Galactosemia type 1 is an autosomal recessive disorder of galactose metabolism, determined by a deficiency in the enzyme galactose‐1‐phosphate uridyltransferase (GALT). GALT deficiency is classified ...as severe or variant depending on biochemical phenotype, genotype and potential to develop acute and long‐term complications. Neonatal symptoms usually resolve after galactose‐restricted diet; however, some patients, despite the diet, can develop long‐term complications, in particular when the GALT enzyme activity results absent or severely decreased. The mechanisms of acute and long‐term complications are still discussed and several hypotheses are presented in the literature like enzymatic inhibition, osmotic stress, endoplasmic reticulum stress, oxidative stress, defects of glycosylation or epigenetic modification. This review summarizes the current knowledge of galactosemia, in particular the putative mechanisms of neonatal and long‐term complications and the molecular genetics of GALT deficiency.
Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5–7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of ...dystrophin, probably because of skewed patterns of X‐chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non‐manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation‐based assay. The results showed that DMD‐manifesting carriers had a preferential inactivation of the X‐chromosome carrying the normal allele, while non‐manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother–daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non‐random patterns of X inactivation.
Abstract The aim of the present study was to evaluate the production of superoxide anion (O2− ) in the trigeminal complex nuclei after a functional mechanical overload of the teeth due to the ...preference for masticating on one side in rats. The preference for masticating on one side was induced by the discomfort due to a small abrasion of one molar; such lateralisation in mastication was confirmed by electromyography. The production of O2− was evaluated in the trigeminal nuclei by fluorescence microscopy after an injection of dihydroethidium. The results showed that there was an increased production of O2− in the subnucleus oralis of the spinal trigeminal nucleus in the same side where the mastication was preferred. This result demonstrates that an increased activity of non-painful sensory neurons can enhance the production of reactive oxygen species within the central second order sensory nuclei.
Highlights ► EDCs mimic hormone function inducing diseases in exposed organisms. ► The effects of some EDCs of phenolic origin has been assessed in vitro. ► The effects on cell proliferation and ...differentiation were studied. ► The oestrogenic ranking between the used endocrine disruptors have been established.
Classical galactosemia is an autosomal recessive inborn error of metabolism due to mutations of the GALT gene leading to toxic accumulation of galactose and derived metabolites. With the benefit of ...early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. However, despite early diagnosis and treatment, the long term outcome for these patients is still unpredictable because they may go on to develop cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30years.
No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications.
A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of <1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype–phenotype correlation in classical galactosemia and underlines the importance of molecular diagnostic testing prior to making any treatment.
Three-dimensional model of the dimeric GALT enzyme. The two chains A and B forming the dimer are colored in green and cyan, respectively. Secondary structures of the enzyme are represented as springs (for helices) and ribbons (for strands). The residues for each monomer affected by the six novel mutations described in this article (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, E271D) are shown in CPK mode and labeled. Display omitted
•Mutational spectrum of galactosemic patients from Northeast Italy was investigated.•A total of 18 different variations on GALT gene were found in the patients.•Six new missense variations were identified in the patients.•In silico analysis showed a potentially damaging effect of the new variations.•Biochemical analysis showed GALT activity <1% in patients with new variations.
This experiment tested the effect of a lesion of cerebral catecholaminergic neurons on the sympathetic and thermogenic effects induced by an intracerebroventicular (icv) injection of orexin A. The ...firing rates of the sympathetic nerves to the interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague–Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 150 min after the injection. Three days before the experiment, the rats were pre-treated with an icv injection of 6-hydroxydopamine (6-OHDA) or 6-OHDA plus desipramine or saline. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate in the rats pre-treated with saline. This increase is blocked by the pre-treatment with 6-OHDA alone or 6-OHDA plus desipramine. These findings indicate that cerebral catecholaminergic neurons (particularly the dopaminergic pathway) play a fundamental role in the complex reactions related to activation of the orexinergic system.
Since no experiment regarding a possible relation between quetiapine and orexin A has been reported in international literature, this experiment tested the effect of quetiapine on the sympathetic and ...thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5
nmol) into the lateral cerebral ventricle and over a period of 150
min after the injection. The same variables were monitored in rats with an intraperitoneal administration of quetiapine (5 or 10
mg/kg bw), injected 30
min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is delayed or reduced by the injection of quetiapine. These findings indicate that quetiapine affects the complex reactions related to activation of orexinergic system. Possible influences on the control of body weight and temperature are discussed.
Bisphenol A (BPA) is an endocrine disruptor (ED) that is abundant in the environment because of its extensive use in human-manufactured products. In this study, the BPA concentration was measured in ...the muscle and liver of five edible fish, characterized by different habitat and habits, caught in two different sites of the Tyrrhenian Sea (Italy). Our results show that: (i) fish livers are about 2.5 times more polluted than muscle; (ii) fish caught in the Gulf of Naples are more polluted than those from the Latium coasts, ranging from 1.2-fold more for White Bream to 6.6-fold for Grey Mullet; and (iii) the percentages of fish found to be BPA-polluted in the Gulf of Naples ranged from 73% (for Bass) to 90% (for Mullet), while the Latium fish range from 60% (for Bass) to 90% (for Mullet). These data indicate that consumers of fish caught in the Gulf of Naples are at a greater risk for BPA-induced endocrine pathologies compared to those who consume fish caught along the Latium coasts.
This experiment tested the involvement of the ventromedial hypothalamus (VMH) in the sympathetic and hyperthermic reactions induced by an intracerebroventricular (i.c.v.) injection of orexin A (1.5 ...nmol). In the first part of the experiment, the firing rate and cytochrome oxidase activity of the VMH neurons, and the colonic temperature were monitored in 12 urethane‐anaesthetized rats before an i.c.v. injection of orexin and over a period of 2 h after the injection. Orexin induced an increase in the firing rate, colonic temperature and cytochrome oxidase activity. A group of 12 rats was used as a control: saline, but not orexin, was injected. No modifications in the firing rate, cytochrome oxidase reactivity and colonic temperature were noted. In the second part of the experiment, 12 rats were anaesthetized and lesioned bilaterally in the VMH with an injection of ibotenic acid. Sham lesions were carried out in 12 control rats. After 48 h, all animals were anaesthetized with ethyl‐urethane. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures and heart rate were monitored before and over a period of 2 h after an i.c.v. injection of orexin or saline in the lesioned and sham‐lesioned rats. Orexin increased the sympathetic firing rate, IBAT and colonic temperatures and heart rate in the sham‐lesioned rats. These increases were reduced by lesion of VMH. Saline did not induce any modification. These findings indicate that the VMH is involved in the control of the orexin‐induced hyperthermia.
Since experiments regarding a possible relation between olanzapine and orexin A has been scarcely reported in international literature, this experiment tested the effect of olanzapine on the ...sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague–Dawley rats before an injection of orexin A (1.5
nmol) into the lateral cerebral ventricle and over a period of 150
min after the injection. The same variables were monitored in rats with an intraperitoneal administration of olanzapine (10
mg/kg bw), injected 30
min before the orexin administration
. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is blocked by the injection of olanzapine. These findings indicate that olanzapine affects the complex reactions related to activation of orexinergic system.
