Solution studies, synthesis and antibacterial activity of Ga(III) complexes with bis-kojate derivatives.

Given the recognized major problem of microbial drug resistance for human health, new metal-based drugs have been currently explored for their antimicrobial properties, including gallium-based compounds as potential metallophores that could perturb Fe's interactions with proteins. Herein we have designed and synthesized two bis-kojate ligands (named L4 and L6) and studied their Ga(III) complexes for their physico-chemical and biological properties. In particular a detailed study of their complexation properties in aqueous solution, showed equilibrium models with formation of quite stable dinuclear 2:3 metal:ligand complexes, though with different stability. Solid state complexes were also prepared and characterized and complementary DFT studies indicated that [Ga2(L4)3] complex, with higher stability, seems to adopt a three-ligand bridging conformation, while that for L6 adopt a one ligand bridging conformation. Preliminary investigation of the antibacterial activity of these gallium complexes showed antipseudomonal activity, which appeared higher for the complex with L4, a feature of potential interest for the scientific community.

Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.

OBJECTIVES: Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations. PATIENTS: Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated. METHODS: The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes. RESULTS: Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown. CONCLUSIONS: Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.

The Role of Magnesium in Pregnancy and in Fetal Programming of Adult Diseases.

Magnesium is an essential trace metal and a necessary factor for multiple biochemical functions in humans. Its role in biology is fundamental in over 600 enzymatic reactions implicated in protein synthesis, mitochondrial functions, neuromuscular activity, bone formation, and immune system competence. Magnesium status is relevant in fetal development during gestation and in the newborn growth during the perinatal period. Moreover, magnesium is able to influence fetal programming and disease presentation in childhood or adulthood. The aim of this review is to focus on this metal homeostasis, analyzing its normal values, the causes of hypomagnesemia, the interaction with drugs and other conditions, and the diseases associated with magnesium value alteration during pregnancy, in order to study its role in fetal programming of adult diseases. The data here reported clearly indicated the existence of a connection between magnesium status and human pathology starting from intrauterine life and extending into childhood and adulthood.

A family with segregation of an unbalanced translocation (7;13) (q36;q32) in three patients with severe mental retardation, microcephaly and dysmorphic features, detected by subtelomere FISH: genetic counselling and prenatal diagnosis.

We report a Sardinian family in which three members showed a mental-retardation-microcephaly-multiple malformations syndrome resulting from an unbalanced translocation (7;13)(q36;q32) which led to subtelomeric trisomy 7q36qter and partial monosomy 13q32qter. The unbalanced translocation was transmitted by alternate segregation from a female and a male carriers of the balanced translocation. The three patients had severe mental retardation, microcephaly and multiple minor facial and fingers anomalies. Neuroimages showed brain atrophy, associated in two patients with partial agenesis of the corpus callosum. FISH with chromosome 13 and 7 specific painting probes and subtelomere specific probes was instrumental for defining and characterizing the chromosomal translocation. Extensive genetic counseling and prenatal diagnosis has been offered to all the members of the family.

Hydroxypyridinones with enhanced iron chelating properties. Synthesis, characterization and in vivo tests of 5-hydroxy-2-(hydroxymethyl)pyridine-4(1H)-one.

The synthesis of 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) is presented, together with the evaluation of its coordination ability towards Fe(3+), studied by a combination of chemical, computational, and animal approaches. The use of complementary analytical techniques has allowed us to give evidence of the tautomeric changes of P1 as a function of pH, and to determine their influence on the coordinating ability of P1 towards Fe(3+). The pFe(3+) value 22.0 of P1-iron complexes is noticeably higher than that of deferiprone (20.6), one of the three clinical chelating agents in therapeutic use for iron overload diseases. This is due on one side to the tautomeric change to the catechol form, and on the other to the lower protonation constant of the OH group. Bio-distribution studies on mice allowed us to confirm in vivo the efficacy of P1. Furthermore the coordinating ability toward Al(3+), Cu(2+) and Zn(2+) has been studied to evaluate the possible use of P1 against a second toxic metal ion (Al(3+)), and to envisage its potential influence on the homeostatic equilibria of essential metal ions. The chelating ability of P1 toward these ions, not higher than that of the corresponding deferiprone, contributes to render P1 a more selective iron chelator.

Evidence for an involvement of GABA receptors in the mediation of the proconvulsant action of ethyl-beta-carboline-3-carboxylate.

The kinetic characteristics of binding of [3H]-GABA and the pattern of isoniazid-induced convulsions were studied in rats treated with repeated intraventricular injections of ethyl-beta-carboline-3-carboxylate (beta-CCE) (10 micrograms/rat, twice daily for 8 days). Thirty-six hours after the last injection, the total number of binding sites for [3H]-GABA was decreased (25%) in the cerebral cortex and hippocampus. On the other hand, there was no significant difference in the dissociation constant (KD) between beta-CCE and solvent-treated rats. The decrease in binding sites for [3H]-GABA was paralleled by a strong potentiation of the convulsant pattern elicited by isoniazid. The results suggest that the proconvulsant effect elicited by beta-CCE is mediated by the decrease in the total number of binding sites for GABA, secondary to the interaction between beta-CCE and the benzodiazepine receptor coupled to the GABA receptor.

Autosomal recessive disorder with muscle contractions resembling neonatal tetanus, characteristic face, camptodactyly, hyperthermia, and sudden death: a new syndrome?

This work describes an autosomal recessive syndrome observed over the past 25 years in 17 newborn babies (8 males, 9 females), from 12 different families in Southern Sardinia. This disorder is evident at birth and is characterized by marked muscular contraction of the facial muscles in response to tactile stimuli or during crying, with trismus and abundant salivation simulating a tetanic spasm. The contractions slowly disappear as the infant calms. There is also neck muscle hypertonia with a tendency to opisthotonus. All patients present facial anomalies such as large face, chubby cheeks, broad nose with anteverted nostrils, and long philtrum. The hands show bilateral camptodactyly. The clinical course in all patients was characterized by marked feeding difficulties and appearance of variable fever at about 38 degrees C, with peaks of irregular hyperthermia of over 42 degrees C, with onset ranging from birth to a few weeks. In some patients these symptoms were accompanied by generalized seizures. Death occurred after a period of a few weeks to some months and coincided with fever above 42 degrees C. Laboratory investigations performed in all of these cases did not give any useful pathogenetic indications. Only patients 10 and 16 are still alive today. Patient 10 is now 14 years old. She presents slow regression of the dystonic symptomatology, while dysthermia and mild psychomotor delay persist.

Two sibs with Malpuech syndrome.

We report on two Italian brothers with facial clefting, hypertelorism, urogenital anomalies including micropenis, shawl scrotum, hearing loss, caudal appendage, and umbilical hernia. We have evaluated the two cases as Malpuech syndrome. This is an extremely rare autosomal recessive syndrome.

Changes in the characteristics of low affinity GABA binding sites elicited by Ro15-1788.

3H-GABA binding was studied in cortical membranes from cerebral cortex of handling-habituated and naive rats after the in vitro addition of Ro15-1788. At low concentrations (10(-8), 10(-9) M) Ro15-1788 increased the total number of low affinity 3H-GABA binding sites in brain tissue from naive rats but failed to modify 3H-GABA binding in tissue from handling-habituated ones. On the contrary, Ro15-1788 at higher concentrations (10(-5), 10(-6)M) decreased the total number of low affinity 3H-GABA binding sites in tissue from handling-habituated rats but failed to modify 3H-GABA binding in tissue from naive animals. Ro15-1788 (10(-7)M) failed to modify significantly low affinity 3H-GABA binding in membranes from both naive and handling-habituated rats. However, this concentration abolished the effect of beta-carbolines and diazepam on 3H-GABA binding in membranes from naive and handling-habituated rats, respectively. The changes in the affinity of 3H-GABA binding were inversely related to the changes in the number. The results suggest that: a) the action "in vitro" of Ro15-1788 on low affinity 3H-GABA binding depends from its concentration at the benzodiazepine recognition sites; b) the benzodiazepine recognition site has a modulatory role in the control of the function of GABA-ergic receptor. Our data might explain the conflicting results obtained with this compound "in vivo".

Characterization of the ionization and spectral properties of mercapto-carboxylic acids Correlation with substituents and structural features.

The ionization constants in aqueous solutions of meso- and dl-dimercaptosuccinic acid and of monomethyl and dimethyl meso-succinates were carefully determined by potentiometric and spectrophotometric methods as a result of the increasing interest in these molecules as heavy metal chelators. In order to explain the influence of various substituents on ionization and (13)C NMR properties, the study was extended to the related oxygen derivatives of succinic acid and to simpler ethanoic derivatives. With the Swain-Lupton dual substituent treatment it was possible to clarify the influence of substituents on both spectral and equilibrium parameters. The differences in pK due to conformation are also discussed.

Characterization of the ionization and spectral properties of sulfonephthalein indicators. Correlation with substituent effects and structural features. Part II.

A spectrophotometric study is presented on the first ionization equilibrium of a class of substituted sulfonephthaleins, whose second ionization was the subject of the first part of this work. The present study was more difficult than the previous in that highly acid media and acidity functions had to be used. Nevertheless the results were of sufficient accuracy to allow the dual substituent analysis of Swain and Lupton (C.G. Swain and A.C. Lupton, Jr., J. Am. Chem. Soc., 90 (1968) 4328). Generally speaking, the dependences of equilibrium and spectral parameters on field and resonance parameters found in this and the previous paper were very similar.

Characterization of the ionization and spectral properties of sulfonephthalein indicators. Correlation with substituent effects and structural features.

The pK values of the second ionization of a set of substituted sulfonephthaleins are studied by spectrophotometry and (13)C NMR spectroscopy. A study of the correlation between equilibrium and spectral data on the one hand and the substituent effects on the other is presented, using the dual substituent analysis of Swain and Lupton. This shows a complete dependence of pK values on the F field variable, and of the wavelengths of the bands of basic forms on the R resonance variable.

Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in Wilson's disease.

PROJECT: Wilson's disease (WD) is an inherited disorder of copper metabolism characterised by juvenile liver cirrhosis and by neurological symptoms. Copper levels in brain in WD have been reported to be 10 to 15 fold normal values, depending on the different brain regions. Being very few data on copper distribution in central nervous system in WD available, it seemed of interest to study the concentration of copper and of other trace elements (Zn, P, Mg, Ca, Fe and S) in the brain of a patient died for WD. PROCEDURE: a 56 year old woman affected by WD was admitted to our hospital with signs of hepatic failure and died few days later. At autopsy, a brain slice extending from the left to the right hemisphere was divided in 28 samples. On each sample Copper, Iron, Magnesium, Phosphorus, Sulphur, Zinc and Calcium were determined by Induced Coupled Plasma Atomic Emission Spectroscopy. RESULTS: the mean concentration of copper, ranging from 88 to 158 microg/g of dry tissue in all the brain specimens was higher than literature reference values, while that of the other tested elements was considerably lower. CONCLUSIONS: 1) In the brain of WD patient examined the status of trace elements was extensively altered. Further studies are necessary to correlate the concentration of trace elements with pathological lesions and with clinical pictures. 2) The elements considered in our study showed an uneven distribution in different brain areas.

Chemometric methods applied to an ICP-AES study of chemical element distributions in autopsy livers from subjects affected by Wilson and beta-thalassemia.

The concentrations of seven elements (Ca, Cu, Fe, Mg, P, S and Zn) in three autopsy livers (from two beta-thalassemic patients and one Wilson's disease patient) were determined by ICP-AES technique. At autopsy the three livers were subdivided into a large number of samples for a detailed study of the distribution of Fe and Cu, the accumulation of which characterizes the two diseases. In the same samples Ca, Mg, P, S and Zn concentrations were also determined in order to study significant variations or anomalous trends that could help identify these diseases. Our results generally show a good coincidence with literature data within the limits of sample variability. Based on Factor Analysis as well as Regression Analysis there is evidence of a high correlation between Fe and P contents in beta-thalassemia. The latter finding led us to propose tentatively an accumulation of Fe as a complex with P-containing molecules.

Antley-Bixler syndrome: case report and review of the literature.

The purpose of this report is to describe a patient with a pattern of malformations very similar to those described by Antley and Bixler. They include craniosynostosis, midface hypoplasia with proptosis, ear anomalies, choanal stenosis, long tapered fingers with a bulbous tip, elbow joint contracture due to radio-ulnar synostosis and talipes equinovarus. Necropsy revealed cardiac and renal malformations. The infant died a few days after birth, of respiratory failure. Unlike previously described cases the elbow joint contracture was due to radio-ulnar synostosis rather than radio-humeral synostosis, she did not have long bone fractures and the femora were not markedly bowed. Since the first report in 1975, at least 23 cases have been reported.

Two patients with varying combinations of sternal cleft, haemangiomas, midline abdominal raphe, coarctation of the aorta with a right aortic arch.

We report two patients, one with sternal cleft, haemangiomas, supraumbilical midline raphe and the other with a sternal cleft, haemangiomas, coarctation of the aorta with a right aortic arch.

Chelating agents for metal intoxication.

In this paper we took into examination the use of chelation therapy for treating metal intoxication in humans. We divided this paper in four main parts: before all the principal causes of toxicity are exposed; second the chemical requirements (thermodynamic and kinetic), the interactions with the endogenous molecules and the target organs, as well as the biomedical restraints; as a third step the classes of chelators in use along with the specific treatments allowed are treated and as a final step the principal toxic metal ions are presented. Based on the presented material some conclusion are drawn on the state of art of metal chelation, and the basis are given for a rationale development of metal chelation, founded on chemical, biological and medical considerations.

X-mapping in man: evidence against measurable linkage between anhidrotic ectodermal dysplasia and G6PD deficiency.

A Sardinian kindred segregating for X-linked anhidrotic ectodermal dysplasia (AED), glucose-6-phosphate dehydrogenase (G6PD) deficiency of Mediterranean type, and Xga blood antigen provides evidence against a measurable linkage between the loci for AED and G6PD. Moreover, from the segregation of the combined phenotypes in four scorable sons from two triple heterozygotes with phase known, it seems highly probable that the AED locus is nearer to the centromere than is the G6PD locus.

Trisomy 16q21 = to qter.

A case of trisomy 16q secondary to a paternal 16/18 translocation is described. A comparison of this case with the few other cases of trisomy 16q described in the literature indicates that trisomy for the long arm of chromosome 16 results in a severely affected phenotype and early death. Conversely, patient with trisomy 16p do not have gross abnormalities. We postulate that the prenatal lethality of full trisomy 16 is mainly due to the trisomy for the long arm.