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Giorgio Battaglia

Publications and source records attributed to Giorgio Battaglia.

18 recordsLinked to original sources
PubMed2006

Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development.

We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Erosion of an esophageal endoprosthesis into the trachea.

Acquired benign non-neoplastic tracheoesophageal fistulas are unusual, demanding clinical entities. Surgical technique and final outcome depends on fistula size. A one-stage procedure with esophageal resection is preferred when the fistula is located in the upper third of the trachea and is less than 1 cm long.

Adult↗
PubMed2006

Neuronal-specific roles of the survival motor neuron protein: evidence from survival motor neuron expression patterns in the developing human central nervous system.

Despite recent data on the cellular function of the survival motor neuron (SMN) gene, the spinal muscular atrophy (SMA) disease gene, the role of the SMN protein in motor neurons and hence in the pathogenesis of SMA is still unclear. The spatial and temporal expression of SMN in neurons, particularly during development, could help in verifying the hypotheses on the SMN protein functions so far proposed. We have therefore investigated the expression and subcellular localization of the SMN protein in the human central nervous system (CNS) during ontogenesis with immunocytochemical, confocal immunofluorescence, and Western blot experiments using a panel of anti-SMN antibodies recognizing the full-length SMN protein. The experiments not only revealed the early SMN expression in all neurons, but also demonstrated the progressive shift in SMN subcellular localization from mainly nuclear to cytoplasmic and then to axons during CNS maturation. This finding was present in selected neuronal cell populations and it was particularly conspicuous in motor neurons. Our data support the idea of a specific role for SMN in axons, which becomes predominant in the ontogenetic period encompassing axonogenesis and axonal sprouting. In addition, the asymmetric SMN staining demonstrated in the germinative neuroepithelium suggests a possible role for SMN in neuronal migration and/or differentiation.

Adult↗
PubMed2006

NMDA receptor composition differs among anatomically diverse malformations of cortical development.

Altered excitatory synaptic activity is likely a key factor in the neuronal hyperexcitability of developmental cerebral malformations. Using a combined morphologic and molecular approach, we investigated the NMDA receptor and related protein composition in human epileptic patients affected by periventricular nodular heterotopia, subcortical band heterotopia, or focal cortical dysplasia. Our results indicate that expression levels of specific NMDA receptor subunits are altered in both cerebral heterotopia and cortical dysplasia. A selective increase in the NR2B subunit was present in all cortical dysplasia, whereas the expression level of NR2A and NR2B subunits was significantly downregulated in all patients with heterotopia. NR2B upregulation in cortical dysplasia was greater in the total homogenate than the postsynaptic membrane fraction, suggesting that mechanisms other than increased ionic influx through the postsynaptic membrane may sustain hyperexcitability in dysplastic neurons. In cerebral heterotopia, the NR2A and NR2B downregulation was accompanied by less evident reduction of the SAP97 and PSD-95 proteins of the MAGUK family, thus suggesting that NMDA impairment was associated with altered molecular structure of the postsynaptic membrane. Our results demonstrate that diverse human developmental malformations are associated with different alterations of the NMDA receptor, which may contribute to the genesis of epileptic phenomena.

Adolescent↗
PubMed2006

Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges.

PURPOSE: Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges. METHODS: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared. RESULTS: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location. CONCLUSIONS: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.

Adolescent↗
PubMed2005

Barrett's epithelium after antireflux surgery.

Barrett's epithelium (BE), defined as endoscopically visible, histologically proved intestinal-type epithelium in the esophagus, is considered the ultimate consequence of long-standing gastro(duodeno)esophageal reflux disease (GERD). Recent reports suggest that effective antireflux therapy may promote the regression of this metaplastic process. This study aimed to establish whether antireflux surgery (laparoscopic fundoplication) can induce any endoscopic and/or histologic changes in BE. Thirty-five consecutive cases of BE (11 short-segment [SBE] and 24 long-segment [LBE]) were considered. All patients underwent extensive biopsy sampling before and after surgery (mean follow-up, 28 months; range, 12-99 mo). In all cases, (a) intestinal metaplasia (IM) extension (H&E), (b) IM phenotype (high-iron diamine [HID]), and (c) Cdx2 immunohistochemical expression were histologically scored in the biopsy material obtained before and after fundoplication. After surgery, a significant decrease in IM extension and a shift from incomplete- to complete-type IM were documented in SBE. No significant changes occurred in the LBE group in terms of IM extension or histochemical phenotype. A drop in the immunohistochemical expression of Cdx2 protein was also only documented in the SBE group. Antireflux surgery significantly modifies the histologic phenotype of SBE, but not of LBE.

Adult↗
PubMed2005

Schizencephaly: clinical spectrum, epilepsy, and pathogenesis.

After almost 60 years since the original description, we have reviewed the results of the more recent studies on schizencephaly in an attempt to delineate its imaging and clinical spectra of presentation and to point out the still unsettled controversies on its pathogenesis. The clinical picture is mainly based on the presence of motor deficits and mental retardation, but the severity of the clinical picture is extremely variable, mainly related to the size and location of the clefts and to the presence of associated cerebral malformations. By contrast, the outcome of epilepsy, which is present in about half of the cases and drug resistant in a third, is not strictly related to the severity of the malformation. Some clinical and functional magnetic resonance imaging studies have suggested that, beside the features of the anatomic damage, the functional reorganization of a malformed and unaffected cortex is most likely crucial in determining the clinical outcome. Review of the genetic studies and the more recent personal data suggests that the role of the EMX2 gene in schizencephaly, if any, is restricted to a minority of cases, leaving the etiopathogenesis of this brain malformation still a matter of study and debate.

Cerebral Cortex↗
PubMed2005

Electroencephalographic recordings of focal seizures in patients affected by periventricular nodular heterotopia: role of the heterotopic nodules in the genesis of epileptic discharges.

Patients affected by periventricular nodular heterotopia are frequently characterized by focal drug-resistant epilepsy. To investigate the role of periventricular nodules in the genesis of seizures, we analyzed the electroencephalographic (EEG) features of focal seizures recorded by means of video-EEG in 10 patients affected by different types of periventricular nodular heterotopia and followed for prolonged periods of time at the epilepsy center of our institute. The ictal EEG recordings with surface electrodes revealed common features in all patients: all seizures originated from the brain regions where the periventricular nodular heterotopia were located; EEG patterns recorded on the leads exploring the periventricular nodular heterotopia were very similar both at the onset and immediately after the seizure's end in all patients. Our data suggest that seizures are generated by abnormal anatomic circuitries, including the heterotopic nodules and adjacent cortical areas. The major role of heterotopic neurons in the genesis and propagation of epileptic discharges must be taken into account when planning surgery for epilepsy in patients with periventricular nodular heterotopia.

Adolescent↗
PubMed2004

Barrett's esophagus: management of high-grade dysplasia and cancer.

Esophagectomy remains the treatment of choice for the appropriate patient with Barrett's adenocarcinoma invading beyond the mucosa, without evidence of distant metastasis or invasion of adjacent organs. On the other hand, therapeutic management of patients with Barrett's high-grade dysplasia (HGD) or mucosal adenocarcinoma should be individualized, taking into account the patient's preferences, willingness to return for frequent endoscopic biopsies, and medical fitness to undergo esophagectomy. Surgery has to be considered the best treatment for HGD or superficial carcinoma, unless contraindicated by severe comorbidities, because it has proven to be the only treatment that is successful in curing the condition and preventing recurrent HGD or the development of invasive cancer. Nonsurgical treatment by photodynamic therapy or endoscopic mucosal resection may be a less invasive and organ-sparing option for elderly, poor-risk patients but it is still to be considered an investigational therapy that should only be conducted under a clinical trial protocol. Finally, intensive endoscopic biopsy surveillance of patients with HGD is another investigational option that may allow prompt treatment of cancer if it develops. However, few data document the safety of this observational approach.

Adenocarcinoma↗
PubMed2004

Randomized controlled trial of botulinum toxin versus laparoscopic heller myotomy for esophageal achalasia.

OBJECTIVE: To compare laparoscopic cardia myotomy and fundoplication with botulinum toxin (BoTx) injection in patients with esophageal achalasia. SUMMARY BACKGROUND DATA: Although myotomy is thought to offer better results, recent studies have reported 80% success rates after 2 BoTx injections a month apart. No randomized controlled trials comparing the 2 treatments have been published so far. MATERIALS AND METHODS: Newly diagnosed achalasia patients were randomly assigned to BoTx injection or laparoscopic myotomy. Symptoms were scored; lower esophageal sphincter resting and nadir pressures were measured by manometry; barium swallow was used to assess esophageal diameter pre- and post-treatment. Eight to one hundred units of BoTx were injected twice, a month apart, at the esophagogastric junction. Myotomy included anterior partial (Dor) or Nissen fundoplication. RESULTS: Eighty patients were involved in the study: 40 received BoTx and 40 underwent myotomy. Mortality was nil. One surgical patient bled from the trocar site. Median hospital stay was 6 days for surgery; BoTox patients were treated as day-hospital admissions. All patients completed the follow-up. After 6 months, the results in the 2 groups were comparable, although symptom scores improved more in surgical patients (82% confidence interval [CI] 76-89 vs. 66% CI 57-75, P < 0.05). The drop in lower esophageal sphincter pressure was similar in the 2 groups; the reduction in esophageal diameter was greater after surgery (19% CI 13-26 vs. 5% CI 2-11, P < 0.05). Later on, symptoms recurred in 65% of the BoTx-treated patients and the probability of being symptom-free at 2 years was 87.5% after surgery and 34% after BoTx (P < 0.05). CONCLUSION: Laparoscopic myotomy is as safe as BoTx treatment and is a 1-shot treatment that cures achalasia in most patients. BoTx should be reserved for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation.

Adolescent↗
PubMed2003

Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice.

We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome c oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: (1) high post-implantation embryonic lethality, affecting approximately 90% of the Surf1(-/-) individuals; (2) early-onset mortality of post-natal individuals; (3) highly significant deficit in muscle strength and motor performance; (4) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; (5) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; (6) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency in vivo, and evaluate the efficacy of treatment.

Alleles↗
PubMed2003

Epileptic and imaging findings in perinatal hypoxic-ischemic encephalopathy with ulegyria.

Hypoxic-ischemic encephalopathy due to fetal or neonatal asphyxia is a major cause of acute mortality and chronic disability involving cerebral palsy, seizures, and mental retardation. The gestational age of the infant is one of the main variables determining the neuropathological picture of hypoxic-ischemic brain injury, and ulegyria (one of its neuropathological correlates) typically affects full-term infants. The damage usually involves the deeper sulcal portion of the convolutions while sparing the crowns, and includes subcortical white matter atrophy and gliosis. The aim of this study was to characterize the electroclinical features of hypoxic-ischemic encephalopathy when ulegyria is one of its main neuropathological features. To this end, nine patients with MRI-proven ulegyria and epilepsy underwent a complete neurological work-up. The ulegyric lesions were mainly distributed in the parasagittal watershed areas and frequently associated with other hypoxic-ischemic lesions. The neurological picture was characterized in most patients by mental retardation, motor deficits, and drug-refractory partial epilepsy. The ulegyria in our patients was associated with a complex clinical picture: epilepsy was a prominent component, and its severity directly correlated with the extent of the ulegyria and the associated hypoxic-ischemic lesions. Drug refractoriness was an almost constant correlate of this form of symptomatic epilepsy.

Adolescent↗
PubMed2003

Neurogenesis in cerebral heterotopia induced in rats by prenatal methylazoxymethanol treatment.

We have previously demonstrated that the antiproliferative agent methylazoxymethanol acetate (MAM) is able to induce in rats cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia (PNH), a cerebral dysgenesis frequently observed in human patients affected by drug-resistant focal epilepsy. In this study, we investigated the time-course of neurogenesis in the cerebral heterotopia of MAM-treated rats, with the idea of understanding why PNH develop in human patients. For these goals, we analyzed the cytoarchitectural features, the time of neurogenesis and the cellular phenotype of the heterotopia, by means of BrdU immunocytochemistry and confocal immunofluorescence experiments. Our data demonstrate that the different types of heterotopia in MAM-treated rats are formed through the same altered neurogenetic process, which follows quite organized neurogenetic gradients. The MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different heterotopic structures. The neurogenesis of MAM-induced heterotopia may explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in human patients.

Animals↗
PubMed2003

The NMDA receptor complex is altered in an animal model of human cerebral heterotopia.

Double intraperitoneal injections of methylazoxymethanol (MAM) in pregnant rats induce developmental brain dysgenesis with nodular heterotopia similar to human periventricular nodular heterotopia (PNH) and composed of hyperexcitable neurons. Here we analyzed the NMDA receptor complex and associated proteins in the heterotopic neurons of 2- to 3-month-old MAM-treated rats by means of a combined immunocytochemical/molecular approach. Our data demonstrated a clear reduction of p286-active form of alphaCaMKII and a selective impairment of both the targeting and the CaMKII-dependent phosphorylation of NR2A/B subunits in the postsynaptic membranes of the MAM-induced heterotopia. The reduced NR2A/B immunofluorescence of the cellular membrane was not due to reduced expression since it was decreased only in postsynaptic fractions but not in the homogenate. NMDA-NR1 and AMPA-GluR2/3 subunits, as well as PSD-95 and total alphaCaMKII protein levels, were not affected in MAM-treated rats, thus revealing that the overall composition of the postsynaptic fraction was not altered. These data clearly suggest that the molecular organization of the NMDA/alphaCaMKII complex is selectively altered in the postsynaptic compartment of heterotopic neurons. This alteration can play a role in determining the hyperexcitability of brain heterotopia in MAM rats as well as in human patients affected by PNH.

Animals↗
PubMed2003

The genesis of epileptogenic cerebral heterotopia: clues from experimental models.

The pre-natal administration of methylazoxymethanol acetate (MAM) in rats is able to induce cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia, a cerebral dysgenesis frequently associated with drug-resistant focal seizures. In the present study, we investigated the mode of neurogenesis in cerebral heterotopia of MAM-treated rats, by analyzing post-natal cytoarchitectural features and time of neurogenesis using bromodeoxyuridine immunocytochemistry. The cytoarchitectural analysis demonstrated the existence, in the early post-natal period, of white matter cellular bands in close anatomical relationship with the heterotopia, which most likely serve as a reservoir of young, migrating neurons for the newly forming heterotopia. The birth dating analysis demonstrated that the period of generation of neurons within the heterotopia and adjacent white matter bands, was extended in comparison to corticogenesis in normal rat brains. In addition, it demonstrated that the heterotopia were formed through a rather precise outside-in (for cortical and periventricular heterotopia) and dorso-ventral (for intra-hippocampal heterotopia) neurogenetic pattern. We hypothesize that the MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different types of heterotopia. On this basis, we suggest a neurogenetic scheme for MAM-induced heterotopia that can also explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in humans.

Animals↗
PubMed2002

AlphaCaMKII and NMDA-receptor subunit expression in epileptogenic cortex from human periventricular nodular heterotopia.

PURPOSE: Periventricular nodular heterotopia (PNH) is the most common human brain dysgenesis, very frequently characterized by focal drug-resistant epilepsy. To understand the cellular mechanisms underlying its intrinsic hyperexcitability, we investigated the expression of glutamate-receptor subunits and related proteins in four human patients affected by PNH. METHODS: PNH was diagnosed by means of magnetic resonance imaging. The epileptogenic area was revealed by depth electrode recordings and removed during epilepsy surgery. Sections from the removed cerebral tissue were analyzed by means of immunocytochemistry (ICC), with antibodies directed against N-methyl-d-aspartate (NMDA)-receptor subunits, the alpha subunit of the Ca2+/calmodulin-dependent kinase II (alphaCaMKII), and its active phosphorylated form. RESULTS: The ICC data demonstrated that the subcortical heterotopic nodules were consistently characterized by lower expression of alphaCaMKII and its activated form. In more pronounced cases (i.e., when the extension of the nodules to the neocortex determined clear layering abnormalities), the heterotopic tissue also was characterized by a decreased expression of NMDA-receptor subunits, which was particularly evident in the dendritic compartment. CONCLUSIONS: These data suggest the existence of an alteration of alphaCaMKII and the NMDA-receptor complex in the epileptogenic brain tissue of human PNH, which may play a role in the basic mechanisms of hyperexcitability associated with this brain dysgenesis.

Adult↗
PubMed2002

Etiology, diagnosis, and treatment of failures after laparoscopic Heller myotomy for achalasia.

OBJECTIVE: To assess the causes of failure of laparoscopic Heller myotomy and to verify whether endoscopic pneumatic dilation is a feasible treatment. SUMMARY BACKGROUND DATA: Laparoscopic Heller myotomy has proved an effective treatment for esophageal achalasia, with good or excellent results in 90% of patients. The treatment of failures remains controversial, however. METHODS: From 1992 to 1999, 113 patients underwent laparoscopic Heller myotomy for esophageal achalasia. Ten patients (8.7%) reported dysphagia (n = 7) or chest pain (n = 3) a median of 5 months after surgery (range 1-12) and were considered surgical failures. Pre- and postoperative radiologic, manometric, and 24-hour pH monitoring findings in patients with achalasia recurrence were compared with those of 74 asymptomatic subjects. RESULTS: The preoperative characteristics of the two groups were comparable. After surgery, a decrease in resting lower esophageal sphincter pressure was observed in both groups, whereas the abdominal and overall lengths were significantly shorter among the asymptomatic patients. No patients with recurrence had abnormal gastroesophageal reflux. Based on time to recurrence and manometric and fluoroscopic findings, the etiology of the recurrences was classified as incomplete myotomy upward (n = 1), incomplete myotomy or sclerosis of the myotomy downward (n = 7), or sigmoid megaesophagus (n = 1); in one patient the authors could not establish the etiology. Seven of nine patients were effectively treated with endoscopic pneumatic dilations (median 2 dilations, range 1-4); one refused to undergo further treatment. Two patients underwent redo surgery. CONCLUSIONS: Recurrence of symptoms after myotomy is mainly related to incomplete myotomy or sclerosis of the distal site of the myotomy; it can be treated by dilations after surgery.

Adolescent↗