was achieved. RESULTS: Although DKA was present in 32% of patients, blood 3HB was significantly increased (3.56 +/- 1.7 mmol/L) in 83% of the patients and correlated with blood glucose (r = 0.39; p < 0.01) according to a bimodal model. The strongest association was found between 3HB and venous pH (r =-0.56; p < 0.0001). Time required for blood 3HB normalization depended strongly on the starting blood KB values (r = 0.44; p < 0.0001) and was significantly lower than that required for disappearance of KB from urine (17.4 +/- 13.6 h, range 1-69 h vs. 19.7 +/- 17.8 h, range 1-120 h; p = 0.004). However, urine KBs disappeared before blood 3HB normalization in 23% of the patients. CONCLUSIONS: Blood 3HB evaluation is a better indicator of metabolic control compared to urine KB detection and is useful to predict the time required for blood KB clearing. Further studies are needed to assess its use in the early detection and management of DKA.

3-Hydroxybutyric Acid↗
PubMed2006

Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects.

Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive K(+) channel (K(ATP) channel), are a common cause of neonatal diabetes. We identified a novel KCNJ11 mutation, R50Q, that causes permanent neonatal diabetes (PNDM) without neurological problems. We investigated the functional effects this mutation and another at the same residue (R50P) that led to PNDM in association with developmental delay. Wild-type or mutant Kir6.2/SUR1 channels were examined by heterologous expression in Xenopus oocytes. Both mutations increased resting whole-cell currents through homomeric and heterozygous K(ATP) channels by reducing channel inhibition by ATP, an effect that was larger in the presence of Mg(2+). However the magnitude of the reduction in ATP sensitivity (and the increase in the whole-cell current) was substantially larger for the R50P mutation. This is consistent with the more severe phenotype. Single-R50P channel kinetics (in the absence of ATP) did not differ from wild type, indicating that the mutation primarily affects ATP binding and/or transduction. This supports the idea that R50 lies in the ATP-binding site of Kir6.2. The sulfonylurea tolbutamide blocked heterozygous R50Q (89%) and R50P (84%) channels only slightly less than wild-type channels (98%), suggesting that sulfonylurea therapy may be of benefit for patients with either mutation.

Adenosine Triphosphate↗
PubMed2005

Matrix metalloproteinase 2 may be a marker of microangiopathy in children and adolescents with type 1 diabetes mellitus.

Matrix metalloproteinases (MMPs) 2 and 9 are responsible for extracellular matrix breakdown and their abnormal circulating levels may pre-date clinical evidence of diabetic angiopathy. We detected by ELISA, plasma MMP-2 and MMP-9 levels and associated activity in 25 children and adolescents with T1DM. Thirteen male and 12 female patients were evaluated at the clinical diagnosis and onset of T1DM and again at a 5-year follow-up. Twelve patients had developed microangiopathic complications at the follow-up evaluation. MMP-2 and MMP-9 levels and activity were detected in samples obtained at T1DM diagnosis and at the 5-year follow-up. As controls, 19 healthy subjects who were the same age as the patients were also evaluated at baseline and again after 5 years. MMP-2 levels and activity were significantly higher in the patients than in the controls at disease onset. This was particularly evident when patients who developed microangiopathic complications were compared to controls and patients without complications. At the 5-year follow-up, a significant increase in MMP-2 levels and a significant decrease in MMP-2 activity were found only in the control group compared to the baseline levels. MMP-2 levels and activity were higher in patients with microangiopathy. MMP-9 levels and activity were increased in all groups compared to baseline levels. MMP-9 levels were lower in patients with microangiopathy compared to controls, but no difference was found between the two patient groups. It is well known that MMP-9 is an index of the severity and stability of macroangiopathy while our results allow us to postulate that MMP-2 may be a marker of microangiopathy.

Adolescent↗
PubMed2005

Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2005

KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.

DNA Mutational Analysis↗
PubMed2005

Antimicrobial use and Pseudomonas aeruginosa susceptibility profile in a cystic fibrosis centre.

The susceptibility patterns of 1315 mucoid and non-mucoid Pseudomonas aeruginosa strains from 224 patients were determined along with antibiotic utilisation in a Cystic Fibrosis Centre from 1993 to 1997. Ceftazidime was the most active agent (86.0% sensitive isolates), followed by piperacillin-tazobactam (81.7%), aztreonam (80.3%), imipenem (80%), piperacillin (76.8%), tobramycin (76.5%), ciprofloxacin (73.7%), ticarcillin (72.4%), ticarcillin-clavulanic acid (70.2%), amikacin (69.5%), netilmicin (56.5%), meropenem (79%) and imipenem (75.5%). The most frequently used compounds were nebulized colistin (mean+/-S.D., 109+/-45 defined daily doses per 1000 patients per day), followed by ciprofloxacin (98+/-8), tobramycin (55+/-9), ceftazidime (31+/-8) and amikacin (55+/-9). The mean antibiotic consumption by our CF patients was 413+/-47 defined daily doses per 1000 patients per day. Trend testing showed a significant decline of susceptibility to aminoglycosides, imipenem and ciprofloxacin, while the susceptibility of P. aeruginosa to piperacillin and ceftazidime was stable.

Adolescent↗
PubMed2005

Beta-cell autoantibodies and diabetes mellitus family history in cystic fibrosis.

OBJECTIVE: To verify whether autoimmunity against beta-cells and family history of type 1 and/or type 2 diabetes mellitus (DM) play a role in the pathogenesis of cystic fibrosis (CF)-related diabetes mellitus (CFRD). PATIENTS AND METHODS: The prevalence of beta-cell autoantibodies (GADA and IA-2A) was investigated in a group of patients with CF compared with patients with type 1 DM (DM1) and controls. Family history of DM1 and/or DM2 was investigated among patients with CF. RESULTS: Frequency of beta-cell autoantibodies was significantly lower (p = 0.0001) in patients with CF with CFRD (IA-2A: 0%; GADA 12.5%) than in patients with DM1 (64.1% vs 52.8%, respectively) and it did not differ from the frequency in patients with CF without CFRD. Prevalence of family history for DM1 or DM2 was not significantly higher in CF patients with CFRD than in CF patients without CFRD. CONCLUSIONS: The investigated factors did not show correlation with the pathogenesis of CFRD.

Adolescent↗
PubMed2004

Epidemiology and clinical course of Burkholderia cepacia complex infections, particularly those caused by different Burkholderia cenocepacia strains, among patients attending an Italian Cystic Fibrosis Center.

In this study, the epidemiology of Burkholderia cepacia complex (Bcc) recovered from the sputum of 75 patients attending the Genoa Cystic Fibrosis (CF) Center at the Gaslini Children's Hospital (Genoa, Italy) was investigated, and the clinical course of the CF patients infected with the different species and genomovars of Bcc was evaluated. All isolates were analyzed for genomovar status by recA gene polymorphism and subsequently random amplified polymorphic DNA fingerprinting. Burkholderia cenocepacia is the predominant species recovered from the CF patients infected with Bcc at the Genoa CF Center. Of the other eight species comprising the Bcc, only a few isolates belonging to B. cepacia genomovar I, Burkholderia stabilis, and Burkholderia pyrrocinia were found. Of the four recA lineages of B. cenocepacia, most patients were infected by epidemic strains belonging to lineages IIIA and IIID, whereas only a few patients harbored IIIB strains. Patient-to-patient spread of Bcc among CF patients was mostly associated with B. cenocepacia, in particular with strains belonging to recA lineages IIIA and IIID. The mortality of CF patients infected with Bcc at the Genoa CF Center was significantly higher than mortality among CF patients not infected with Bcc. All of the deaths were associated with the presence of B. cenocepacia, except the case of a patient infected with B. cepacia genomovar I. Within B. cenocepacia, infection with epidemic strains belonging to lineages IIIA and IIID was associated with higher rates of mortality than was infection with lineage IIIB strains. No significant differences in lung function, body weight, and mortality rate were observed between patients infected with epidemic strains belonging to either B. cenocepacia IIIA or B. cenocepacia IIID.

Adolescent↗
PubMed2004

Diabetes incidence in 0- to 14-year age-group in Italy: a 10-year prospective study.

OBJECTIVE: The Registry for Type 1 Diabetes Mellitus in Italy (RIDI) Study Group was established to coordinate the registries of type 1 diabetes in Italy. This report is based on 3,606 children younger than 15 years diagnosed with type 1 diabetes and prospectively registered during 1990-1999 by nine centers, covering >35% of the Italian population. RESEARCH DESIGN AND METHODS: Registries were pooled in four geographic macro-areas: north, central, south, and insular. The completeness of registration was assessed by the capture-recapture method. Poisson regression analysis was used to evaluate temporal trend in incidence. RESULTS: Large variations in incidence were confirmed not only between Sardegna and the mainland but also among peninsular areas. In Sardegna, there was an excess of boys (the boy-to-girl incidence ratio was 1.4). The overall incidence showed average increases of 3.6% (P <0.001) and 3.7% (P <0.001) per year in peninsular Italy and in Sardegna, respectively. Significant increases in incidence rates were found in boys aged 10-14 years (6.7%, 95% CI 0.5-13.3) and in girls aged 5-9 years (6.6%, 0.5-13.1) living in the southern area. The incidence rate also increased in boys aged 10-14 years (5.0%, 0.3-10) and in girls aged 0-4 years (4.9%, 0.8-9.1) living in Sardegna. CONCLUSIONS: Italy is a country with large geographical variations in incidence rates of type 1 diabetes. However, the rates are evenly increasing both in the mainland and Sardegna, suggesting that similar environmental factors are operating over populations that have different genetic backgrounds.

Adolescent↗
PubMed2004

Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study.

OBJECTIVE: To estimate the prevalence of biopsy-confirmed celiac disease in Italian children and adolescents with type 1 diabetes and to assess whether age at onset of type 1 diabetes is independently associated with diagnosis of celiac disease. RESEARCH DESIGN AND METHODS: The study group was a clinic-based cohort of children and adolescents with type 1 diabetes cared for in 25 Italian centers for childhood diabetes. Yearly screening for celiac disease was performed using IgA/IgG anti-gliadin and IgA anti-endomysium antibodies. RESULTS: Of the 4,322 children and adolescents (age 11.8 +/- 4.2 years) identified with type 1 diabetes, biopsy-confirmed celiac disease was diagnosed in 292 (prevalence 6.8%, 95% confidence interval [CI] 6.0-7.6), with a higher risk seen in girls than in boys (odds ratio [OR] 1.93, 1.51-2.47). In 89% of these, diabetes was diagnosed before celiac disease. In logistic regression analyses, being younger at onset of diabetes, being female, and having a diagnosis of a thyroid disorder were independently associated with the risk of having diabetes and celiac disease. In comparison with subjects who were older than 9 years at onset of diabetes, subjects who were younger than 4 years at onset had an OR of 3.27 (2.20-4.85). CONCLUSIONS: We have provided evidence that 1) the prevalence of biopsy-confirmed celiac disease in children and adolescents with type 1 diabetes is high (6.8%); 2) the risk of having both diseases is threefold higher in children diagnosed with type 1 diabetes at age <4 years than in those age >9 years; and 3) girls have a higher risk of having both diseases than boys.

Adolescent↗