Papers by Emanuela Maderna
HOMO
The paper presents the skeletal remains of an adult male of 30-40 years with bone lesions and def... more The paper presents the skeletal remains of an adult male of 30-40 years with bone lesions and deformity on the left hip, recovered during the archaeological excavation below the former Basilica of San Dionigi, dated to Late Antiquity (3 rd-5 th century AD) Milan. Biological profile and paleopathological analysis were performed following standard references and the bones underwent radiological examination. Differential diagnosis included congenital anomaly, active rickets, infectious diseases, femoral neck trauma, Legg-Carvé-Perthes disease, Slipped Capital Femoral Epiphysis (SFCE), osteogenesis imperfecta and osteoporosis. While the lesions were highly consistent with Legg-Calvé-Perthes disease, they were typical of SFCE, complicated by an avascular necrosis and secondary osteoarthrosis. The alteration of the femoral head led to a 7.8% leg-length discrepancy, causing gait alteration with partial compensation though increased muscular activity on the right leg, reduced mobility of the joint and potentially hip pain, difficulty in walking and running and even limping. This paper explores a case of physical disability from the Roman era found near a Christian place of worship and represents a rare case of SFCE in the paleopathological record.
Journal of Alzheimer's Disease, 2014
American Academy of Forensic Sciences 67th Annual Meeting, 2015
In the classical Bonus-Malus System (BMS) in automobile insurance, the premium for the next year ... more In the classical Bonus-Malus System (BMS) in automobile insurance, the premium for the next year is adjusted according to the policyholder's claim history (particularly frequency) in the previous year. Some variations of the classical BMS have been considered by taking more of driver's claim experience into account to better assess individual's risk. Nevertheless, we note that in practice it is common for a BMS to adopt transition rules according to the claim history for the past multiple years in countries such as Belgium, Italy, Korea, and Singapore. In this paper, we revisit a modified BMS which was briefly introduced in Lemaire (1995) and Pitrebois et al. (2003a). Specifically, such a BMS extends the number of Bonus-Malus (BM) levels due to an additional component in the transition rules representing the number of consecutive claim-free years. With the extended BM levels granting more reasonable bonus to careful drivers, this paper investigates the transition rules in a more rigorous manner, and provides the optimal BM relativities under various statistical model assumptions including the frequency random effect model and the dependent collective risk model. Also, numerical analysis of a real data set is provided to compare the classical BMS and our proposed BMS.
Medical History, 2022
The Ospedale Maggiore, known as Ca’ Granda, was founded in 1456 by will of Francesco Sforza, Duke... more The Ospedale Maggiore, known as Ca’ Granda, was founded in 1456 by will of Francesco Sforza, Duke of Milan, and was considered for almost five centuries a model for Milanese, Italian and even European healthcare. Attracting patients from all over Europe, the Ca’ Granda distinguished itself for the introduction of new treatments and innovative health reforms. In the burial ground of the hospital still lie the bodies of the deceased patients, who came from the poorest strata of the population. The study of their remains aims to give back a general identity and a story to each of these persons as well as reconstruct a fraction of the sixteenth century population of Milano as concerns lifestyle and disease and examine practises and therapy of this exceptional hospital. It is estimated that about two million commingled bones and articulated skeletons rest in the crypt, together with other types of findings (e.g., ceramic, coins, clothing). These remains are the object of a large project ...
All'Insegna del Giglio, 2019
Il volume Una favola breve riunisce una serie di contributi scientifici che in prospettiva diacro... more Il volume Una favola breve riunisce una serie di contributi scientifici che in prospettiva diacronica affrontano il tema della salute dell'infanzia, dell'abuso sul minore e della morte prematura, dal mondo antico (greco, italico e romano) fino all'era moderna. Il volume è parte di un più ampio progetto, intitolato Mors immatura, nato nel 2017 con l'obiettivo di costruire un fecondo dialogo interdisciplinare su temi delicati e non privi di ricadute nell'attualità: archeologia, antropologia, storia del diritto e della medicina possono scrivere pagine importanti sull'infanzia, contribuendo alla formazione di una coscienza civica e di un'attenta responsabilità sociale rispetto a tematiche tuttora di grande urgenza. Una favola breve Archeologia e antropologia per la storia dell'infanzia a cura di Claudia Lambrugo.
Case Report Radiation-induced glioblastoma in a medulloblastoma patient: A case report with molec... more Case Report Radiation-induced glioblastoma in a medulloblastoma patient: A case report with molecular features Abstract Journal Menu
Molecular Neurobiology, 2018
Delivering peptide-based drugs to the brain is a major challenge because of the existence of the ... more Delivering peptide-based drugs to the brain is a major challenge because of the existence of the blood-brain barrier (BBB). To overcome this problem, cell-penetrating peptides derived from proteins that are able to cross biological membranes have been used as cell-permeable and brain-penetrant compounds. An example is the transactivator of transcription protein transduction domain (Tat) of the human immunodeficiency virus. The basic domain of Tat is formed of arginine and lysine amino acid residues. Tat has been used as brain-penetrant carrier also in therapies for Alzheimer disease (AD), the most common form of dementia characterized by extracellular cerebral deposits of amyloid made up of Aβ peptide. The aim of our study was to assess whether Tat bind to amyloid deposits of AD and other amyloidoses. An in situ labeling using biotinylated Tat 48-57 peptide was employed in the brain tissue with amyloid deposits made up of Aβ (patients with AD and transgenic AD mice), of prion protein (patients with Gerstmann-Straussler-Scheinker disease), and other amyloidosis, processed by different fixations and pretreatments of histological sections. Our results showed that Tat peptide binds amyloid deposits made up of Aβ, PrP, and immunoglobulin lambda chains in the brain and other tissues processed by alcoholic fixatives but not in formalin-fixed tissue. The fact that biotinylated Tat peptide stains amyloid of different biochemical composition and the specific charge characteristics of the molecules suggests that Tat may bind to heparan sulfate glicosaminoglicans, that are present in amyloid deposits. Inhibition of the binding by Tat pre-incubation with protamine reinforces this hypothesis. Binding of Tat to amyloid deposits should be kept in mind in interpreting the results of studies employing this molecule as brain-penetrating compound for the treatment of cerebral amyloidoses. Our results also suggest that Tat may be helpful for the analysis of the mechanisms of amyloidogenesis, and in particular, the interactions between specific amyloid peptides and glicosaminoglicans.
European Journal of Neurology, 2022
Interpreting Bone Lesions and Pathology for Forensic Practice
Neurosurgery, 2008
OBJECTIVE Enterogenous cysts (ECs) of the central nervous system are developmental malformations ... more OBJECTIVE Enterogenous cysts (ECs) of the central nervous system are developmental malformations that occur in the spinal canal, posterior fossa, or cerebral hemispheres. They are usually benign lesions, and malignant transformation is rare. To date, only three cases of malignant transformation have been reported in the literature. We present a case of a cerebellopontine EC showing foci of epithelial dysplasia and malignant transformation into a low-grade papillary mucinous adenocarcinoma. CLINICAL PRESENTATION A 25 year-old man with a 6-year history of hypoacusia presented to our department with facial nerve deficit, visual disturbances, and gait instability. A magnetic resonance imaging scan demonstrated a multiloculated cerebellopontine angle cyst with supratentorial hydrocephalus. INTERVENTION A retrosigmoidal approach was used to achieve cyst removal. This was followed several months later by ventriculoperitoneal shunt placement. The cyst was adherent to the brainstem, cranial ...
Neuropathology, 2008
We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medullobla... more We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15-year-old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation-induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation-induced MGMT hyper-methylation and p53 mutations may have a role in the development of a subgroup of radio-induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post-irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.
Neuro-Oncology, 2007
To gain insight into the lineage of origin of medulloblastomas, the mRNA expression of NEUROG1, a... more To gain insight into the lineage of origin of medulloblastomas, the mRNA expression of NEUROG1, a gene encoding a proneural transcription factor transiently detected during nervous system development, was investigated in 27 human medulloblastomas characterized for mRNA expression of ATOH1, a marker of cerebellar granule precursors and corresponding medulloblastomas. Expression of Ngn1, the mouse homolog of NEUROG1, was also analyzed in the mouse cerebellar primordium. In addition, we studied mRNA expression of GLI1 as a marker of the SHH pathway activation, and nuclear b-catenin staining, b-catenin mutations, and mRNA expression of MYC as indicators of the WNT pathway status. In 15 cases, we also examined expression of OTX2, a transcription factor recently indicated as a positive marker of medulloblastomas originating from cerebellar granule precursors. The mRNA expression of NEUROG1 and Ngn1 was selectively found in medulloblastomas not expressing ATOH1 and in progenitors of the cerebellar ventricular zone, respectively. GLI1 transcript was expressed in medulloblastomas with ATOH1 transcript, whereas high levels of MYC transcript were
Neurological Sciences, 2010
The biological mechanisms associated with the development and rupture of intracranial aneurysms a... more The biological mechanisms associated with the development and rupture of intracranial aneurysms are not fully understood. To clarify the role of VEGF and the related receptors in the pathophysiology of aneurysm, immunostaining for VEGF, VEGFR1 and VEGFR2 was performed on specimens from six unruptured aneurysms and on two specimens of normal arteries wall as a control. The results were correlated
Journal of Neuro-Oncology, 2009
The hypothesis addressed by this study is that a glutamine synthetase (GS) deficiency in neoplast... more The hypothesis addressed by this study is that a glutamine synthetase (GS) deficiency in neoplastic astrocytes is a possible molecular basis associated with seizure generation in glioblastoma multiforme (GBM). Methods Quantitative Western blot analysis of GS was performed in 20 individuals operated for malignant glioma. Results The levels of GS in patients with GBM and epilepsy were significantly lower (range 0.04-1.15; mean 0.35 ± 0.36; median 0.25) than in non-epileptic GBM individuals (range 0.78-3.97; mean 1.64 ± 0.99; median 1.25; P = 0.002). No relationship has been found between histological features (i.e. necrosis, gliosis, stroma, inflammatory cells, giant cells, and haemosiderine) and GS expression or epilepsy. Discussion Even though the epileptogenesis in glioma is multifactorial, it is conceivable that a down-regulation of GS may have an important proepileptogenic role in GBM, through the slowing of glutamate-glutamine cycle. This study suggests that seizures in GBM are coupled with a highly localized enzyme deficiency. The manipulation of GS activity might constitute a novel principle for inhibiting seizures in patients with glioma epilepsy.
Cancer Research, 2012
The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of... more The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype and was mutually exclusive with amplification and expression of the EGF receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met high subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro and enhanced growth kinetics in vivo. In Met high cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas. Cancer Res; 72(17); 4537-50. Ó2012 AACR.
Cancer Biology & Therapy, 2006
Both clinical and biological features have been reported as prognostic factors in lowgrade glioma... more Both clinical and biological features have been reported as prognostic factors in lowgrade gliomas. Among these, histotype, tumor size, enhancement, age and genetic pattern. Microvessel density (MVD) has been correlated to clinical outcome in astrocytomas, but its impact in oligodendrogliomas and mixed tumors is not sure. The pro-angiogenic chemokine stromal cell-derived factor (SDF-1/CXCL12) and its receptor CXC chemokine receptor 4 (CXCR4) have been described in low-grade gliomas, with a correlation between CXCL12 expression and shorter time to progression (TTP). The intermediate filament Nestin is expressed in proliferating vessels. Platelet-derived growth factor B (PDGF-B) and its receptor PDGFR-β are also involved in angiogenesis and malignant progression in gliomas. The aim of this study was to retrospectively investigate the MVD and immunohistochemical expression of CXCL12, CXCR4, PDGF-B, PDGFR-β and Nestin in 40 patients (11 oligodendrogliomas and 29 oligoastrocytomas). In our study, oligodendroglioma histotype was associated with a trend to a more prolonged TTP than mixed tumors (p = 0.12). Age younger than 32, presurgery lack of enhancement at CT/MRI and total versus partial resection were not associated with longer TTP. Positivity for CXCL12 on tumor/endothelial cells was the only factor associated with a significantly shorter TTP (p = 0.011). Positivity for CXCL12 in tumor cells was predictive of a shorter survival time (p = 0.014). Since CXCL12 is not only related to angiogenesis, but also exerts an anti-apoptotic effect that may contribute to tumor progression/endothelial escape from apoptotic mechanisms, expression of CXCL12 by these tumors might add prognostic information to available clinical and bio-molecular indexes.
American Journal of Physical Anthropology, 2015
The variation and persistence of blood components, in particular red blood cells (RBCs), within b... more The variation and persistence of blood components, in particular red blood cells (RBCs), within bone tissue during the decomposition process, especially at the early stages and in different taphonomic conditions, has never been thoroughly investigated, regardless of the fact that knowing how blood survives or degrades within bone could be of help in solving many anthropological issues, such as trauma analysis and interpretation. This research investigated the influence of time and taphonomy on the persistence and detectability of blood components in parietal bone fragments (of different post mortem periods and taphonomic conditions) through histological (Hematoxilin and Eosin, HE) and immunohistochemical (Glycophorin A, GYPA) analyses. The immunohistochemical investigation for GYPA showed the presence of RBCs under the form of erythrocyte debris or residues otherwise morphologically unidentifiable using only HE staining. Hence, while well-defined RBCs can be observed only in the first week of decomposition, afterward these structures can be detectable with certainty only by immunohistochemical analysis, which reveals discrete quantities of RBC residues also in dry bone (post mortem interval, or PMI, of 15 years), but not in archaeological samples, in which the greater PMI and the different taphonomic conditions together could be the answer behind such difference. This study highlights the usefulness and potential of immunohistochemical detection of GYPA in RBC investigation and gives a realistic idea of the persistence and detectability of erythrocytes in different osteological taphonomic conditions, in contrast to results reported by some authors in literature. Another important result concerns the detection of RBC residues in dry bone, which opens the way to the possible use of RBCs in trauma interpretation. Am J Phys Anthropol, 2015. © 2015 Wiley Periodicals, Inc.
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Papers by Emanuela Maderna
These methods (macroscopic, microscopic and biomolecular) were applied on femora and tibiae of adult individuals, which came from four different known populations of different contexts of Milan (dated back from late roman age to contemporary).
To evaluate how the bone degrades at a (1) macroscopic level, Behrensmeyer’s classification was employed; instead to research the presence of (2) chemical elements (haemoglobin) we performed the Luminol test; finally for (3) histological analysis we employed the Oxford Histological Index (OHI) on calcified thin sections; the samples were also decalcified and stained in hematoxylin and eosin to evaluate the state of preservation of the organic components. A Decalcified Histological Index (DHI) was also created.
This study finally proves that macroscopic, microscopic and chemical preservation may not depend from each other, since bone conservation may be different according to the level at which one examines it. Therefore, the estimation of the diagenetic process cannot be limited to the macroscopic aspect of the bone tissue but must take into account microscopic and chemical alterations, since these may react differently.
Bone degradation can be employed to estimate post mortem interval, or to reconstruct the environment of the deposition of human remains or to verify the applicability of biological tests. However the evaluation of taphonomical alterations has to be performed at different levels, because bone surface is not a good predictor of the survival of the histological component; equally, luminol test performance is not necessarily in accordance to collagen preservation.