26 research outputs found
Salivary PYY: A Putative Bypass to Satiety
Peptide YY3-36 is a satiation hormone released postprandially into the bloodstream from L-endocrine cells in the gut epithelia. In the current report, we demonstrate PYY3-36 is also present in murine as well as in human saliva. In mice, salivary PYY3-36 derives from plasma and is also synthesized in the taste cells in taste buds of the tongue. Moreover, the cognate receptor Y2R is abundantly expressed in the basal layer of the progenitor cells of the tongue epithelia and von Ebner's gland. The acute augmentation of salivary PYY3-36 induced stronger satiation as demonstrated in feeding behavioral studies. The effect is mediated through the activation of the specific Y2 receptor expressed in the lingual epithelial cells. In a long-term study involving diet-induced obese (DIO) mice, a sustained increase in PYY3-36 was achieved using viral vector-mediated gene delivery targeting salivary glands. The chronic increase in salivary PYY3-36 resulted in a significant long-term reduction in food intake (FI) and body weight (BW). Thus this study provides evidence for new functions of the previously characterized gut peptide PYY3-36 suggesting a potential simple and efficient alternative therapeutic approach for the treatment of obesity
PROP1 gene mutations and pituitary size: A unique case of two consecutive cycles of enlargement and regression
Background: Pituitary enlargement, which can regress with time, has been
described in a number of PROP1-deficient patients. We report a
PROP1-deficient patient with a unique variation in pituitary size. Case
Description: A 4-year-old boy was first examined in 1989 for short
stature (- 2.3 standard deviation score). Growth hormone (GH)
insufficiency was confirmed, and human GH (hGH) therapy was initiated
and administered up to the age of 18.2 years. Levothyroxine was added 6
months after hGH initiation. Pituitary magnetic resonance imaging (MRI)
obtained when the patient was 5 years old showed an enlarged pituitary
gland, which grew larger by the age of 8.5 years and then regressed to
normal size by the time the patient was 9.8 years old. MRI when the
patient was 19 years old disclosed pituitary reenlargement, and another
3 years later indicated regression. On DNA analysis, the patient was
found to be homozygous for the mutation 301-302 Delta GA of the PROP1
gene. When the patient was 18.8 years old and asymptomatic, an impaired
cortisol response to glucagon was detected. Conclusions: Regression of
the pituitary enlargement in PROP1-deficient patients does not seem to
constitute an end stage with respect to pituitary pathology. Further
changes in pituitary morphology and size can be expected; therefore,
long-term followup with pituitary MRI is advised. Copyright (c) 2007 S.
Karger AG, Basel
Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes
Context: Holoprosencephaly (HPE) is a developmental defect characterized
by wide phenotypic variability, ranging from minor midline malformations
(eg, single central incisor) to severe deformities. In 10-15% of HPE
patients, mutations in specific genes have been identified (eg, SHH,
TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a
distinct abnormality of unknown pathogenesis, whereas isolated pituitary
hypoplasia (IPH) has been linked to various developmental genes.
Objective: Three of our patients with PSIS had a single central incisor,
a malformation encountered in some HPE cases. Based on this observation,
we initiated a search for mutations in HPE-associated genes in 30
patients with PSIS or IPH.
Design and Participants: The entire coding region of the TGIF, SHH, and
SIX3 genes was sequenced in patients with combined pituitary hormone
deficiency associated with either PSIS or IPH and in healthy controls.
Results: Two novel mutations in the HPE-related genes were detected (ie,
c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH
gene) in 2 of our patients. The overall incidence of HPE-related gene
mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No
molecular defect in the SIX3 gene was detected in our cohort.
Conclusions: The data suggest that HPE-related gene mutations are
implicated in the etiology of isolated pituitary defects (PSIS or IPH).
Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE
spectrum. (J Clin Endocrinol Metab 98: E779-E784, 2013
Non-inferiority of liquid thyroxine in comparison to tablets formulation in the treatment of children with congenital hypothyroidism
Objectives The aim of the current prospective randomized control study
was to assess efficacy, safety, and non-inferiority of a new liquid
L-thyroxine formulation dissolved in glycerol and water (T4(R) drops,
produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece)
in comparison to the standard Tablets form (T4(R) tablets, Uni-Pharma,
Athens, Greece) in the substitutive treatment of children with
congenital hypothyroidism (CH). Methods Thirty-nine children with CH,
aged 3-12 years old, were enrolled in the study, after parental Informed
Consent has been obtained, while three patients were lost from
follow-up. At baseline, all participants had normal thyroid-stimulating
hormone (TSH) and Free T4 values. Patients were randomly subdivided
according to the assigned treatment in Group A (n=17)-Tablet Form and
Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0,
2, 4, and 6 months. Results TSH values showed a statistically
significant difference (p=0.017) between groups only at six months
(Group A having higher TSH levels than Group B, albeit within the normal
range), while Free T4 levels had no statistical difference throughout
the six month study period and were always within the normal range.
Moreover, dose adjustments were more frequent in Group A (p=0.038)
during the six months. Liquid L-thyroxine substitutive treatment
exhibited no statistically significant adverse effects in comparison to
the widely used tablets. Conclusions Levothyroxine (LT4) as liquid
solution formulation is safe and noninferior to the widely used
L-thyroxine Tablets, with less need for dose adjustment, and can
therefore be safely used in the treatment of children with CH
Long-term clinical data and molecular defects in the STAR gene in five Greek patients
Context: Steroidogenic acute regulatory (STAR) gene mutations lead to
adrenal and gonadal failure. Interesting, though as yet unexplained,
features are the formation of ovarian cysts and the potential presence
of CNS findings.
Objective: To report biochemical, genetic, and long-term clinical data
in five Greek patients from four different families with STAR gene
defects (three 46, XX and two 46, XY).
Methods and results: All patients presented in early infancy with
adrenal insufficiency. The STAR gene mutation c.834del11bp, detected in
three of our patients, completely alters the carboxyl end of the STAR
protein and has not thus far been described in other population groups.
These three patients belong to three separate families, possibly
genetically related, as they live in different villages located in a
small region of a Greek island. However, their interrelationship has not
been proven. A second mutation, p.W250X, detected in our fourth family,
was previously described only in two Serbian patients. Ovarian cysts
were detected ultrasonographically in our 46, XX patients and seemed to
respond to a low dose of a contraceptive. The histology of an excised
ovarian cyst was diagnosed as a corpus luteum (CL) cyst. In two out of
the four patients who had undergone brain magnetic resonance imaging,
asymptomatic Chiari-1 malformation was observed.
Conclusions: The occurrence of STAR gene mutation c.834del11bp in three
families living in a restricted geographic region could indicate either
a founder effect or simply reflect a spread of this defect in a highly
related population. The ovarian histological findings suggest that
ovarian cysts detected ultrasonographically in 46, XX individuals with
STAR gene defects may be CL cysts. The Chiari-1 malformation in two of
our patients may be part of the STAR gene mutation phenotype.
Nevertheless, more data are needed to confirm or disprove the existence
of specific CNS pathology in patients with STAR gene mutations. European
Journal of Endocrinology 168 351-35
Adeno-Associated Virus Type 12 (AAV12): a Novel AAV Serotype with Sialic Acid- and Heparan Sulfate Proteoglycan-Independent Transduction Activity▿
Recombinant adeno-associated virus (rAAV) is a promising vector for gene therapy. Recent isolations of novel AAV serotypes have led to significant advances by broadening the tropism and increasing the efficiency of gene transfer to the desired target cell. However, a major concern that remains is the strong preexisting immune responses to several vectors. In this paper, we describe the isolation and characterization of AAV12, an AAV serotype with unique biological and immunological properties. In contrast to those of all other reported AAVs, AAV12 cell attachment and transduction do not require cell surface sialic acids or heparan sulfate proteoglycans. Furthermore, rAAV12 is resistant to neutralization by circulating antibodies from human serum. The feasibility of rAAV12 as a vector was demonstrated in a mouse model in which muscle and salivary glands were transduced. These characteristics make rAAV12 an interesting candidate for gene transfer applications
Glucose dysregulation in obese children: Predictive, risk, and potential protective factors
Objective: The aim of our study was to determine the prevalence of
impaired glucose tolerance (IGT) and type 2 diabetes (DM2) in obese
children and adolescents of Greek origin and compare our data with
pertinent literature findings in an attempt to uncover predictive, risk,
and preventive factors.
Research Methods and Procedures: A total of 117 obese children and
adolescents 12.1 +/- 2.7 years old underwent a 2-hour oral glucose
tolerance test (OGTT). Insulin resistance (IR) and beta-cell function
were estimated using the homeostasis model assessment (HOMA)-IR and the
insulinogenic index, respectively.
Results: A total of 17 patients (14.5%) had IGT, and none had DM2. The
overall prevalence rates of both IGT and DM2 in our subjects were lower
than those reported in a recent multiethnic U.S. study. Nevertheless,
the difference between our IGT data and those of the U.S. study was due
mostly to the prepubertal subjects (9% vs. 25.4%), whereas no
difference was observed in the pubertal population (18% vs. 21%).
Fasting glucose, insulin, and HOMA-IR values were not predictive of IGT.
The absolute value of insulin at 2 hours of the OGTT combined with the
time-integrated glycemia (AUCG) can strongly predict IGT, whereas higher
area under the curve for insulin (AUCI) values were found to be
protective.
Discussion: In ethnic groups less prone to diabetes development, IGT or
DM2 in obese subjects is more likely to develop at puberty than at the
prepubertal stage. It is advisable that physicians caring for obese
adolescents perform an OGTT for early detection of IGT because HOMA-IR
values, although higher in IGT subjects and indicative of IR, cannot
predict IGT
Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and increased retinol binding protein 4 in a patient with chronic graft-versus-host disease post bone marrow transplantation
Livadas S, Voutetakis A, Bourhis J-C, Maratou E, Dimitriadis G, Margeli
A, Chandrinou H, Goussetis E, Papassotiriou I, Dacou-Voutetakis C.
Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and
increased retinol binding protein 4 in a patient with chronic
graft-versus-host disease post bone marrow transplantation. ?Pediatr
Transplantation 2011. (c) 2011 John Wiley & Sons A/S. Abstract:
Hyperinsulinemia with or without DM2 is a frequent long-term sequela of
BMT, especially following cGvHD. In this report, an extensive evaluation
of a patient with cGvHD is described: glucose and insulin during OGTT,
markers of inflammation, adiponectin and RBP4, body composition
analysis, and the kinetics of GLUT3 and GLUT4 in circulating monocytes
were evaluated. Hyperinsulinemia, associated with partial lipodystrophy,
elevated RBP4, low adiponectin levels, and decreased expression of GLUT3
and GLUT4 were detected. The defects disclosed in this particular
patient possibly explain, at least in part, the mechanisms underlying
insulin resistance in patients undergoing BMT. It is not clear whether
insulin resistance was caused by the drugs, the process itself, or the
residual damage to the muscles and/or adipose tissue
Elevated coagulation and inflammatory markers in adolescents with a history of premature adrenarche
Females with a history of premature adrenarche are at high risk of
developing polycystic ovary syndrome (PCOS) and features of the
metabolic syndrome later in life. Coagulation disorders, subclinical
inflammation, and oxidative stress have been reported in patients with
PCOS and metabolic syndrome. These factors were studied in a group of
adolescents with a history of premature adrenarche. This is a
cross-sectional study that determined the biochemical-hormonal profile
and indices of inflammation, coagulation, and oxidative stress in 45
adolescent girls with a history of premature adrenarche and 19 age- and
body mass index-matched controls. Girls with premature adrenarche had
hyperandrogenism and higher indices of insulin resistance than controls.
They also had significantly higher C-reactive protein (0.76 +/- 0.65 vs
0.41 +/- 0.31 mg/L, P =.0001) and plasminogen activator inhibitor 1
(37.6 +/- 24.7 vs 24.47 +/- 4.6 ng/mL, P = .034), and lower tissue
plasminogen activator values in comparison with controls (3.5 +/- 1.5 vs
5.2 +/- 2.12 ng/mL, P = .0019). Both C-reactive protein(r = 0.545, P
=.0001) and plasminogen activator inhibitor I (r = 0.36, P =.04) were
positively correlated with oxidative stress, whereas tissue plasminogen
activator was positively correlated (r = 0.37, P.02) with total
antioxidant status. None of these factors was correlated with androgens
or indices of insulin resistance. Adolescent girls with a history of
premature adrenarche display metabolic deviations usually encountered in
Subjects with PCOS and metabolic syndrome, such as subclinical
inflammation and fibrinolytic abnormalities. Crown Copyright (C) 2009
Published by Elsevier Inc. All rights reserved
Advances in vector-mediated gene transfer
Clinical applications of gene transfer technology initially targeted the treatment of inherited monogenetic disorders and cancers refractory to conventional therapies. Today, gene transfer approaches are being developed for most tissues and for multiple disorders including those affecting quality of life. The focus herein is eventual application of gene transfer technology for the management of organ-directed autoimmunity. A specific example is presented: Sjögren's syndrome and localized salivary gland gene transfer. The status of relevant pre-clinical gene transfer studies is reviewed, with an emphasis on use of adenoviral and adeno-associated viral vectors. Current limitations of effective organ-directed gene transfer are also discussed