Objective Non-Invasive Bio-Parametric Evaluation of Regenerated Skin: A Comparison of Two Acellular Dermal Substitutes.

Several dermal substitutes are available on the market, but there is no precise indication that helps surgeons choose the proper one. Few studies have tried to compare different xenogeneic bioengineered products, but no objective bio-parametric comparison has been made yet. Fifteen patients who underwent skin reconstruction with Integra® or Pelnac® were retrospectively evaluated. After at least 12 months of follow-up, an objective and quantitative assessment of several skin biophysical properties, such as color, texture, elasticity, hydration, glossiness and trans-epidermal water loss, were measured with non-invasive skin measurement devices. The grafted skin showed a reduction of the superficial hydration level and a tendency to lower values of trans-epidermal water loss with both dermal substitutes. Melanic and hemoglobin pigmentation were higher in comparison to the donor site in both groups, while a melanic pigmentation increase versus the surrounding skin was seen just with Integra®. Finally, the skin was found to be more elastic when reconstructed with Integra®. The skin barrier appeared to be intact in both groups. Hence, these substitutes are valuable means of skin regeneration. Integra® seems to be more advantageous for reconstructing areas that need more skin flexibility.

Brain perivascular spaces and autism: clinical and pathogenic implications from an innovative volumetric MRI study.

Introduction: Our single-center case-control study aimed to evaluate the unclear glymphatic system alteration in autism spectrum disorder (ASD) through an innovative neuroimaging tool which allows to segment and quantify perivascular spaces in the white matter (WM-PVS) with filtering of non-structured noise and increase of the contrast-ratio between perivascular spaces and the surrounding parenchyma. Methods: Briefly, files of 65 ASD and 71 control patients were studied. We considered: ASD type, diagnosis and severity level and comorbidities (i.e., intellectual disability, attention-deficit hyperactivity disorder, epilepsy, sleep disturbances). We also examined diagnoses other than ASD and their associated comorbidities in the control group. Results: When males and females with ASD are included together, WM-PVS grade and WM-PVS volume do not significantly differ between the ASD group and the control group overall. We found, instead, that WM-PVS volume is significantly associated with male sex: males had higher WM-PVS volume compared to females (p = 0.01). WM-PVS dilation is also non-significantly associated with ASD severity and younger age (< 4 years). In ASD patients, higher WM-PVS volume was related with insomnia whereas no relation was found with epilepsy or IQ. Discussion: We concluded that WM-PVS dilation can be a neuroimaging feature of male ASD patients, particularly the youngest and most severe ones, which may rely on male-specific risk factors acting early during neurodevelopment, such as a transient excess of extra-axial CSF volume. Our findings can corroborate the well-known strong male epidemiological preponderance of autism worldwide.

The attitudes of European medical students towards the clinical importance of neuroanatomy.

The attitudes of medical students towards the clinical importance of neuroanatomy have been little studied. Because it has been reported that medical students find neuroanatomy difficult and can have 'neurophobia', here we test the hypothesis that early-stage medical students across Europe have a low regard for neuroanatomy's clinical relevance. The work was conducted under the auspices of the Trans-European Pedagogic Research Group (TEPARG), with just over 1500 students from 12 European medical schools providing responses to a survey (52% response rate) that assessed their attitudes using Thurstone and Chave methodologies. Regardless of the university surveyed, and of the teaching methods employed for neuroanatomy, our findings were not consistent with our hypothesis. However, the students had a less favourable opinion of neuroanatomy's importance compared to gross anatomy; although their attitudes were more positive than previously reported for histology and embryology. The extent to which neuroanatomy plays a significant role in the early years of medical education is moot. Nevertheless, we conclude that in addition to newly recruited medical students being informed of the subject's role in a healthcare profession, we advocate the use of modern imaging technologies to enhance student understanding and motivation and cognisance of the core syllabus for the subject being developed by the International Federation of Associations of Anatomists (IFAA).

Erdheim-Chester disease presenting with cough, abdominal pain, and headache.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytic disorder. The diagnosis was based on the relationship between radiologic findings, clinical manifestations, and pathologic features of the bone biopsy. We report a case of ECD with unusual presenting symptoms: a 56 year-old man presented with cough, abdominal pain, and recurrent episodes of headache associated without any seizures. Peculiar computer tomography (CT) findings were key for the diagnostic suspicion. Bone biopsy and other radiological investigations confirmed the diagnosis. CT findings can help raise the suspicion of ECD. CT is easy to perform and widely available in comparison with kinetic cardiac magnetic resonance imaging and nuclear imaging. Therefore, CT findings of ECD can reduce the therapeutic delay between diagnosis and therapy prescription.

Neuroanatomy, the Achille's Heel of Medical Students. A Systematic Analysis of Educational Strategies for the Teaching of Neuroanatomy.

Neuroanatomy has been deemed crucial for clinical neurosciences. It has been one of the most challenging parts of the anatomical curriculum and is one of the causes of "neurophobia," whose main implication is a negative influence on the choice of neurology in the near future. In the last decades, several educational strategies have been identified to improve the skills of students and to promote a deep learning. The aim of this study was to systematically review the literature to identify the most effective method/s to teach human neuroanatomy. The search was restricted to publications written in English language and to articles describing teaching tools in undergraduate medical courses from January 2006 through December 2017. The primary outcome was the observation of improvement of anatomical knowledge in undergraduate medical students. Secondary outcomes were the amelioration of long-term retention knowledge and the grade of satisfaction of students. Among 18 selected studies, 44.4% have used three-dimensional (3D) teaching tools, 16.6% near peer teaching tool, 5.55% flipped classroom tool, 5.55% applied neuroanatomy elective course, 5.55% equivalence-based instruction-rote learning, 5.55% mobile augmented reality, 5.55% inquiry-based clinical case, 5.55% cadaver dissection, and 5.55% Twitter. The high in-between study heterogeneity was the main issue to identify the most helpful teaching tool to improve neuroanatomical knowledge among medical students. Data from this study suggest that a combination of multiple pedagogical resources seems to be the more advantageous for teaching neuroanatomy.

Real-time telemetry monitoring of oxygen in the central complex of freely-walking Gromphadorhina portentosa.

A new telemetric system for the electrochemical monitoring of dissolved oxygen is showed. The device, connected with two amperometric sensors, has been successfully applied to the wireless detection of the extracellular oxygen in the central complex of freely-walking Gromphadorhina portentosa. The unit was composed of a potentiostat, a two-channel sensor conditioning circuit, a microprocessor module, and a wireless serial transceiver. The amperometric signals were digitalized and sent to a notebook using a 2.4 GHz transceiver while a serial-to-USB converter was connected to a second transceiver for completing the communication bridge. The software, running on the laptop, allowed to save and graph the oxygen signals. The electronics showed excellent stability and the acquired data was linear in a range comprised between 0 and -165 nA, covering the entire range of oxygen concentrations. A series of experiments were performed to explore the dynamics of dissolved oxygen by exposing the animals to different gases (nitrogen, oxygen and carbon dioxide), to low temperature and anesthetic agents (chloroform and triethylamine). The resulting data are in agreement with previous O2 changes recorded in the brain of awake rats and mice. The proposed system, based on simple and inexpensive components, can constitute a new experimental model for the exploration of central complex neurochemistry and it can also work with oxidizing sensors and amperometric biosensors.

Agenesis of the posterior arch of the atlas and complex alterations of the craniovertebral junction: A case report.

The craniovertebral junction is a unique part of the somite-derived axial skeleton. The absence or hypoplasia of the posterior arch of C1 is frequently associated with compensatory hypertrophy of the anterior arch of C1 and of the spinous process of C2. Here, we report a patient with agenesis of the posterior arch of C1 without neurologic deficits. Our patient presented with complex alterations of the craniovertebral junction that involved interactions between the condyles, clivus, atlas, and epistropheus. To our knowledge, dislocation of the odontoid process above the Chamberlain line, including cranial migration of the anterior arch of C1, has not been reported in the literature.

Association of Klippel-Feil syndrome, Dandy-Walker malformation, spina bifida: A case report.

Klippel-Feil syndrome is a congenital malformation characterized by the fusion of at least 2 cervical vertebrae. It may occur in association with other clinical syndromes and disorders. We describe a case of prenatal diagnosis of a Klippel-Feil syndrome with Dandy-Walker malformation, and spina bifida, proved by ultrasound examination. A postmortem x-ray and autopsy were performed in a female fetus of 16 + 6 weeks of gestation: several malformations have been discovered. To the best of our knowledge, no similar cases have been reported in the medical literature. This case report underscores the importance of a careful ultrasound screening during pregnancy for an adequate diagnostic and therapeutic management.

Trace elements in ALS patients and their relationships with clinical severity.

An exploratory study of trace elements in ALS and their relationships with clinical severity was detected. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that causes irreversible damage in humans, with the consequent loss of function of motoneurons (MNs), with a prognosis up to 5 years after diagnosis. Except to genetic rare cases it is not known the etiology of the disorder. Aim of our research is to investigate the possible role of heavy metals in the severity of the disease. In this study, by the use of plasma mass (ICP-MS), we have analyzed the content of essential and heavy metals such: Pb, Cd, Al, Hg, Mn, Fe, Cu, Zn, Se, Mg, and Ca, in blood, urine and hair of ALS patients and controls; moreover we divided the patients in two groups for disease severity and analyzed the difference among the groups, in order to study a possible involvement of metals in the severity of the damage. Our results suggest a protective role of Selenium, involved in protective antioxidant mechanisms, and a risk factor in the case of presence of Lead in blood. The levels of the other metals are not easy to interpret, because these may be due to life style and for essential metals a consequence of the disease condition, not a cause.

Essential trace elements in amyotrophic lateral sclerosis (ALS): Results in a population of a risk area of Italy.

Sardinian (Italy) island population has a uniquely high incidence of amyotrophic lateral sclerosis (ALS). Essential trace element levels in blood, hair, and urine of ALS Sardinian patients were investigated in search of valid biomarkers to recognize and predict ALS. Six elements (Ca, Cu, Fe, Mg, Se, and Zn) were measured in 34 patients compared to 30 age- and sex-matched healthy controls by a validated method. Levels of Ca and Cu in blood and of Se and Zn in hair were significantly higher in ALS than in controls, while urinary excretion of Mg and Se was significantly decreased. The selected cut-off concentrations for these biomarkers may distinguish patients with or without ALS with sufficient sensitivity and specificity. Many positive (as Se-Cu and Se-Zn) and negative associations (as Ca-Mg and Ca-Zn) between elements suggested that multiple metals involved in multiple mechanisms have a role in the ALS degeneration.

Epidemiology of multiple sclerosis in the pediatric population of Sardinia, Italy.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Several authors report MS affecting not only young adults but also children and adolescents. Sardinia is one of the regions at the highest risk for MS worldwide in the adult population; to date, no definite data exist on the pediatric population. The aim of this study was to estimate the incidence and prevalence of pediatric MS (pMS) in northern Sardinia. Patients with diagnosis of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), demyelinating disorders, MS, or clinically isolated syndrome (CIS) according to McDonald criteria were enrolled, when disease onset occurred within the range of 0-18 years. From January 1, 2001 to December 31, 2012, 21 cases of pMS and 5 cases of CIS were found in northern Sardinia. The annual mean pMS incidence was 2.85 cases per 100,000 pediatric population, and the annual mean CIS incidence was 0.68 cases per 100,000 pediatric population. The pMS and CIS prevalence computed on 31 December 2012 was 26.92 and 6.41 per 100,000 pediatric population, respectively. CONCLUSION: Our pMS data among Sardinians corroborate the epidemiological scenario described in the adult population being the incidence estimates significantly higher than those reported elsewhere. WHAT IS KNOWN: Sardinia is one of the regions at the highest risk for MS worldwide in the adult population. To date, no definite data exist on the pediatric population. WHAT IS NEW: The pediatric MS incidence in Sardinia is estimated to be significantly higher than those reported elsewhere. The pediatric MS prevalence in Sardinia is among the highest values worldwide.

Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis.

The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and ß-tubulin (ß-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and ß-Tub II proteins were significantly higher (p < 0.0001) in MS than in OND group; no significant difference (p > 0.05) was found between MS and OND with regard to ß-Tub III. Interestingly, levels of ß-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of ß-Tub II and GFAP were found in remitting MS forms. However, with the exception of ß-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate ß-Tub II as a potential candidate for diagnostic and ß-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.

ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations.

BACKGROUND: In the isolated population of Sardinia, a Mediterranean island, ∼25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene. OBJECTIVE: To describe the co-presence of two genetic mutations in two Sardinian ALS patients. METHODS: We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene. RESULTS: The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus. CONCLUSIONS: Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.

C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population.

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

Genes, environment, and susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease of the central nervous system affecting young adults and thus representing a major burden also for their families and communities. The etiology of MS is obscure and its pathogenesis is yet incompletely depicted. Increased evidences indicate a strong genetic contribution to MS susceptibility, although others support the view that it is also influenced by environmental factors, possibly related to still unidentified pathogens. MS appears to be more heterogeneous than previously believed at the immunological level, and new pathological studies indicate a series of subset of conditions under the common denominator MS. The use of genetically homogeneous and geographically isolated populations at high MS risk, such as that of Sardinia, insular Italy, becomes in principle a vital requirement to reduce biological variables and the intrinsic complexity of the disease. This review will focus on recent findings on the peculiarity of Sardinian MS concerning epidemiological, genetic, and environmental aspects. Epidemiological studies reveal a clear heterogeneous distribution of MS cases in the Northern province of Sassari which may not be uniquely assigned to genetic variations. Furthermore, a different immunogenetic profile, including the association with other immunomediated diseases, and a progressive change in clinical phenotype, including age at onset, are present in this island which gives us unexpected variations at the level of patients' cohort and territorial distribution, especially when the northern province is compared to the southern one. This renders MS etiopathogenesis more complex than formerly thought even in this selected and genetically stable population.