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Background: Sudden Infant Death Syndrome (SIDS) is characterized by the death of an infant that cannot be explained, despite a systematic case examination, including death scene investigation, autopsy and review of the clinical history. Nowadays, Sudden Unexpected Infant Death (SUID) is a wide-ranging concept used to describe any sudden and unexpected death, whether explained or unexplained, including SIDS, which occurs during the first year of life. Several differing and sometimes contradictory hypotheses of the underlying mechanisms of SIDS have been proposed. The most reliable seems to be the “triple risk hypothesis”. Based on this theory, unexpected infant deaths might arise as a consequence of the combination of three factors coming together: a vulnerable infant, a vulnerable phase of development and a final insult occurring in this window of vulnerability. Recently, a unified neuropathological theory contributes to describing SIDS. According to this, serotonergic neurons play a crucial homeostatic function in the cardiorespiratory brainstem centres. A high incidence of morphological abnormalities and biochemical defects of serotoninergic neurotransmission have been reported in the brainstem of SIDS victims. This brain region includes the main nuclei and structures that coordinate the vital activities, such as cardiovascular function and breathing, perinatal and after birth. Nevertheless, evidence suggests likely genomic complexity and a degree of overlap among SIDS, Sudden Intrauterine Death (SIUD), Sudden Cardiac Death (SCD) and Sudden Unexpected Death in Epilepsy (SUDEP). In SUDEP, which has clinical parallels with SIDS, alterations to medullary serotoninergic neural populations and autonomic dysregulation have been shown too. Molecular profiling of SUDEP cases and the investigation of genetic models have directed to the identification of putative SUDEP genes of which most are ion channel active along the neurocardiac, neuroautonomic, and neurorespiratory pathway. Concurrently, anomalous time- activation, transcription or regional expression of candidate neuro-cardiac-respiratory genes implicated for SUDEP, could be similarly involved in other unexpected sudden deaths. A small but significant proportion of infants who die suddenly and unexpectedly have been shown on postmortem genetic testing to have Developmental Serotonopathies, Cardiac Channelopathies and Autonomic Nervous System Dysregulation, with considerable implications for surviving and future family members. This has led to the demonstration that neuro-cardiac genes are expressed in both tissues (brain and heart) and recently in the respiratory system. Aim: Despite their decreasing incidence, SIDS and SUDEP are still important causes of death. There are many nuclei in the cardio and respiratory centres of the brain involved in unexpected and sudden deaths. Cardiac, sympathetic, and respiratory motor activities can be viewed as a unified rhythm controlled by brainstem neural circuits for effective and efficient gas exchange. We aim to describe abnormalities in these nuclei, in part because robust molecular or functional examination of these nuclei has not been carefully performed. We intend to perform detailed functional mapping of these brainstem nuclei. Specifically, the cardiorespiratory and cardioventilatory coupling can be understood as a unified vital rhythm controlled by brainstem neural circuits. By cardiorespiratory coupling, we mean the Respiratory Sinus Arrhythmia (RSA) that is characterized by a heart rate (HR) increasing during inspiration and an HR decrease during expiration. Conversely, Cardioventilatory coupling (CVC) is considered the influence of heartbeats and arterial pulse pressure on respiration with the tendency for the next inspiration to start at a preferred latency after the last heartbeat in expiration. We hypothesized that these two reflex systems are not separate, but constitute an integrated network. We defined this last concept as "unifying theory". By studying all the maps of the cardiorespiratory nuclei of the Literature, we integrated this concept into a reworking map of brainstem nuclei that could also explain the gasping and blocking cardiorespiratory of sudden deaths. The theory of a unique, unifying cardiorespiratory network, it has been recently demonstrated in some cases of arrhythmia, in some cases of SUDEP with striking systolic hypotensive changes and in some cases of SIDS too. Material and Methods: We investigated articles, reviews indexed in PubMed describing putative neuro-cardiac-respiratory genes and cardiorespiratory, and cardioventilatory coupling theories. Specifically, we evaluated cardiorespiratory brainstem nuclei and whole brains of fetal, infant and adult autopsies respectively to detect congenital errors in the cerebral development or malformations, but also to identify the “normal” or “dysplastic” brainstem centres. Results: Based on the Literature, we identified a brain-heart gene mapping and a scheme of cardiorespiratory brainstem nuclei network. Contemporary, we collected a large pool of fetal brain malformations and cardiorespiratory nuclei dysgenesis both in infants both in adult sudden deaths. We found dysgenesia, agenesia and hypoplasia of brainstem nuclei associated with SIDS cases, compared with post-mortem infant control cases. However, the arcuate nucleus showed insignificant inter-variations regarding adults autoptic cases. Discussion: Many intrinsic and extrinsic factors increase fetal, perinatal, infant, and adult sudden death susceptibility. The final common pathway for SIDS and SUDEP involves a failure to arouse and autoresuscitate in response to environmental challenge. The different risk factors, among these a prone position, can directly alter the function of cardiorespiratory nuclei and impair the ability of this network to coordinate cardiorespiratory–cardioventilatory coupling. Conclusions: Neuropathological analysis of the infant brainstem and neuro-cardiac-respiratory gene mapping represents a good tool to infer on the final events of SIDS and SUDEP, although nothing it is clear regarding the role of adult cardiorespiratory centres. An integrated study of postmortem neuropathology and molecular autopsies could help to understand the network of this beating-breathing-thinking unit.

We report a new case of p63/cytokeratin 7 (CK7) positive syringocystadenocarcinoma papilliferum (SCACP), on the shoulder of an 88-year-old man, with superficial dermal infiltration and squamoid differentiation. We describe the 24th case of SCACP, the malignant counterpart of syringocystadenoma papilliferum (SCAP). At the present, we do not know whether SCACP arises from eccrine or apocrine glands because of the contrasting opinions in the literature. Only few histochemical and ultrastructural studies have previously advised that SCACP could arise from pluripotent stem cells. Through our case, we wish to suggest the stem cell-like properties of the syringocystadenocarcinoma papilliferum. This rare neoplasm shows two different patterns of stem cell marker expression in the glandular and squamous components, respectively. For the double phenotype of SCACP, we propose it like an intriguing model to study histogenesis and stem cell properties for more wide-ranging epithelial tumors.

Introduction. The subcortical region underneath Wernicke’s area (WA) is a critical crossing of the eloquent language pathways involved in all semantic, phonological, syntactic, and working memory elaboration. We report the resection of a CA located underneath the dominant WA discussing the functional and anatomical evidence provided by fMRI, dissections with Klingler’s technique, and intraoperative mapping during awake surgery. Case Report. A 64-year-old right-handed female affected by daily complex focal seizures underwent f-MRI, showing language activations in the middle and inferior temporal gyri and an unusual free entry zone in the “classical” WA. The cortical intraoperative mapping partially confirmed the f-MRI results, and we approached the lesion directly through WA. Subcortical DES allowed the identification of the eloquent language pathways and the radical resection of the perilesional gliotic rim. The patient did not report deficits and she is seizures and drug free after 1-year surgery. Discussion. Cortical DES demonstrated the variability of the eloquent areas within the cortex of the dominant temporal lobe. The subcortical DES confirmed the crucial role in language elaboration and the anatomical course of the bundles underneath WA. Conclusions. Awake surgery with DES represents a reliable and dynamic technique also for safer and functional-customized resection of CAs.

The microRNAs (miRNAs) are small size non-coding RNAs that regulate expression of target mRNAs at post-transcriptional level. miRNAs differentially expressed under pathological conditions may help identifying mechanisms underlying the disease and may represent biomarkers with prognostic value. However, this kind of studies are difficult in the brain because of the cellular heterogeneity of the tissue and of the limited access to fresh tissue. Here, we focused on a pathology affecting specific cells in a subpopulation of epileptic brains (hippocampal granule cells), an approach that bypasses the above problems. All patients underwent surgery for intractable temporal lobe epilepsy and had hippocampal sclerosis associated with no granule cell pathology in half of the cases and with type-2 granule cell pathology (granule cell layer dispersion or bilamination) in the other half. The expression of more than 1000 miRNAs was examined in the laser-microdissected dentate granule cell layer. Twelve miRNAs were differentially expressed in the two groups. One of these, miR487a, was confirmed to be expressed at highly differential levels in an extended cohort of patients, using RT-qPCR. Bioinformatics searches and RT-qPCR verification identified ANTXR1 as a possible target of miR487a. ANTXR1 may be directly implicated in granule cell dispersion because it is an adhesion molecule that favors cell spreading. Thus, miR487a could be the first identified element of a miRNA signature that may be useful for prognostic evaluation of post-surgical epilepsy and may drive mechanistic studies leading to the identification of therapeutic targets.