Luigi Manzo

Publications of Luigi Manzo

• An insidious skin rash without itch.

  Authors: Davide Lonati, Arturo Zancan, Andrea Giampreti, Diego Sparpaglione, Carlo Alessandro Locatelli, Luigi Manzo

  Clinical toxicology (Philadelphia, Pa.). 02/2012; 50(2):149-50.

  Abstract A 74-year-old female with a 5-year medical history of breast infiltrating lobular carcinoma was admitted to our Rehabilitation Unit ward for left hemiparesis secondary to neurosurgicalAbstract A 74-year-old female with a 5-year medical history of breast infiltrating lobular carcinoma was admitted to our Rehabilitation Unit ward for left hemiparesis secondary to neurosurgical removal of frontal and right parietal metastatic lesions. After the intervention, prophylactic treatment with the antiepileptic diphenylhydantoin 100 mg/tid was started. On 38th day of drug administration an erythema without itch appeared in jugular and parasternal region and absent in the clothing covered areas, suggesting a contact dermatitis. Next day, the erythema extended to the neck with poorly delineated red plaques. During the following 4 days the patient presented oral stomatitis with fetid breath, atypical targetoid and erythematous confluenced macules. The clinical picture rapidly worsened with vesiculate, bullate lesions and frank skin erosions. The patient was sent to a Dermatology Burn Unit where a therapy with corticosteroids, antibiotics, fluids, albumin and immunoglobulins was administrated. Complete clinical resolution was observed after 1 month without long-term sequelae. Toxic epidermal necrolysis (TEN) is a rare (incidence about 0.01%) adverse drug reaction related to idiosyncratic mechanism, burdened by a mortality rate ranging from 3.2 to 90%. In our patient, TEN covered 63% of body surface, a condition associated with a death risk of 58.3% according to the specific severity illness scale SCORTEN. The disease onset may be insidious, and it could appear as a skin rash without itch; the cutaneous manifestations appear quite lately, then the disease quickly progresses. Early recognition of the disease, especially in oncologic patients, is critical for effective management of this condition in terms of mortality reduction.

• Fatal course of foodborne botulism in an eight-month old infant.

  Authors: Davide Lonati, Carlo Alessandro Locatelli, Lucia Fenicia, Fabrizio Anniballi, Paolo Landri, Andrea Giampreti, Valeria Margherita Petrolini, Sarah Vecchio, Luigi Manzo

  Pediatric reports. 09/2011; 3(4):e31.

  An 8-month old girl, weighing 9 kg, was brought by her parents at 8.15 am to the Emergency Department (ED) for a progressive worsening of weakness and acute respiratory failure. On admission, theAn 8-month old girl, weighing 9 kg, was brought by her parents at 8.15 am to the Emergency Department (ED) for a progressive worsening of weakness and acute respiratory failure. On admission, the baby presented with poor oral intake, a weak cry and extremely weak muscular body control. Poor gag and suck, unreactive mydriasis, hypotonia, lethargy and absence of peristalsis were noted. Laboratory data showed severe respiratory acidosis. Chest X-ray, electroencephalography, encephalic CT scan and MRI were all normal, as were cerebrospinal fluid analysis and viral tests. Orotracheal intubation and continuous mechanical ventilation were applied. The patient received fluids, corticosteroids, aerosol therapy, large-spectrum antibiotics and enteral-nutrition. Further investigation revealed ingestion of an improperly prepared home-canned homogenized turkey meal. Type A botulinum neurotoxin was identified. Trivalent botulinum antitoxin, prostigmine and oral activated charcoal were administered. Generalized flaccid paralysis, areflexic bilateral mydriasis, gastric stasis and deep coma persisted for the duration of the hospital stay, and the patient died of severe respiratory failure and cardiac arrest 12 days after ED admission. Botulism poisoning should be suspected in any infant presenting with feeding difficulties, constipation, descendent paralysis or acute respiratory failure. Supportive treatment and antidotal therapy should be performed as soon as a clinical diagnosis is made. We describe a case of foodborne botulism in an 8-month old infant caused by ingestion of an improperly prepared home-canned homogenized turkey meal, representing the youngest fatal case reported in medical literature.

• A young Indian male with abdominal pain.

  Authors: Andrea Giampreti, Chiara Bonetti, Davide Lonati, Luigi Manzo, Carlo Alessandro Locatelli

  Clinical toxicology (Philadelphia, Pa.). 03/2011; 49(3):191-2.

  A young man with abdominal pain who had radiopaque tablets in his gut is described. Investigations showed the diagnosis of lead poisoning from ayurvedic medicines.

• Developmental exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) affects cerebral dopamine D1-like and D2-like receptors of weanling and pubertal rats.

  Authors: Teresa Coccini, Elisa Roda, Anna F Castoldi, Diana Poli, Matteo Goldoni, Maria Vittoria Vettori, Antonio Mutti, Luigi Manzo

  Archives of toxicology. 02/2011; 85(10):1281-94.

  MeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) ofMeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) of dopamine D1-like (D1-Rs) and D2-like receptors (D2-Rs), by saturation binding studies. D1-Rs decreased density in both cortex and striatum (15-30%) by MeHg and PCB153, either alone or combined, without additivity in PND21 males. Changes disappeared by PND36. In females, only MeHg caused a 15% Bmax decrease in striatum. D2-Rs enhanced density (23-50%) and reduced affinity in cortex to a similar extent by all treatments in both weanling and pubertal males. Affinity was also decreased in females by all types of exposure at both ages, while density was enhanced by PCB153 only in a delayed manner (PND36). No changes were detected in striatum. In MeHg and MeHg + PCB153 pup cortex, Hg concentrations ranged, on PND21, between 0.25 and 0.89 and 0.94-1.40 μg/g tissue, respectively, and were 5- to sixfold lower 2 weeks later. PCB153 levels, in PCB153 ± MeHg treated rats, were about 15 μg/g tissue (PND21) and 4-8 μg/g tissue (PND36). In striatum, the Hg and PCB153 concentrations were similar to those in cortex. Brain kinetics trend also applied to blood PCB153 or Hg levels. Perinatal exposure to MeHg and/or PCB153 affects D1- and D2-Rs in a gender-, time-, and brain area-dependent manner. Combined treatment does not exacerbate the neurochemical effects of the individual compounds.

• Reduced platelet monoamine oxidase type B activity and lymphocyte muscarinic receptor binding in unmedicated children with attention deficit hyperactivity disorder.

  Authors: Teresa Coccini, Alessandro Crevani, Giorgio Rossi, Francesca Assandri, Umberto Balottin, Roberta Di Nardo, Luigi Manzo

  Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 11/2009; 14(7):513-22.

  Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmissionSeveral lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) and lymphocyte muscarinic cholinergic receptor binding (l-MR) in 44 unmedicated ADHD children (aged 9.1 +/- 2.87 years) and in 26 age-matched controls for comparison. Lower levels of p-MAO-B (approximately 35%) and l-MR (approximately 55%) in ADHD were observed compared with controls. Differences were gender-dependent: p-MAO-B was reduced in males only (5.20 +/- 2.99 vs 8.46 +/- 5.1 nmol mg(-1) protein h(-1) in ADHD and controls, respectively) and l-MR in females only (ADHD vs control: 6.63 +/- 1.75 and 15.30 +/- 8.35 fmol 10(-6) cells). The clinical significance was corroborated by the correlation between these markers and severity of specific symptoms: lower p-MAO-B associated with increased inattention scores (Conners' teacher-rating scale); lower l-MR associated with increased score for oppositional-defiant disorder (ODD) (SNAP-IV); and trend towards correlation between increased inattention (SNAP-IV) and lower l-MR.

• No changes in lymphocyte muscarinic receptors and platelet monoamine oxidase-B examined as surrogate central nervous system biomarkers in a Faroese children cohort prenatally exposed to methylmercury and polychlorinated biphenyls.

  Authors: Teresa Coccini, Luigi Manzo, Frodi Debes, Ulrike Steuerwald, Pal Weihe, Philippe Grandjean

  Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 04/2009; 14(2):67-76.

  Experimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury andExperimental evidence suggests that monoamine oxidase B (MAO-B) and muscarinic cholinergic receptors (mAChRs) are involved in the pathogenesis of neurotoxicity caused by methylmercury and polychlorinated biphenyls (PCBs). Blood samples from 7-year-old exposed children were analyzed for platelet MAO-B and lymphocyte mAChRs as potential markers of exposure to these neurotoxicants. The blood neurotoxicity biomarkers were compared with prenatal and current exposures and with neuropsychological test results. Both biomarkers showed homogeneous distributions within this cohort (mAChR, range 0.04-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol mg(-1) protein h(-1)). No correlation was found between the two biomarkers and either blood neurotoxicant concentrations or clinical findings. MAO-B and mAChR sensitivity may not be sufficiently high to assess early, subclinical responses to low/moderate methylmercury and/or PCB exposure, whereas these markers are significantly altered in sustained exposure scenarios, as shown by clinical studies in drug addicts or patients treated with psychopharmacological agents.

• Neurodevelopmental toxicity of methylmercury: Laboratory animal data and their contribution to human risk assessment.

  Authors: Anna F Castoldi, Natalia Onishchenko, Carolina Johansson, Teresa Coccini, Elisa Roda, Marie Vahter, Sandra Ceccatelli, Luigi Manzo

  Regulatory toxicology and pharmacology : RTP. 08/2008; 51(2):215-29.

  Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of theMethylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.

• Human developmental neurotoxicity of methylmercury: Impact of variables and risk modifiers.

  Authors: Anna F Castoldi, Carolina Johansson, Natalia Onishchenko, Teresa Coccini, Elisa Roda, Marie Vahter, Sandra Ceccatelli, Luigi Manzo

  Regulatory toxicology and pharmacology : RTP. 08/2008; 51(2):201-14.

  Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainlyMethylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from large scale epidemiological studies concerning childhood development and neurotoxicity in relation to in utero exposure in various fish eating communities around the world. Despite the extensive literature and research, the threshold dose for MeHg neurotoxic effects is still unclear, in particular when it comes to subtle effects on neurobehaviour. In this article clinical and epidemiological findings concerning the neurodevelopmental toxicity of MeHg are reviewed. Much attention is focussed on the potential impact of factors, such as diet and nutrition, gender, pattern of exposure and co-exposure to other neurotoxic pollutants, which may modulate MeHg toxic effects. These factors, together with the notion that some symptoms may ensue or exacerbate with aging, contribute to the difficulties in the definition of safe levels for developmental exposure.

• Human developmental neurotoxicity of methylmercury and variables.

  Authors: Anna F Castoldi, Carolina Johansson, Natalia Onishchenko, Teresa Coccini, Elisa Roda, Marie Vahter, Sandra Ceccatelli, Luigi Manzo

  Regulatory toxicology and pharmacology : RTP. 07/2008;

• Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat.

  Authors: Elisa Roda, Teresa Coccini, Davide Acerbi, Anna Castoldi, Graziella Bernocchi, Luigi Manzo

  Journal of chemical neuroanatomy. 06/2008; 35(3):285-94.

  The developing central nervous system (CNS) is a target of the environmental toxicant methylmercury (MeHg), and the cerebellum seems the most susceptible tissue in response to this neurotoxicant. TheThe developing central nervous system (CNS) is a target of the environmental toxicant methylmercury (MeHg), and the cerebellum seems the most susceptible tissue in response to this neurotoxicant. The cholinergic system is essential for brain development, acting as a modulator of neuronal proliferation, migration and differentiation processes; its muscarinic receptors (MRs) play pivotal roles in regulating important basic physiologic functions. By immunohistochemistry, we investigated the effects of perinatal (GD7-PD21) MeHg (0.5 mg/kg bw/day in drinking water) administration on cerebellum of mature (PD36) and immature (PD21) rats, evaluating the: (i) M2- and M3-MR expression; (ii) presence of gliosis; (iii) cytoarchitecture alterations. Regarding to M2-MRs, we showed that: at PD21, MeHg-treated animals did not display any differences compared to controls, while, at PD36 there was a significant increase of M2-immunopositive Bergmann cells in the molecular layer (ML), suggesting a MeHg-related cytotoxic effect. Similarly to M2-MRs, at PD21 the M3-MRs were not affected by MeHg, while, at PD36 a lacking immunoreactivity of the granular layer (IGL) was observed after MeHg treatment. In MeHg-treated rats, at both developmental points, we showed reactive gliosis, e.g. a significant increase in Bergmann glia of the ML and astrocytes of the IGL, identified by their expression of glial fibrillar acidic protein. No MeHg-related effects on Purkinje cells were detected neither at weaning nor at puberty. These findings suggest: (i) a delayed MeHg exposure-related effect on M2- and M3-MRs, (ii) an overt MeHg-related cytotoxic effect on cerebellar oligodendroglia, e.g. reactive gliosis, (iii) a selective vulnerability of granule cells and Purkinje neurons to MeHg, with the latter that remain unharmed.

• Perinatal co-exposure to methylmercury and PCB153 or PCB126 in rats alters the cerebral cholinergic muscarinic receptors at weaning and puberty.

  Authors: Teresa Coccini, Elisa Roda, Anna F Castoldi, Matteo Goldoni, Diana Poli, Graziella Bernocchi, Luigi Manzo

  Toxicology. 09/2007; 238(1):34-48.

  In the last few decades, combined exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) from fish and seafood, and their potentially interactive effects on neurodevelopment, have beenIn the last few decades, combined exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) from fish and seafood, and their potentially interactive effects on neurodevelopment, have been giving increasing cause for concern. We examined the combined effects of MeHg and either a non-dioxin PCB (PCB153) or a dioxin-like PCB (PCB126) congener on the developing brain cholinergic muscarinic receptors (MRs). These receptors are known to play a major role in many central functions including higher cognitive processes and the modulation of extrapyramidal motor activity. MRs in pup rat brains diminished following prenatal and lactational exposure, from gestational day [GD]7 to postnatal day [PND]21, to MeHg (0.5mg/kgbodyweight[bw]/day), PCB153 (5mg/kgbw/day), and PCB126 (100ng/kg/day), alone or in combination. Total MR density, as well as M1, M2, and M3 receptor subtypes of the weanling and pubertal rats, were affected in a brain-area-, gender-, time- and compound-dependent fashion. MeHg decreased (by 15-20%) the total MR density in a delayed (PND36) manner in the cerebral cortex of both genders, and early (at weaning) in the cerebellum of both genders, with the effect lasting until puberty (in males only). MeHg decreased the ACh M1- and M3-immunopositive neurons in the cerebral cortex and also increased the M2-immunopositive Bergmann glia in the cerebellum. PCB153 also induced a delayed (PND36) decrease (of 20%) in total MR number in the cerebellum of the male offspring and in the cerebral cortex of both genders. The latter effect was coupled with a decrease in ACh M1- and ACh M3-immunopositive neuron populations. PCB126 decreased (by 30-40%) total MR density in a gender-dependent manner, males being more sensitive than females. The effect was evident early (at PND21) and lasted until puberty in the cerebellum, while it was observed later (at PND36) in the cerebral cortex. The M1 and M3 receptors were similarly affected by PCB126. Co-exposure to MeHg and either PCB153 or PCB126 had the same effect on the cerebral MRs as exposure to each compound alone. The results rule out additive or synergistic interactions between MeHg and PCB153 or PCB126 on MRs in the brain areas examined. Some early-onset changes persisted until puberty, while other modifications became manifest only at the advanced time point (PND36), when the brain levels of total Hg, PCB153, and PCB126 had declined. These data support the ability of MeHg and PCBs to induce delayed neurotoxicity after developmental exposure.

• Neurobehavioural and molecular changes induced by methylmercury exposure during development.

  Authors: Carolina Johansson, Anna F Castoldi, Natalia Onishchenko, Luigi Manzo, Marie Vahter, Sandra Ceccatelli

  Neurotoxicity research. 05/2007; 11(3-4):241-60.

  There is an increasing body of evidence on the possible environmental influence on neurodevelopmental and neurodegenerative disorders. Both experimental and epidemiological studies have demonstratedThere is an increasing body of evidence on the possible environmental influence on neurodevelopmental and neurodegenerative disorders. Both experimental and epidemiological studies have demonstrated the distinctive susceptibility of the developing brain to environmental factors such as lead, mercury and polychlorinated biphenyls at levels of exposure that have no detectable effects in adults. Methylmercury (MeHg) has long been known to affect neurodevelopment in both humans and experimental animals. Neurobehavioural effects reported include altered motoric function and memory and learning disabilities. In addition, there is evidence from recent experimental neurodevelopmental studies that MeHg can induce depression-like behaviour. Several mechanisms have been suggested from in vivo- and in vitro-studies, such as effects on neurotransmitter systems, induction of oxidative stress and disruption of microtubules and intracellular calcium homeostasis. Recent in vitro data show that very low levels of MeHg can inhibit neuronal differentiation of neural stem cells. This review summarises what is currently known about the neurodevelopmental effects of MeHg and consider the strength of different experimental approaches to study the effects of environmentally relevant exposure in vivo and in vitro.

• Methylmercury interaction with lymphocyte cholinergic muscarinic receptors in developing rats.

  Authors: Teresa Coccini, Giovanna Randine, Anna F Castoldi, Davide Acerbi, Luigi Manzo

  Environmental research. 03/2007; 103(2):229-37.

  Cerebral cholinergic muscarinic receptors (MR) have been suggested as one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to the widespreadCerebral cholinergic muscarinic receptors (MR) have been suggested as one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to the widespread seafood contaminant methylmercury (MeHg). In adult rats, MeHg has been shown to alter MR binding both in the brain and lymphocytes, supporting the use of MR in blood cells as a surrogate marker of CNS changes. The effects of MeHg have been evaluated on rat lymphocyte MR binding (using [3H]QNB as specific muscarinic ligand) in vivo (after perinatal exposure) and in vitro. For comparison, in vitro studies were also performed on human lymphocytes. Exposure to 1 mg MeHg/kg/day during pregnancy and lactation (from GD7 to PND7) significantly enhanced lymphocyte MR density in both adult and young rats 21 days after delivery, with a more pronounced effect in the mothers (B(max) increase of 139%) than in the male offspring (+49%) and female offspring (+73%) as compared with their respective controls (33+/-4, 41+/-8, and 37+/-4 fmol/million cells), in accordance with the higher Hg levels detected in the adult blood (11.3+/-2.2 microg/mL) than in pups (1.3+/-0.4 microg/L in both genders). A lower MeHg dose (0.5 mg/kg/day) was without any effect on lymphocyte MRs. In in vitro studies, MeHg was an almost equipotent inhibitor of (3)H-QNB binding to rat and human lymphocyte MRs (IC50 values were 4.1+/-0.29, 5.2+/-0.51, and 5.0+/-0.9 microM for total rat lymphocytes, rat T lymphocytes, and total human lymphocytes, respectively). Notably, the IC50 values for MeHg to lymphocyte MRs were comparable to the Hg levels reached in blood (5-50 microM) of the PND21 rats exposed to MeHg. The finding that the MR binding is a target for the effects of MeHg in peripheral blood cells is in accordance with our previous data in brain [Coccini et al., 2006. Effects of developmental co-exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) on cholinergic muscarinic receptors in rat brain. Neurotoxicology, in press], and supports the use of this peripheral endpoint as a biomarker of MeHg-induced cerebral muscarinic alterations. The similarity of MeHg IC50 binding data between human and rat in peripheral tissues suggests the possible application of such biomarker to humans exposed to environmental chemicals.

• Brain monoaminergic neurotransmission parameters in weanling rats after perinatal exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153).

  Authors: Anna F Castoldi, Fabio Blandini, Giovanna Randine, Alberta Samuele, Luigi Manzo, Teresa Coccini

  Brain research. 10/2006; 1112(1):91-8.

  The individual and joint effects of methylmercury (MeHg; 1 mg/kg body weight/day, GD7-PND7) and PCB153 (20 mg/kg body weight/day, GD10-GD16), administered orally to rat dams, were explored inThe individual and joint effects of methylmercury (MeHg; 1 mg/kg body weight/day, GD7-PND7) and PCB153 (20 mg/kg body weight/day, GD10-GD16), administered orally to rat dams, were explored in 21-day-old rat offspring brain in terms of monoamine oxidase B (MAO-B) activity and regional content of dopamine (DA), serotonin (5-HT), 5-hydroxy-indole-3-acetic acid (5-HIAA) and homovanillic acid (HVA). Neither treatment altered MAO-B in striatum, hippocampus, cerebellum and cerebral cortex of female pups. In males the cerebellum displayed a significantly reduced enzyme activity (25-45%) following all treatments. Concerning biogenic amines, 5-HT levels were decreased by 30-50% in the cerebral cortex of males and females by PCB153 alone and combined with MeHg, without changes in 5-HIAA and dopaminergic endpoints. In cerebellum of all pups, MeHg enhanced 5-HIAA levels, whereas PCB153, either alone or combined with MeHg, did not affect this endpoint. In striatum, PCB153 reduced the content of DA, HVA and 5-HIAA (respective control values: 2-3; 60-80; 8-10 ng/mg protein) to a similar extent when administered alone or together with MeHg (20-40%). Perinatal exposure to MeHg and/or PCB153 results in regionally and/or gender-specific alterations in the central dopaminergic and serotonergic systems at weaning. The combined treatment with MeHg and PCB153 does not exacerbate the neurochemical effects of the individual compounds.

• Effects of developmental co-exposure to methylmercury and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) on cholinergic muscarinic receptors in rat brain.

  Authors: Teresa Coccini, Giovanna Randine, Anna F Castoldi, Philippe Grandjean, Guido Ostendorp, Birger Heinzow, Luigi Manzo

  Neurotoxicology. 08/2006; 27(4):468-77.

  The developing nervous system is thought to be particularly sensitive to polychlorinated biphenyls (PCBs) present as food contaminants together with methylmercury (MeHg). Effects of perinatalThe developing nervous system is thought to be particularly sensitive to polychlorinated biphenyls (PCBs) present as food contaminants together with methylmercury (MeHg). Effects of perinatal co-exposure to PCB153 and MeHg on brain cholinergic muscarinic receptors (MRs) were investigated by saturation binding studies in mature and immature rats. MeHg alone (1mg/kg/day, GD7-PND7) enhanced cerebral MRs more in dams (87% and 60% in cerebellum and cerebral cortex, respectively) than in PND21 pups (0-50%) in accordance with the higher Hg levels detected in the adult brain (7-9 microg/g) than in the male and female offspring's brain (1.5-2.8 microg/g). Prenatal administration of PCB153 (20mg/kg/day, GD10-GD16), leading to higher contaminant levels in the offspring brain than in that of adults (25-66 microg/g versus 3 microg/g), induced cerebral MR changes of similar extent at both ages, namely decreased cerebellar (20-30%) and increased cortical MR density (40-50%). Co-exposure to PCB and MeHg had no more effect than exposure to either compound alone on cerebral cortex MRs, whereas, in the cerebellum, the combined treatment induced a PCB-like lowering of the MR density that masked the MeHg-induced receptor increase. None of the treatments affected the striatal and hippocampal MRs. A lower MeHg dose (0.5 mg/kg/day) was without any effect on cerebral MRs. These results show that MRs are one of the sensitive biochemical endpoints of the central nervous system altered by developmental exposure to MeHg and PCB153. Cerebral cortex and cerebellum were the most susceptible targets in the response to these neurotoxicants. MR changes were detected in both immature and adult animals and the interaction of MeHg and PCB153 at the level of these receptors occurred in a non-additive manner.

• Lymphocyte cytochrome c oxidase, cyclic GMP and cholinergic muscarinic receptors as peripheral indicators of carbon monoxide neurotoxicity after acute and repeated exposure in the rat.

  Authors: Anna F Castoldi, Teresa Coccini, Giovanna Randine, Mariluz Hernández-Viadel, Vicente Felipo, Luigi Manzo

  Life sciences. 04/2006; 78(17):1915-24.

  Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbonChanges in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neurotoxicity. The early and delayed effects of repeated and acute in vivo CO inhalation were investigated on COX activity, cGMP formation and MR binding in rat brain and lymphocytes to assess whether each endpoint was similarly affected both centrally and peripherally. Male Wistar rats either inhaled 500 ppm CO, 6 h/day, 5 days/week, 4 weeks (repeated exposure) or 2,400 ppm, 1 h (single exposure). Neither treatment altered brain or lymphocyte COX activity 1 and 7 days post-treatment. Also ineffective were repeated and acute CO treatments towards (3)H-quinuclidinyl benzilate (QNB) binding to MRs in cerebral cortex, hippocampus, striatum, cerebellum (respective controls, mean+/-S.D.: 171 +/- 45, 245 +/- 53, 263 +/- 14 and 77 +/- 7 fmol/mg protein) and lymphocytes (24 +/- 10 fmol/million cells) at the same time points. In lymphocytes control cGMP levels averaged 1.98 +/- 0.99 pmol/mg protein under basal conditions, and 3.94 +/- 0.55 pmol/mg protein after NO-stimulation. One day after chronic treatment cessation, the CO-treated group displayed about a 50% decrease in both basal and NO-stimulated cGMP values, which persisted up to 7 days after, compared to air-exposed rats. Acutely, CO caused a delayed enhancement (+140%) of NO-induced activation of soluble guanylate cyclase. The finding that the NO-cGMP pathway is a target for the delayed effects of CO in peripheral blood cells is in accordance with our data in brain [Hernández-Viadel, M., Castoldi, A.F., Coccini, T., Manzo, L., Erceg, S., Felipo, V., 2004. In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum. Journal of Neurochemistry 89, 1,157-1,165], and supports the use of this peripheral endpoint as a biomarker of CO central effects.

• [Antidotes availability in Emergency Departments of the Italian National Health System and development of a national data-bank on antidotes]

  Authors: Carlo Locatelli, Valeria Petrolini, Davide Lonati, Raffaella Butera, Angelo Bove, Lidia Mela, Luigi Manzo

  Annali dell'Istituto superiore di sanità. 02/2006; 42(3):298-309.

  The availability of antidotes in Italian hospitals has been evaluated through the answers to a specific questionnaire sent to all Italian Emergency Departments, Intensive Care Units, 118 emergencyThe availability of antidotes in Italian hospitals has been evaluated through the answers to a specific questionnaire sent to all Italian Emergency Departments, Intensive Care Units, 118 emergency response system, and Poison Centres. Five Poison Centres and, approximately, the 30% of the Emergency Departments and Intensive Care Units of all Italian emergency hospitals answered to the questionnaire. The results point out an insufficient availability of antidotes in the Italian emergency hospitals, with an almost total absence of those necessary for the treatment of less frequent and less known poisonings (e.g. digoxin, industrial agents), also when the antidote is a lifesaving drug. To improve the antidotes availability for the toxicological emergencies and to facilitate its supplying, a "national antidotes data-base" (BaNdA) has been realized, freely available to the hospital services which register themselves and make their antidotes stockpile available.

• Lymphocyte muscarinic receptors and platelet monoamine oxidase-B as biomarkers of CNS function: effects of age and gender in healthy humans.

  Authors: Teresa Coccini, Giovanna Randine, Anna F Castoldi, Laura Balloni, Paola Baiardi, Luigi Manzo

  Environmental toxicology and pharmacology. 05/2005; 19(3):715-20.

  Lymphocyte cholinergic muscarinic receptors (MRs) and platelet monoamine oxidase-B (MAO-B) activity are considered surrogate markers of the same parameters in the central nervous system. LymphocyteLymphocyte cholinergic muscarinic receptors (MRs) and platelet monoamine oxidase-B (MAO-B) activity are considered surrogate markers of the same parameters in the central nervous system. Lymphocyte MR binding and platelet MAO-B activity were measured in a consistent number of healthy human adults and analysed according to gender and age. The mean value±S.D. of MR binding neither differed between males (12.2±10.0fmol/10(6)cells, range: 0.5-37.9, n=86) and females (10.7±9.7fmol/10(6)cells, range: 0.5-39.7, n=69) nor among age groups. MAO-B activity was significantly higher in women (geometric mean: 11.3nmol/mgprotein/h, with 65% of values from 7.3 to 17.6; n=43), than in men (7.7nmol/mgprotein/h, with 65% of values from 4.5 to 13; n=95). Males aged 56-66 years displayed a higher, though not statistically significant, basal enzyme activity than younger subjects. Altogether these data indicate gender-related differences in MAO activity, but not in MR binding, and inter-individual differences in the basal values of both peripheral blood markers in healthy subjects.

• [Exotic snakes in Europe. A case of Mexican Moccasin (Agkistrodon bilineatus) snakebite]

  Authors: Davide Lonati, Raffaella Butera, Mauro Cima, Susanna Cozzio, Carlo Locatelli, Luigi Manzo

  Presse médicale (Paris, France : 1983). 01/2005; 33(22):1582-4.

  INTRODUCTION: In the last years exotic snakebite envenomations are increasingly reported. These cases are difficult to manage because of the limited experience of European physicians in the treatmentINTRODUCTION: In the last years exotic snakebite envenomations are increasingly reported. These cases are difficult to manage because of the limited experience of European physicians in the treatment of bites from such venomous snakes; moreover, specific antivenoms are unevenly stocked and they are difficult to find in case of a medical emergency. OBSERVATION: A 39-year-old herpetologist was bitten in his right hand by a mexican moccasin (Agkistrodon bilineatus) at the workplace, and presented in the Emergency Department 19 hours later. At admission, clinical evaluation showed local necrosis, swelling involving the entire limb up to the trunk, and severe pain. The specific antidote, not stocked in Italy, was sought abroad; its finding and routeing up to spot delivery required 12 hours. The antivenom, given 32 hours after the bite with no adverse reactions, was only partially effective. The clinical course was characterized by extensive edema with rhabdomyolysis. The necrotic wound at the bite site required after several days surgical debridement, and eventually skin graft. At 3 months follow-up, motor impairment of his right hand fingers with functional disability was still present. COMMENTS: The envenomation by Agkistrodon bilineatus has some clinical aspects in common with that by European viper species, although crotalid venom usually causes more severe manifestations. The antivenom supply from a foreign country may delay its administration. A specific legislation aimed to simplify antidotes importing procedures for professional snake handlers may improve antivenoms availability and allow their timely use, as soon as clinically indicated.

• In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum.

  Authors: Mariluz Hernández-Viadel, Anna F Castoldi, Teresa Coccini, Luigi Manzo, Slaven Erceg, Vicente Felipo

  Journal of neurochemistry. 07/2004; 89(5):1157-65.

  Carbon monoxide induces delayed neurological and neuropathological alterations, including memory loss and cognitive impairment. The bases for the delay remain unknown. Activation of soluble guanylateCarbon monoxide induces delayed neurological and neuropathological alterations, including memory loss and cognitive impairment. The bases for the delay remain unknown. Activation of soluble guanylate cyclase by nitric oxide modulates some forms of learning and memory. Carbon monoxide binds to soluble guanylate cyclase, activating it but interfering with its activation by nitric oxide. The aim of this work was to assess whether exposure of rats to carbon monoxide alters the activity of soluble guanylate cyclase or its modulation by nitric oxide in cerebellum or cerebral cortex. Rats exposed chronically or acutely to carbon monoxide were killed 24 h or 7 days later. Acute carbon monoxide exposure decreased cyclic guanosine monophosphate (cGMP) content and reduced activation of soluble guanylate cyclase by nitric oxide. Cortex was more sensitive than cerebellum to chronic exposure, which reduced activation of soluble guanylate cyclase by nitric oxide in cortex. In cerebellum, chronic exposure induced delayed impairment of soluble guanylate cyclase activation by nitric oxide. Acute exposure effects were also stronger at 7 days than at 24 h after exposure. This delayed impaired modulation of soluble guanylate cyclase by nitric oxide may contribute to delayed memory loss and cognitive impairment in humans exposed to carbon monoxide.