The Journal of Clinical Endocrinology & Metabolism
Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glu... more Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation—beta-cell function, insulin clearance, and insulin sensitivity—in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and <200 mg/dL), referred to as AGT140. Methods A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis–related diabetes CFRD]) was assessed with a general linear model. Results Beta-cell function and insulin sensitivity progressively worse...
The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases,... more The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.
The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric... more The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower (p = 0.060) and a BMI z-score significantly (p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celi...
1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of... more 1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of 1 in 50.000 births. In 2001, the genetic defect of SDS was mapped to the centromeric region of chromosome 7 and in 2003 the defect was narrowed down to a single gene, which was named the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. The mutations in the SBDS gene were identified in 90% of patients. Pancreatic exocrine insufficiency, bone marrow dysfunction with peripheral blood cytopenias, skeletal abnormalities, short stature and immune dysfunction characterize the disorder. Neutropenia plays a crucial role in the occurrence of recurrent and severe infectious complications representing one of the major causes of death in SDS patients. The aim of our study is to better comprehend the marrow dysfunction occurring in SDS patients, by analysing the functional properties of bone marrow (BM)-derived mesenchymal stem cells (MSCs). BM cells obtained from patients and healthy donors (HDs) were...
ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominan... more ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominant manifestations include exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive and susceptibility to short stature. Average birth weight is at the 25th percentile; by the first birthday, >50% of patients drop below the third percentile for height and weight.The study aims at estimating the growth charts for patients affected by SDS in order to give a reference tool helpful for medical care and growth surveillance through the first 8 years of patient’s life.Setting and participantsThis retrospective observational study includes 106 patients (64 M) with available information from birth to 8 years, selected among the 122 patients included in the Italian National Registry of SDS and born between 1975 and 2016. Gender, birth date and auxological parameters at repeated assessment times were collected. The General Add...
Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Sh... more Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15–20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.
Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations... more Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably,...
Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-c... more Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-cell instability. ... Passerini L, Olek S, Di Nunzio S, Federica B, Hambleton S, Abinun M, Tommasini A, Vignola S, Cipolli M, Amendola M, Naldini L, Guidi L, Cecconi M, Roncarolo MG, ...
To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cys... more To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cystic fibrosis (CF). Retrospective cohort study. Single-centre study. From January 1986 to December 2011, 401 infants with CF (69 with MI) presented to our centre. (1) incidence of cholestasis, (2) identification of risk factors for cholestasis, (3) association between the presence of cholestasis and MI and the development of clinically significant CF-associated liver disease (CFLD) defined as multilobular cirrhosis with portal hypertension. Cholestasis occurred in 23 of 401 infants (5.7%). There was a significantly higher incidence of cholestasis in infants with MI (27.1%) compared to those without MI (1.2%) (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Infants with MI had a 30.36-fold increased risk of developing cholestasis compared to those without MI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Cholestasis resolved in all children, at a median (range) age of 9.2 (0.8-53.2) months in the MI group and 10.2 (2.0-19.4) months in the non-MI group. The majority of cholestatic infants (87.0%) and infants with MI (92.8%) did not develop clinically significant CFLD, not significantly different than either the 93.9% of non-cholestatic infants nor the 93.7% infants without MI. Cholestasis is an uncommon condition in CF affecting only 5.7% of the screened newborn CF population. The greatest risk factor for developing cholestasis is the presence of MI. However, the presence of MI appears not to be associated with the development of CFLD. An effect of neonatal cholestasis on the development of CFLD cannot be excluded by this study.
The Journal of Clinical Endocrinology & Metabolism
Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glu... more Objective We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation—beta-cell function, insulin clearance, and insulin sensitivity—in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and <200 mg/dL), referred to as AGT140. Methods A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis–related diabetes CFRD]) was assessed with a general linear model. Results Beta-cell function and insulin sensitivity progressively worse...
The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases,... more The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.
The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric... more The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower (p = 0.060) and a BMI z-score significantly (p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celi...
1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of... more 1336 Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with an incidence of 1 in 50.000 births. In 2001, the genetic defect of SDS was mapped to the centromeric region of chromosome 7 and in 2003 the defect was narrowed down to a single gene, which was named the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. The mutations in the SBDS gene were identified in 90% of patients. Pancreatic exocrine insufficiency, bone marrow dysfunction with peripheral blood cytopenias, skeletal abnormalities, short stature and immune dysfunction characterize the disorder. Neutropenia plays a crucial role in the occurrence of recurrent and severe infectious complications representing one of the major causes of death in SDS patients. The aim of our study is to better comprehend the marrow dysfunction occurring in SDS patients, by analysing the functional properties of bone marrow (BM)-derived mesenchymal stem cells (MSCs). BM cells obtained from patients and healthy donors (HDs) were...
ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominan... more ObjectivesShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominant manifestations include exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive and susceptibility to short stature. Average birth weight is at the 25th percentile; by the first birthday, >50% of patients drop below the third percentile for height and weight.The study aims at estimating the growth charts for patients affected by SDS in order to give a reference tool helpful for medical care and growth surveillance through the first 8 years of patient’s life.Setting and participantsThis retrospective observational study includes 106 patients (64 M) with available information from birth to 8 years, selected among the 122 patients included in the Italian National Registry of SDS and born between 1975 and 2016. Gender, birth date and auxological parameters at repeated assessment times were collected. The General Add...
Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Sh... more Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15–20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.
Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations... more Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably,...
Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-c... more Forkhead box protein 3 (FOXP3) mutations lead to increased T(H)17 cell numbers and regulatory T-cell instability. ... Passerini L, Olek S, Di Nunzio S, Federica B, Hambleton S, Abinun M, Tommasini A, Vignola S, Cipolli M, Amendola M, Naldini L, Guidi L, Cecconi M, Roncarolo MG, ...
To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cys... more To identify the incidence and outcomes of cholestasis and meconium ileus (MI) in infants with cystic fibrosis (CF). Retrospective cohort study. Single-centre study. From January 1986 to December 2011, 401 infants with CF (69 with MI) presented to our centre. (1) incidence of cholestasis, (2) identification of risk factors for cholestasis, (3) association between the presence of cholestasis and MI and the development of clinically significant CF-associated liver disease (CFLD) defined as multilobular cirrhosis with portal hypertension. Cholestasis occurred in 23 of 401 infants (5.7%). There was a significantly higher incidence of cholestasis in infants with MI (27.1%) compared to those without MI (1.2%) (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Infants with MI had a 30.36-fold increased risk of developing cholestasis compared to those without MI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Cholestasis resolved in all children, at a median (range) age of 9.2 (0.8-53.2) months in the MI group and 10.2 (2.0-19.4) months in the non-MI group. The majority of cholestatic infants (87.0%) and infants with MI (92.8%) did not develop clinically significant CFLD, not significantly different than either the 93.9% of non-cholestatic infants nor the 93.7% infants without MI. Cholestasis is an uncommon condition in CF affecting only 5.7% of the screened newborn CF population. The greatest risk factor for developing cholestasis is the presence of MI. However, the presence of MI appears not to be associated with the development of CFLD. An effect of neonatal cholestasis on the development of CFLD cannot be excluded by this study.
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Papers by Marco Cipolli