New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus.

This study aimed to investigate, for the first time, the potential role of the gigantocellular nucleus, a component of the reticular formation, in the pathogenetic mechanism of Sudden Infant Death Syndrome (SIDS), an event frequently ascribed to failure to arouse from sleep. This research was motivated by previous experimental studies demonstrating the gigantocellular nucleus involvement in regulating the sleep-wake cycle. We analyzed the brains of 48 infants who died suddenly within the first 7 months of life, including 28 SIDS cases and 20 controls. All brains underwent a thorough histological and immunohistochemical examination, focusing specifically on the gigantocellular nucleus. This examination aimed to characterize its developmental cytoarchitecture and tyrosine hydroxylase expression, with particular attention to potential associations with SIDS risk factors. In 68% of SIDS cases, but never in controls, we observed hypoplasia of the pontine portion of the gigantocellular nucleus. Alterations in the catecholaminergic system were present in 61% of SIDS cases but only in 10% of controls. A strong correlation was observed between these findings and maternal smoking in SIDS cases when compared with controls. In conclusion we believe that this study sheds new light on the pathogenetic processes underlying SIDS, particularly in cases associated with maternal smoking during pregnancy.

Sudden intrauterine unexplained death: time to adopt uniform postmortem investigative guidelines?

BACKGROUND: Worldwide approximately 2.6 million are stillborn, mostly occurring in developing countries. In the great part these deaths are inexplicable. The evenness and standardisation of the diagnostic criteria are prerequisites to understand their pathogenesis. The core goal of this article is to propose new evidence based investigative post-mortem guidelines that should be adopted in all the Institutions especially when a fetal death, after a routine autopsy procedure, is diagnosed as "unexplained". The proposed protocol is mainly focused on the anatomopathological examination of the autonomic nervous system and in particular of the brainstem where the main centers that control vital functions are located. METHODS: Updated investigative guidelines for the examination of unexplained stillbirths, prevalently focused on the histological examination of the brainstem, where the main centers that are involved in monitoring the vital functions are located, are here presented. A section of this protocol concerns the Immunohistochemical evaluation of specific functional markers such as the neuronal nuclear antigen, nicotinic acetylcholine receptors, serotonin, orexin, apoptosis and gliosis. The important role of risk factors, having regard in particular to maternal smoking and air pollution is also contemplated in these guidelines. RESULTS: Specific morphological and/or functional alterations of vital brainstem structures have been found with high incidence in over 100 cases of unexplained fetal death sent to the "Lino Rossi Research Center" of the Milan University according to the Italian law. These alterations were rarely detected in a group of control cases. CONCLUSIONS: We hope this protocol can be adopted in all the Institutions notably for the examination of unexplained fetal deaths, in order to make uniform investigations. This will lead to identify a plausible explanation of the pathogenetic mechanism behind the unexplained fetal deaths and to design preventive strategies to decrease the incidence of these very distressing events for both parents and clinicians. TRIAL REGISTRATION: not applicable for this study.

Neuropathology of Early Sudden Infant Death Syndrome-Hypoplasia of the Pontine Kolliker-Fuse Nucleus: A Possible Marker of Unexpected Collapse during Skin-to-Skin Care.

OBJECTIVE: To find a possible pathogenetic mechanism of the early sudden infant death occurring in newborns during the skin-to-skin care (SSC), through the examination of neuronal centers regulating the vital activities. STUDY DESIGN: This is an in-depth examination of the brain stem in 22 healthy term newborns, suddenly died in the first hour of life without the identification of a cause at autopsy (early sudden infant death syndrome [eSIDS]), 12 of them concomitantly with SSC, and 10 with age-matched controls died of known pathology. RESULTS: Developmental alterations of neuronal structures of the brain stem were highlighted in 19 of the 22 eSIDS, but not in control. The hypoplasia of the pontine Kölliker-Fuse nucleus (KFN), an important respiratory center, was diagnosed at the histological examination, validated by morphometric quantifications, in 11 of the 12 eSIDS while they were placed on the mother's chest and in 2 of the 10 SSC unrelated neonatal deaths. CONCLUSION: The delayed development of the KFN could represent a specific finding of eSIDS occurring during SSC. Therefore, it is necessary to point out that the SSC represents a further risk factor that must be added to others already known for sudden infant death syndrome. Then this practice needs appropriate monitoring strategies of the infant's conditions.

Bi-parametric magnetic resonance imaging applied to obstetrics.

Foetal magnetic resonance imaging (MRI) plays an increasingly important role in the diagnosis of foetal abnormalities. Over the years, we have successfully applied bi-parametric MRI (bp-MRI) to the following obstetric conditions: (1) neurologic vascular diseases; (2) assessment of lung parenchyma maturation; (3) renal pathologies, such as polycystic kidney, suspected renal infarction, unilateral or bilateral renal agenesis; (4) placental pathologies, as twin-twin transfusion syndrome or placenta accreta; (5) benignant and malignant congenital tumours or cysts of the liver, such as haemangioendothelioma, hepatoblastoma or metastatic neuroblastoma, of the kidney (e.g. mesoblastic nephroma) and of the retroperitoneum, such as teratoma. The information derived from bp-MRI, and concerned with water motions in different tissues, improved the morphologic details provided by conventional foetal MRI. It has the potential to increase the value of MRI in the assessment of a wide range of foetal pathologies, particularly in renal diseases, allowing an adequate management decision and therapy.

Loss of CDKN2A Promoter Methylation Coincides With the Epigenetic Transdifferentiation of Uterine Myosarcomatous Cells.

Leiomyosarcoma is the most common type of uterine sarcoma and usually displays typical morphology. Heterologous leiomyosarcoma is the rarest variant, in which the tumor contains liposarcomatous, osteosarcomatous, or rhabdomyosarcomatous components. We have investigated the largest series of uterine leiomyosarcoma with a rhabdomyosarcomatous component and we have disclosed a molecular finding, which coincides to the process of transdifferentiation from smooth muscle into striated muscle phenotype. The surgical specimens of 5 rare cases of uterine leiomyosarcoma with a rhabdomyosarcomatous component were formalin fixed and paraffin embedded. In addition to hematoxylin/eosin stains, phosphotungstic acid hematoxylin staining, immunohistochemistry, and methylation-specific polymerase chain reaction the CDKN2A promoter region were performed. Leiomyosarcomatous cells were found to be strongly immunoreactive for both desmin and α-smooth muscle actin. Rhabdomyosarcomatous cells were immunoreactive for sarcomeric actin, desmin, vimentin, CD10, and p16. The methylation-specific polymerase chain reaction revealed the presence of a methylated allele and an unmethylated allele in the microdissected samples, coming from leiomyosarcomatous cells. On the contrary, 2 unmethylated alleles, molecular expression of a loss of heterozygosity, were detected in all the microdissected samples in the rhabdomyosarcomatous cells. The loss of heterozygosity methylation in the promoter region of the CDKN2A gene, occurred only in the rhabdomyosarcomatous cells with increases in both p16 and p14 expression. This event may result in an inhibition of cdk4/cdk6 activity, stabilizes the tumor suppressor protein p53, and coincides with the transdifferentiation from smooth muscle into striated muscle.

Testosterone Aromatization to Estradiol in Course of Ovarian Functioning Brenner Tumor Associated With Endometrial Carcinoma and Endometriosis (Roncati-Manenti Triad).

OBJECTIVE: Aromatization is the biochemical process in which aromatase catalyzes the conversion of testosterone into estradiol, the fundamental pathway for the synthesis of estrogens. When enhanced, it can lead to hyperestrogenism, a well-known risk factor for gynecological cancers. METHODS: The surgical specimens, coming from 2 postmenopausal women with hyperestrogenism on pap smear and bioptic diagnosis of endometrial endometrioid carcinoma, were fixed in 10% neutral buffered formalin, paraffin embedded, and then submitted for routine hematoxylin/eosin staining and immunohistochemical characterization for antiestrogen, antiprogesterone, antitesterone, anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6. RESULTS: The presence of an undescribed triad represented by ovarian functioning Brenner tumor, endometrial carcinoma, and pelvic endometriosis has been ascertained. The immunohistochemical investigation proved a normal expression of the DNA mismatch repair proteins and revealed a bimodal hormonal status in the pathological tissues, that is, the Brenner tumor cells showed a high expression of testosterone, contrariwise endometrioid carcinoma and endometriosis a high estrogen and progesterone immunolabeling. CONCLUSIONS: This synchronous triad underlines the importance of aromatization and hyperestrogenism in the development of gynecological malignancies in which the immunohistochemical detection of an active source of hormone production - to always keep in consideration during synchronous diseases - can guide subsequent antihormone chemotherapy based on aromatase inhibitors.

The first investigative science-based evidence of Morgellons psychogenesis.

Morgellons disease is an infrequent syndromic condition, that typically affects middle-aged white women, characterized by crawling sensations on and under the skin, associated with itchy rashes, stinging sores, fiber-like filaments emerging from the sores, severe fatigue, concentrating difficulty, and memory loss. The scientific community is prone to believe that Morgellons is the manifestation of various psychiatric syndromes (Munchausen, Munchausen by proxy, Ekbom, Wittmaack-Ekbom). Up until now, no investigative science-based evidence about its psychogenesis has ever been provided. In order to close this gap, we have analyzed the filaments extracted from the skin lesions of a 49-year-old Caucasian female patient, by using a Field Emission Gun-Environmental Electron Scanning Microscope equipped with an X-ray microprobe, for the chemico-elemental characterization of the filaments, comparing them with those collected during a detailed indoor investigation, with careful air monitoring, in her apartment. Our results prove the self-introduction under the epidermis of environmental filaments. For the first time in the literature, we have scientifically demonstrated the self-induced nature of Morgellons disease, thereby wiping out fanciful theories about its etiopathogenesis.

The First 5-Year-Long Survey on Intrauterine Unexplained Sudden Deaths from the Northeast Italy.

PURPOSE: Sudden intrauterine unexplained death syndrome (SIUDS) represents one of the main open issues in the scientific and social setting of the modern medicine, and our efforts have aimed to understand its possible causes and risk factors. METHODS: A 43-case series of consecutive unexplained fetal deaths coming from Northeast Italy, collected in a 5-year period (2011-2015), has been submitted to an in-depth investigation, based on neuropathological and cardiopathological examinations, immunohistochemistry for neuronal nuclear antigen (NeuN), genetic characterization for the serotonin transporter (5-HTT) gene polymorphisms, and toxicological environmental analyses. RESULTS: The overall survey from the neuropathological findings highlights one or more congenital morphological abnormalities of the autonomic nervous system in 77% of cases of sudden fetal deaths. CONCLUSIONS: From our results emerges the need to perform a complete autopsy of all SIUDS victims with an in-depth examination of the neuronal centers of the brainstem, which modulate the vital functions.

ESEM Detection of Foreign Metallic Particles inside Ameloblastomatous Cells.

Ameloblastoma is a borderline tumor of odontogenic origin, with a high recurrence rate and possible local aggressiveness. The etiopathogenetic factors involved in its occurrence are not still defined and our study has been precisely aimed to search for novel factors associated with its development. Sections cut from paraffin blocks, containing the representative specimens of 18 different ameloblastomas, collected in a 15-year period (1999-2014), have been observed by an environmental scanning electron microscope, in order to search micro- and nano-sized particles and to identify their composition. In all the neoplastic cases, micro- and nano-sized metallic debris, differing in size and composition, have been detected inside the ameloblastomatous cells. On the contrary, the total absence of metallic particles in the healthy control cases has been emerged. Our results reveal a relationship between ameloblastoma and metallic particulate. The cigarette smoke and the routine dental practice appear the most probable source for the presence of these biopersistant inorganic particles inside the neoplastic cells.

Detection of small (≤ 2 cm) pancreatic adenocarcinoma and surrounding parenchyma: correlations between enhancement patterns at triphasic MDCT and histologic features.

BACKGROUND: The aim is to assess the time-density curves (TDCs) and correlate the histologic results for small (≤ 2 cm) PDA and surrounding parenchyma at triphasic Multidetector-row CT (MDCT). METHODS: Triphasic MDCT scans of 38 consecutive patients who underwent surgery for a small PDA were retrospectively reviewed. The TDCs were analyzed and compared with histologic examination of the PDA and pancreas upstream/downstream in all cases. Three enhancement patterns were identified: 1) enhancement peak during pancreatic parenchymal phase (PPP) followed by a rapid decline on portal venous phase (PVP) and delayed phase (DP) at 5 minutes (type 1 pattern: normal pancreas); 2) maximum enhancement in PVP that gradually decreases in DP (type 2 pattern: mild chronic pancreatitis or PDA with mild fibrous stroma); 3) progressive enhancement with maximum peak in DP (type 3 pattern: severe chronic pancreatitis or PDA with severe fibrous stroma). A p value less than 0.05 was considered statistically significant. Sensitivity was calculated for PDA detection and an attenuation difference with the surrounding tissue of at least 10 HU was considered. RESULTS: PDA showed type 2 pattern in 5/38 cases (13.2%) and type 3 pattern in 33/38 cases (86,8%). Pancreas upstream to the tumor had type 2 pattern in 20/38 cases (52,6%) and type 3 pattern in 18/38 cases (47,4%). Pancreas downstream to the tumor had type 1 pattern in 19/25 cases (76%) and type 2 pattern in 6/25 cases (24%). Attenuation difference between tumor and parenchyma upstream was higher of 10 UH on PPP in 31/38 patients (sensitivity = 81.6%), on PVP in 29/38 (sensitivity = 76.3%) and on DP in 17/38 (sensitivity = 44.7%). Attenuation difference between tumor and parenchyma downstream was higher of 10 UH on PPP in 25/25 patients (sensitivity = 100%), on PVP in 22/25 (sensitivity = 88%) and on DP in 20/25 (sensitivity = 80%). Small PDAs were isodense to the pancreas upstream to the tumor, and therefore unrecognizable, in 8 cases (8/38; 21%) at qualitative analysis and in 4 cases (4/38; 10,5%) at quantitative analysis. CONCLUSIONS: The quantitative analysis increases the sensitivity for detection of small PDA at triphasic MDCT.

Involvement of the Superior Colliculus in SIDS Pathogenesis.

The aim of this study was to investigate the involvement of the mesencephalic superior colliculus (SC) in the pathogenetic mechanism of SIDS, a syndrome frequently ascribed to arousal failure from sleep. We analyzed the brains of 44 infants who died suddenly within the first 7 months of life, among which were 26 infants with SIDS and 18 controls. In-depth neuropathological investigations of serial sections of the midbrain showed the SC layered cytoarchitectural organization already well known in animals, as made up of seven distinct layers, but so far never highlighted in humans, albeit with some differences. In 69% of SIDS cases but never in the controls, we observed alterations of the laminar arrangement of the SC deep layers (precisely, an increased number of polygonal cells invading the superficial layers and an increased presence of intensely stained myelinated fibers). Since it has been demonstrated in experimental studies that the deep layers of the SC exert motor control including that of the head, their developmental disorder could lead to the failure of newborns who are in a prone position to resume regular breathing by moving their heads in the sleep-arousal phase. The SC anomalies highlighted here represent a new step in understanding the pathogenetic process that leads to SIDS.