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Background and objectives: To explore cognitive, EEG, and MRI features in COVID-19 survivors up to 10months after hospital discharge. Methods: Adult patients with a recent diagnosis of COVID-19 and reporting subsequent cognitive complaints underwent neuropsychological assessment and 19-channel-EEG within 2months (baseline, N = 49) and 10months (follow-up, N = 33) after hospital discharge. A brain MRI was obtained for 36 patients at baseline. Matched healthy controls were included. Using eLORETA, EEG regional current densities and linear lagged connectivity values were estimated. Total brain and white matter hyperintensities (WMH) volumes were measured. Clinical and instrumental data were evaluated between patients and controls at baseline, and within patient whole group and with/without dysgeusia/hyposmia subgroups over time. Correlations among findings at each timepoint were computed. Results: At baseline, 53% and 28% of patients showed cognitive and psychopathological disturbances, respectively, with executive dysfunctions correlating with acute-phase respiratory distress. Compared to healthy controls, patients also showed higher regional current density and connectivity at delta band, correlating with executive performances, and greater WMH load, correlating with verbal memory deficits. A reduction of cognitive impairment and delta band EEG connectivity were observed over time, while psychopathological symptoms persisted. Patients with acute dysgeusia/hyposmia showed lower improvement at memory tests than those without. Lower EEG delta band at baseline predicted worse cognitive functioning at follow-up. Discussion: COVID-19 patients showed interrelated cognitive, EEG, and MRI abnormalities 2months after hospital discharge. Cognitive and EEG findings improved at 10months. Dysgeusia and hyposmia during acute COVID-19 were related with increased vulnerability in memory functions over time.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

Background: Alzheimer’s disease (AD) pathological hallmarks were found in retinas of AD patients. Several studies showed a significant reduction of neuro-retina thickness measured through optical coherence tomography (OCT) in AD patients, but possible correlations between retina morphology, cognition, and cerebrospinal fluid (CSF) AD biomarkers (Aβ42, t-tau, and p-tau) have been poorly investigated so far. Objective: In the present cross-sectional study, we measured the thickness of neuro-retinal layers through OCT searching for possible correlations with patients’ cognitive performances and CSF AD biomarkers. Methods: 137 consecutive subjects [43 with AD, 37 with mild cognitive impairment (MCI), and 57 healthy controls (HC)], received an OCT scan acquisition to measure the peripapillary retinal nerve fiber layer (RNFL) thickness. In a subsample of 21 AD, 18 MCI, and 18 HC, the macular volume of ganglion cell layer (GCL), inner plexiform layer (IPL), and inner nuclear layer was computed. A comprehensive neuropsychological assessment and CSF AD biomarkers’ concentrations were available in AD and MCI patients. Results: Peripapillary RNFL, global, and in superior quadrant was significantly thinner in AD and MCI patients when compared to HC, while macular GCL volume was significantly reduced only in AD. RNFL thickness in nasal and inferior quadrants was correlated with single CSF AD biomarker concentrations, but no differences were found in retina morphology depending on the presence of a CSF profile typical for AD. Memory performances were positively associated with GCL and IPL volume. Conclusion: Our findings might propose OCT as a reliable and easy to handle tool able to detect neuro-retinal atrophy in AD in relation with cognitive performances.

«Dove collocare lo spazio per la memoria in un siffatto sistema di comunicazione? Quale memoria?». Paola Bernasconi nel suo commento al saggio di Giuseppe Carlo Marino su globalizzazione e crisi del “pensare storico” prova a rispondere a queste domande interrogandosi sui mutamenti che la rivoluzione elettronico-informatica e le dinamiche politico-economiche hanno impresso sul valore della cultura storica per la società globalizzata. «Where can we place the space for the memory in such a communication system? What memory?». In her comment to Giuseppe Carlo Marino’s essay about the globalization and crisis of “historical thought”, Paola Bernasconi tries to answer these questions, wondering about the changes that technology revolution and the politic economic dynamics have impressed on the value of the historical culture for the globalized society.

One of the aspects of the formation of consensus under the Fascist state concerns the construction of the Fascist ‘man’. This article takes up this notion and explores it in relation to children. The first part deal with the legislative process according to which Fascist rituals and myths were introduced into the school curriculum. The second part examines the letters that were sent to the Duce by children during the period of the regime. The majority of letters appear to have been dictated by elementary school teachers according to precise directives, but nonetheless there is some evidence of the spontaneous manifestation of the feelings of infants. The most significant aspect concerns the transfiguration of the Duce himself into a figure of fable in ways that could not but impact on the imagination of those who were born and raised between the 1920s and later 1930s.

BACKGROUND Correctly diagnosing Alzheimer's disease (AD) in prodromal phases would allow the adoption of experimental therapeutic strategies that could selectively interrupt the pathogenetic process before neuronal damage becomes irreversible. Therefore, great efforts have been aimed at finding early reliable disease markers. OBJECTIVE The aim of this study was to identify a simple, cost effective, and reliable diagnostic algorithm to predict conversion from mild cognitive impairment (MCI) to AD. METHODS 96 consecutive MCI patients admitted to the Neurology department of San Raffaele Hospital in Milan between January 2009 and January 2015 were included. All patients underwent neuropsychological assessment and lumbar puncture with CSF analysis of amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Each patient underwent clinical and neuropsychological follow-up, in order to identify a possible progression from MCI to AD. The mean follow up time was 36.73 months. RESULTS 37 out of 96 MCI converted to AD during follow up. CSF analysis and neuropsychological assessment reliably detected MCI patients who developed AD. In a subsample of 43 subjects, a Composite Cognitive Score (CCS) was calculated including episodic memory, executive function, and verbal fluency tests. Combining together CSF biomarkers and CCS increased the accuracy of the single predictors, correctly classifying 86% of patients with a specificity of 96% and a Positive Predictive Value of 93%. DISCUSSION Even if preliminary, our data seem to suggest that CSF analysis and neuropsychological assessment could detect MCI patients who will convert to AD with high confidence. Their relative low cost and availability could make them worldwide essential tools in future clinical trials.

The time of death can be established by determining the length of the postmortem interval. Many methods have been proposed to achieve this goal. Flow cytometric evaluation of DNA degradation seems to be reliable for the first 72 hours after death. Our study evaluated the correspondence of the corruption process between in vitro and corpse tissues. We chose spleen tissue to perform our investigation because it is rich in nucleated cells. Results showed a precise correspondence between the two kinds of samples in the time period between 24 and 36 hours. The period from 36 to 72 hours is characterized by a much looser correspondence than that found in the first period. After the first 72 hours, DNA denaturation is massive and does not allow useful cytofluorimetric readings. The spleen does not seem to be the most suitable organ for this type of investigation because it tends to colliquate very rapidly. We therefore are evaluating other organs to identify a more suitable tissue source for the investigation of longer postmortem period using flow cytometry.

A 76-year-old woman had progressive memory loss for 2 years. Neurologic examination confirmed the memory deficit and also demonstrated ideative-ideomotor apraxia and visuospatial disturbances (Mini-Mental State Examination 17/30). A diagnosis of probable Alzheimer disease dementia (AD) was formulated. She showed us notebooks filled with drawings she had completed as a hobby, covering a period form before the illness (figure 1) to the present (figure 2). These sketches provide an inside into AD-related changes in creativity and visuospatial skills.1 Drawing performance is related to perceptual and executive dysfunctions in the visuospatial domain.

Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil can depolarize deeper and wider structures compared with focal coils, thus targeting widespread networks involved in neurodegenerative disorders. We aimed to evaluate H-coil rTMS safety and efficacy in AD. Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3 weekly for 4 weeks, 1 weekly for other 4 weeks), over fronto-parieto-temporal lobes at 10 Hz. Neuropsychological assessment was performed at baseline, after 4 weeks (4w), at the end of treatment (8w). Primary outcome was an improvement in Alzheimer’s disease scale-cognitive (ADAS-cog). No serious side effects were reported. Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. At 4w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group (p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups (p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only in the real. These findings suggest that H-coil may be safe and effective in AD and that deep rTMS may better impact the course of the disease when administered at earlier stages.

Background Three variants of primary progressive aphasia (PPA) have been currently characterized: non fluent/agrammatic (nfv-PPA), semantic (sv-PPA), and logopenic variant (lv-PPA). lv-PPA is most commonly associated with Alzheimer's disease (AD), while nfv-PPA and sv-PPA are related to frontotemporal lobar degeneration. Objective We aimed to determine whether cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), total tau protein (t-tau), and phosphorylated tau (p-tau), frequently abnormal in AD, could constitute a useful tool in the PPA diagnostic work up, in order to identify subjects with an underlying AD pathology. Methods We measured CSF biomarker levels in a group of twenty-eight patients, fourteen lv-PPA, nine nfv-PPA, and five sv-PPA. Results Since there were no significant differences in any of the parameters investigated between nfv-PPA and sv-PPA, the two groups were considered as one (nfv/sv-PPA). At diagnosis, lv-PPA were older than nfv/sv-PPA patients (mean values: 70.7 versus 64.6 years, p = 0.02). CSF biomarker mean concentrations were significantly different in lv-PPA versus nfv/sv-PPA patients (p = 0.000): Aβ42 350.64 versus 661.64 ng/L; tau 631.21 versus 232.71 ng/L; p-tau 101 versus 38.21 ng/L. According to the recent AD diagnostic criteria, (Cummings et al., 2013) eleven lv-PPA and only one nfv/sv-PPA showed a liquoral pattern typical for AD. Finally lv-PPA had CSF biomarker levels very similar to a sample of 72 AD patients from our Department. Conclusions Our data showed that CSF biomarkers can easily and reliably detect those patients with language disorders due to an underlying AD pathology, thus offering the possibility of targeted therapeutic interventions. However, because of the small sample size, such analyses should be reproduced in larger populations of patients to confirm our data.

The authors describe four cases of suicide by hara-kiri. This very painful form of suicide consists of self-inflicting a wound in the abdomen using a sharp instrument. It was first reported in 988 A.D. in the East but has now become rare in both the East and West. These four cases occurred over a 40-year period in the Trieste and Bari medicolegal area. In two of our cases the victims were afflicted with mental illness, whereas the other two suffered from depression. In cases of death by hara-kiri, it is important to establish a differential diagnosis between suicide and homicide; the presence of trial wounds (inflicted by the victim as a form of practice to overcome any hesitation before stabbing the abdomen with the cutting weapon) can prove very helpful.

Objective Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil depolarize deeper and wider structures compared with focal coils, maybe targeting widespread networks involved in neurodegenerative disorders. We explored H-coil safety and efficacy in AD. Methods Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3/week for 4 weeks, 1/week for other 4 weeks), over fronto-parieto-temporal lobes (10 Hz). Neuropsychological assessment was performed at baseline, after 4 weeks (4 w), at the end (8 w). Primary outcome: improvement in Alzheimer’s disease Scale-cognitive (ADAS-cog). Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. Results No serious side effects were reported. At 4 w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group ( p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups ( p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only after real stimulation. Conclusions Excitatory deep rTMS appears feasible in AD with a promising safety and efficacy profile and may better impact the course of the disease when administered at earlier stages.

A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resulting 3D-QSAR model rationalizes the steric and electronic factors which modulate affinity to the MBR with a cross-validation standard error of 0.648 pIC 50 unit. A set of seven novel pyrrolobenzothiazepine congeners has successively been synthesized and tested. The CoMFA model forecasts the binding affinity values of these new compounds with a prediction standard error of 0.536

A novel class of ligands specific for MBR receptors has been identified: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. The majority of newly synthesized esters 37-64 as well as some intermediate ketones showed micro- or nanomolar affinity for [3H]PK 11195 binding inhibition. A SAR study on 42 compounds and a molecular modeling approach led to a preliminary structural selectivity profile: the 6,7-double bond, the carbamoyloxy, alcanoyloxy, and mesyloxy side chains at the 7-position, and the prospective chloro substitution at the 4-position seemed to be the most important structural features improving affinity. Therefore, 7-[(dimethylcarbamoyl)oxy]- and 7-acetoxy-4-chloro-6-phenylpyrrolo[2,1-d][1,5]benzothiazepine (43 and 57) were synthesized. With 7-[(dimethylcarbamoyl)oxy]-6-(p-methoxyphenyl)pyrrolo[2,1- d][1,5]benzothiazepine (65), these were the most promising compounds with IC50s of respectively 9, 8, and 9 nM, under conditions where PK 11195 had an IC50 of 2 nM.

This paper proposes the use of radiographic magnification to detect the effects of neck traumas. This technique, both fast and economical, has proved to be particularly useful in all those cases where post mortem examinations failed to detect valid evidence of lesions of the hyoid-larynx complex. This is the case with corpses in an advanced stage of putrefaction where death occurred as a result of pressure or when a soft object is placed between the victim's neck and the assailant's hands. The radiological study was performed "on site" on four cases of medicolegal interest and its potential was confirmed.

THE AMERICAN JOURNAL OF SURGICAL PATHOLOGY (NEW YORK)

In our previous experimental work we suggested that the frequent nephritogenicity of type II cryoglobulins could depend on a particular affinity of the immunoglobulin (Ig) M kappa rheumatoid factor (RF) component for mesangial matrix. Since cellular fibronectin (cFN) in the human kidney is mainly represented in glomerular mesangium, we studied the binding capacity to cFN of IgM kappa RFs from type II cryoglobulins compared with other different monoclonal and polyclonal IgM and IgM RFs. We purified 13 IGM kappa from human IgM kappa/IgG cryoglobulins, eight monoclonal IgM from patients with Waldenström's macroglobulinemia, nine polyclonal IgM from normal donors, and eight polyclonal IgM RFs from patients with rheumatoid arthritis. Purified IgM were used at the same concentration in enzyme-linked immunosorbent assay (ELISA) on cFN-coated plates. All the cryoglobulin IgM showed high specific binding to cFN while IgM from Waldenström's macroglobulinemia, normal IgM, and polyclonal IgM RFs had low or absent binding. These data were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cFN followed by Western blot analysis with purified IgM. The IgM kappa binding to cFN persisted using IgM kappa monomers, and was inhibited by cFN but not by plasma FN in a specific inhibition test. Further enzyme-linked immunosorbent assay studies showed that cryoglobulin IgM kappa RFs are still able to bind IgG in a dose-dependent manner once linked to solid-phase cFN. The data suggest that the affinity of cryoglobulin IgM kappa RFs for immobilized cFN could be involved in the particular high nephritogenicity of type II cryoglobulins and might lead to in situ immune complex formation.

The use of the newest nonionic, water-soluble, low-osmolar radiographic contrast media (CM) is still associated with occasional adverse reactions affecting the neural tissues. Because these CM display lipophilic potential in their interactions with biological membranes when diffusing within the brain parenchyma, they could affect neurotransmitter binding to the receptors. Two representative nonionic CM, iopamidol and iohexol, were studied to assess whether CM-related neurotoxicity derived from their interactions with specific receptors on neural membranes.Binding assays were carried out in vitro on crude total membrane or crude synaptic membrane preparations from selected brain areas (cortex, striatum, hippocampus, cerebellum). The concentrations of CM and reference drugs that reduce specific binding of each ligand by 50% of its maximum value (IC50) were determined using radioligands to the receptors of the most common neurotransmitters in the central nervous system, including excitatory amino acids.Neither iopamidol nor iohexol inhibited the (3H) ligand binding to any kind of receptor up to very high concentrations (100 microM).The nonionic, low-osmolar CM did not influence the normal functions of neural membranes in our model. This suggests that occasional neurotoxic effects do not occur as a consequence of specific action on brain receptors. These CM may have an indirect, postmembrane site of action.

We present a case of death caused by voluntary ingestion of non-organic foreign bodies observed at the Institute of Legal Medicine of the University of Trieste. The victim was a young schizophrenic patient whose death, at first giving rise to suspicions of murder by another psychiatric patient, was found to be caused by an uncommon chronic permanence of foreign bodies at different locations of the digestive tract which suddenly evolved into a series of simultaneous lethal complications as yet never described. The case also raised the issue of possible responsibilities of the subject's healthcare providers.

Nephrotoxicity of intravenous contrast media is more frequent and striking in patients with risk factors, the major one being preexisting chronic renal insufficiency. New nonionic low-osmolal contrast media allegedly have less nephrotoxicity than the traditional ionic high-osmolal ones. This was tested for two contrast media in a group of 18 patients with stable chronic renal insufficiency. The urinary excretion of two brush-border enzymes (alanine aminopeptidase, AAP, and gamma-glutamyl transpeptidase, gamma-GT) and of a lysosomal enzyme (N-acetyl-beta glucosaminidase, NAG), functional markers of tubular injury, were measured before and after intravenous urography with an ionic high-osmolal radiocontrast medium, meglumine sodium diatrizoate, or with a non ionic low-osmolal one, iopamidol. Urinary NAG excretion did not change significantly after administration of either contrast media. Urinary AAP and gamma-GT excretion increased significantly (p less than 0.01) after diatrizoate. After iopamidol, only gamma-GT excretion increased significantly (p less than 0.05). Our data suggest that the nonionic low-osmolal radiocontrast medium iopamidol is less toxic to tubules than the ionic high-osmolal medium diatrizoate and that the brush-border enzymes AAP and gamma-GT are sensitive markers for this toxicity.

The authors describe an unusual case of suicide that required particular attention to establish whether the victim was murdered, was preparing a terrorist attack or had committed suicide. Examination of the corpse and the crime scene, as well as testimonies, led the authors to determine the real cause of death, namely, an unusual method of suicide.

A novel class of ligands specific for MBR receptors has been identified: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. The majority of newly synthesized esters 37-64 as well as some intermediate ketones showed micro- or nanomolar affinity for [3H]PK 11195 binding inhibition. A SAR study on 42 compounds and a molecular modeling approach led to a preliminary structural selectivity profile: the 6,7-double bond, the carbamoyloxy, alcanoyloxy, and mesyloxy side chains at the 7-position, and the prospective chloro substitution at the 4-position seemed to be the most important structural features improving affinity. Therefore, 7-[(dimethylcarbamoyl)oxy]- and 7-acetoxy-4-chloro-6-phenylpyrrolo[2,1-d][1,5]benzothiazepine (43 and 57) were synthesized. With 7-[(dimethylcarbamoyl)oxy]-6-(p-methoxyphenyl)pyrrolo[2,1- d][1,5]benzothiazepine (65), these were the most promising compounds with IC50s of respectively 9, 8, and 9 nM, under conditions where PK 11195 had an IC50 of 2 nM.