Risk factors and incidence of long-COVID syndrome in hospitalized patients: does remdesivir have a protective effect?

BACKGROUND: The definition of 'long-COVID syndrome' (LCS) is still debated and describes the persistence of symptoms after viral clearance in hospitalized or non-hospitalized patients affected by coronavirus disease 2019 (COVID-19). AIM: In this study, we examined the prevalence and the risk factors of LCS in a cohort of patients with previous COVID-19 and followed for at least 6 months of follow-up. DESIGN: We conducted a prospective study including all hospitalized patients affected by COVID-19 at our center of Infectious Diseases (Vercelli, Italy) admitted between 10 March 2020 and 15 January 2021 for at least 6 months after discharge. Two follow-up visits were performed: after 1 and 6 months after hospital discharge. Clinical, laboratory and radiological data were recorded at each visit. RESULTS: A total of 449 patients were included in the analysis. The LCS was diagnosed in 322 subjects at Visit 1 (71.7%) and in 206 at Visit 2 (45.9); according to the post-COVID-19 functional status scale we observed 147 patients with values 2-3 and 175 with values >3 at Visit 1; at Visit 2, 133 subjects had the score between 2-3 and 73 > 3. In multivariate analysis, intensive care unit (ICU) admission (OR = 2.551; 95% CI = 1.998-6.819; P = 0.019), time of hospitalization (OR = 2.255; 95% CI = 1.018-6.992; P = 0.016) and treatment with remdesivir (OR = 0.641; 95% CI = 0.413-0.782; P < 0.001) were independent predictors of LCS. CONCLUSIONS: Treatment with remdesivir leads to a 35.9% reduction in LCS rate in follow-up. Severity of illness, need of ICU admission and length of hospital stay were factor associated with the persistence of PCS at 6 months of follow-up.

NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease.

Disarrangement in functions and quality control of mitochondria at synapses are early events in Alzheimer's disease (AD) pathobiology. We reported that a 20-22 kDa NH2-tau fragment mapping between 26 and 230 amino acids of the longest human tau isoform (aka NH2htau): (i) is detectable in cellular and animal AD models, as well in synaptic mitochondria and cerebrospinal fluids (CSF) from human AD subjects; (ii) is neurotoxic in primary hippocampal neurons; (iii) compromises the mitochondrial biology both directly, by inhibiting the ANT-1-dependent ADP/ATP exchange, and indirectly, by impairing their selective autophagic clearance (mitophagy). Here, we show that the extensive Parkin-dependent turnover of mitochondria occurring in NH2htau-expressing post-mitotic neurons plays a pro-death role and that UCHL-1, the cytosolic Ubiquitin-C-terminal hydrolase L1 which directs the physiological remodeling of synapses by controlling ubiquitin homeostasis, critically contributes to mitochondrial and synaptic failure in this in vitro AD model. Pharmacological or genetic suppression of improper mitophagy, either by inhibition of mitochondrial targeting to autophagosomes or by shRNA-mediated silencing of Parkin or UCHL-1 gene expression, restores synaptic and mitochondrial content providing partial but significant protection against the NH2htau-induced neuronal death. Moreover, in mitochondria from human AD synapses, the endogenous NH2htau is stably associated with Parkin and with UCHL-1. Taken together, our studies show a causative link between the excessive mitochondrial turnover and the NH2htau-induced in vitro neuronal death, suggesting that pathogenetic tau truncation may contribute to synaptic deterioration in AD by aberrant recruitment of Parkin and UCHL-1 to mitochondria making them more prone to detrimental autophagic clearance.

ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice.

ProNGF, the precursor of mature nerve growth factor (NGF), is the most abundant form of NGF in the brain. ProNGF and mature NGF differ significantly in their receptor interaction properties and in their bioactivity. ProNGF increases markedly in the cortex of Alzheimer's disease (AD) brains and proNGF\NGF imbalance has been postulated to play a role in neurodegeneration. However, a direct proof for a causal link between increased proNGF and AD neurodegeneration is lacking. In order to evaluate the consequences of increased levels of proNGF in the postnatal brain, transgenic mice expressing a furin cleavage-resistant form of proNGF, under the control of the neuron-specific mouse Thy1.2 promoter, were derived and characterized. Different transgenic lines displayed a phenotypic gradient of neurodegenerative severity features. We focused the analysis on the two lines TgproNGF#3 and TgproNGF#72, which shared learning and memory impairments in behavioral tests, cholinergic deficit and increased Aß-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Aß oligomer immunoreactivity, as well as late diffuse astrocytosis. Both TgproNGF lines also display electrophysiological alterations related to spontaneous epileptic-like events. The results provide direct evidence that alterations in the proNGF/NGF balance in the adult brain can be an upstream driver of neurodegeneration, contributing to a circular loop linking alterations of proNGF/NGF equilibrium to excitatory/inhibitory synaptic imbalance and amyloid precursor protein (APP) dysmetabolism.

Intrabodies for protein interference in Alzheimer’s disease.

Several open questions call for new studies on pathogenic mechanisms leading to Alzheimer’s Disease (AD), with the search for upstream drivers of the neurodegeneration cascade, such as neurotrophic deficits, early misfolding events of AD-related proteins (Abeta and tau) and understanding the multifactorial basis of AD pathogenesis. Since seminal immunosympathectomy experiment which represents the first example of a knock out experiment (albeit a protein knock-out), antibodies have had a long and successful history as a tool to selectively interfere with the function of proteins in cells and in organisms and antibody technologies represent a major weapon in the set of target validation techniques. Here, we describe a technology, pioneered by our group, based on recombinant antibody domains exploited as intracellular antibodies (intrabodies) whereby antibodies are used as genes, rather than as proteins. We discuss several applications and new promising developments of the intrabody approach for protein interference, especially in the field of AD research.

Transient bilateral Basal Ganglia lesions in rotavirus encephalopathy. A case report.

Rotavirus gastroenteritis may be associated with the onset of an acute reversible encephalitis. We describe a case of transient bilateral basal ganglia lesions after a prodromal gastroenteritis which completely resolved four months later. Diffusion weighted images were determinant to depict the basal ganglia abnormalities and were helpful to evaluate the prognosis. A review of the literature indicates that many diseases may be accompanied by signal abnormalities within the basal ganglia and that differential diagnosis is possible only through the simultaneous evaluation of imaging, clinical and laboratory findings.

Morphometric evaluation of the temporomandibular joint and the masticatory spaces: the role of high-definition MRI.

AIM: The aim of this work was to describe the anatomy of the temporomandibular joint (TMJ), the masticator spaces and their possible variance by means of magnetic resonance imaging MRI. METHODS: We evaluated one TMJ in each of 28 volunteers (14 males and 14 females) without temporomandibular disorders. The TMJ with mouth closed was evaluated on axial, coronal and sagittal planes obtained with a 1.5 Tesla magnetic resonance scanner. MRI scans of the anatomic patterns of the temporomandibular region were analyzed and compared with the classical anatomy notions reported in the literature. Morphometric evaluation of the temporomandibular region and the medial and lateral pterygoid muscles was carried out. RESULTS: MRI anatomy of the TMJ, the masticator spaces and their possible variance were accurately described. In addition, morphometric evaluation of the TMJ and the masticator spaces was performed. Statistical analysis of the measurements showed that the length of the structures related to the glenoid fossa were usually longer in the female than in the males, whereas the condyle and masticator muscles were usually greater in the males than in the females. T-tests showed no significant differences (P > 0.05) between the measurements of the right and left TMJ. CONCLUSIONS: In preoperative maxillofacial surgery assessment, MRI is a useful tool to reduce operating time, avert surgical complications and improve patient outcome.

Neuropathic pain in temporomandibular joint disorders: case-control analysis by MR imaging.

BACKGROUND AND PURPOSE: Temporomandibular joint disorders (TMJ-D) may be associated with the onset of neuropathic pain. The purpose of this study was to prospectively assess if, at the open-mouth position, the distance between the temporomandibular joint (TMJ) disk and the mandibular nerve is shorter in patients with TMJ-D and neuropathic pain vs patients with TMJ-D without neuropathic pain or in healthy people. MATERIALS AND METHODS: After ethical committee approval, we evaluated by MR imaging 16 TMJs with TMJ-D and neuropathic pain, 16 TMJs with TMJ-D without neuropathic pain, and 16 TMJs of healthy volunteers. All of the subjects were informed about the study procedure. We evaluated the distance between the TMJ disk and the mandibular nerve at the oval foramen level. Furthermore, the presence within the TMJs of internal derangement, osteoarthrosis, joint effusion, and bone marrow edema was evaluated. RESULTS: At the maximal open-mouth position, the distance between the TMJ disk and the mandibular nerve is shorter in patients with TMJ-D and neuropathic pain than in patients with TMJ-D without neuropathic pain or in healthy volunteers (P < .05). The imaging findings of TMJ internal derangement, effusion, osteoarthrosis, and bone marrow edema were present both in patients with TMJ-D without neuropathic pain and in patients with TMJ-D and neuropathic pain. CONCLUSIONS: We suggest that a closer proximity between the TMJ disk and the mandibular nerve could be one of the causes of the onset of neuropathic pain in patients with TMJ-D and neuropathic pain.

An interpretation of optic nerve tortuosity. A case report.

Magnetic resonance imaging disclosed both optic nerve tortuosity and kinking in a 64-year-old man with orbital pain and monolateral abducens nerve palsy. The association between optic nerve tortuosity and abducens nerve palsy is often described in literature reports of idiopathic intracranial hypertension. However the diagnosis of idiopathic intracranial hypertension was excluded in our patient because of the absence of other signs such as papilledema (universally present in the cases of idiopathic intracranial hypertension), visual loss, headache and flattening of the posterior sclera. Other possible diagnoses to be considered when looking at a case of optic nerve tortuosity are neurofibromatosis and/or optic nerve glioma. Tortuosity of both optic nerves seems to be isolated in our patient and not associated with other diseases or disorders. We suggest that in some patients optic nerve tortuosity could be correlated with an aberrant anatomical development of the optic nerve. Further studies are necessary to confirm this hypothesis which currently remains conjectural.

Osteoblastoma of the orbit. A case report and review of the literature.

We describe a case of benign orbital tumour involving the frontal sinus and ethmoidal cells. CT findings were typical of "bone tumour of the orbit", histological analysis yielded a diagnosis of benign osteoblastoma. A review of the literature disclosed only 13 well documented cases. We compared out radiological findings with the features described in these reports. CT patterns were similar in most cases. The lesion generally appears as a heterogeneous mass where it is possible to appreciate both high density portions and low density areas. On MRI osteoblastoma shows an iso- low signal both in T1 and in T2 sequences. Less frequently the lesion may yield a high signal in T2 images. The orbit is rarely involved by bone tumours, but all bone tumours may theoretically involve the orbit, often making it difficult to establish the right differential diagnosis by imaging. Thirteen cases are insufficient to describe general radiological criteria to improve the specificity in detection of this disease and a broader outlook is essential. For this reason we also examined the radiological signs of bone tumours involving other portions of the body. Even though many literature reports suggest CT is the landmark in bone tumour diagnosis, we think it should always be accompanied by MRI. MRI is known to overestimate local staging, but its contribution to differential diagnosis among various tumours may be decisive.

Imaging of Rathke's Cleft Cysts: Criteria for a Differential Diagnosis.

Rathke's cleft cysts are a congenital disorder of the pituitary gland and derive from abnormalities of the development of the adenohypophisis. The variability of the MRI signal of Rathke's cleft cyst hampers the differential diagnosis with the other cystic lesions of the pituitary gland. Nevertheless a comparison between the various findings reported from by author we reviewed indicates that a description of useful criteria for a differential diagnosis is possible. We suggest that the mean age at onset, the symptoms, the magnetic signal intensity, the location within the gland, the relations with the surrounding structures and the behaviour after contrast injection should always be considered in the diagnostic work-up of Rathke 's cleft cysts. There is no consensus in the literature on the correct therapeutic protocol. We suggest following up a small asymptomatic Rathke's cleft cyst (except mucoid cysts) because they do not generally enlarge. Surgery is instead the gold standard for symptomatic Rathke's cleft cysts, large Rathke's cleft cysts and mucoid Rathke's cleft cysts. Mucoid Rathke's cleft cysts, even when small, may cause an intense pituitary inflammation which could lead to irreversible endocrine dysfunction.

Hemifacial Spasms and Involuntary Facial Movements. Role of Magnetic Resonance in the Diagnostic Work-up. A Case Report.

Caution is required when dealing with patients presenting hemifacial spasm as the symptom is common to many disorders (tumours, herpes zoster, a frigore paralysis, neurovascular conflict…). Often no reasonable cause of the spasm is found, but treatment must be attempted because hemifacial spasm can be highly debilitating. We describe a case of hemifacial spasm, initially deemed idiopathic, in which MRI demonstrated neurovascular conflict as the cause. It is not always easy to find a clear MRI pattern, but if the scan identifies the tortuousness of the arteries in the vicinity of the VII nerve root exit, it is highly probable that this is the true cause of hemifacial spasm. Even when it is not possible to identify this pattern, neurovascular compression cannot be ruled out. The good results of microvascular decompression in patients without a typical MRI pattern suggest that MRI is specific, but not always sensitive. There is no consensus in the literature on the sensitivity of MRI in the detection of neurovascular compression and values vary widely. It is generally believed that experience and different performance of the MR systems strongly influence the diagnosis of neurovascular conflict.

Carotid body paraganglioma. Diagnosis and treatment by angiography.

Paraganglioma is a rare neoplasia of neural crest origin. It most commonly arises in carotid body, jugular bulb, tympanic plexus on the promontory, and along the vagal nerve pathway or anywhere along the paraganglia pathway. This review describes our experience of cervical paraganglioma. Although there is no consensus in the literature on preoperative angiographic embolization, we think angiography is the gold standard in the diagnosis and treatment of paraganglioma. A small paraganglioma probably does not usually require preoperative embolization because the risks may exceed the benefits. But angiography is mandatory in the diagnosis and treatment of large highly vascular paragangliomas. Imaging of the vascular map of the tumor, that is only possible by angiography, will help the neurosurgeon evaluate the real extension of the neoplasia and chose treatment modalities. Embolization is performed to decrease operative bleeding, shorten the surgery timing and avoid cranial nerve deficit. Cemal Umit Isik et al. studied four brothers with familial paragangliomas noting unexplained concomitant thyroid functional disorders in their patients. Because of the pedigree they thought this may have been a coincidence. Our reported case, unrelated to the Turkish family, also had hypothyroidism suggesting that the relation between paraganglioma and thyroid dysfunction may not be merely a coincidence.

Diabetic patients and retinal proliferation: an evaluation of the role of vascular endothelial growth factor (VEGF).

Vascular endothelial growth factor (VEGF) has been shown to play a major role in intraocular neovascularisation in ischaemic retinal diseases. The aim of this study was to evaluate the concentration of VEGF in vitreous, aqueous and epiretinal membranes of diabetic and non-diabetic patients, with other pathological conditions requiring surgical intervention. Higher VEGF concentration were found in samples from the eyes of diabetic patients versus other pathologies as well as in epiretinal membranes versus the other eye compartments in diabetic patients. However, high VEGF levels were also found in retinal detachment and proliferative vitreoretinopathy of non-diabetic patients. We concluded that VEGF is produced locally and plays a fundamental, but not specific, role in diabetic retinal neovascularisation and proliferation.

[Mixed-type pancreatoblastoma. Report of a clinical case]. / Pancreatoblastoma di tipo misto. Presentazione di un caso clinico.

Pancreatoblastoma is a very rare tumor of the pancreas, affecting children in the first decade of life. Ultrasound and CT scan may be useful but pre-operative diagnosis is often quite difficult. High level of seric alpha-fetoprotein could be suggestive of pancreatoblastoma. The definitive diagnosis is however made by histologists when an organoid structure, well encapsulated, consisting of acinar cells with zymogen-like granules and squamoid corpuscle is demonstrated, sometimes associated with mesenchymal tissue (mixed-type pancreatoblastoma). Immunohistochemical studies may help in differentiating pancreatoblastoma from papillary cystic tumors, acinar cell carcinomas and endocrine pancreatic tumors of the pancreas. We report a case of mixed-type pancreatoblastoma in a 12-year-old female patient, located in the head of the pancreas. The treatment has been surgical, consisting of a duodeno-cephalo-pancreasectomy. Neither radiotherapy nor chemotherapy has been performed. The patient is alive, without recurrence, four months after the operation. Diagnostic, therapeutic and prognostic aspects are discussed.

[Treatment of iatrogenic lesions of the common bile duct]. / Il trattamento delle lesioni iatrogene della via biliare principale.

The authors report 32 patients admitted to the hospital with iatrogenic bile duct stricture. Cholecystectomy with or without bile duct exploration was the most frequent (84.3%) surgical procedure responsible for the lesion, followed by BII gastric resection. Six patients had undergone one previous attempt at repair in another institution. Most patients had undergone a hepatojejunostomy, which has the procedure of choice in the last cases. Mortality and morbidity rates were 0 and 15%, respectively. The complications reported were a biliary fistula and 2 post-repair bile strictures that required one or more re-operations. During the follow-up 2 other patients developed episodes of cholangitis, treated medically. Clinical, diagnostic and therapeutic aspects of iatrogenic bile duct strictures are reviewed.

Gas chromatography-mass spectrometry determination of ethylenethiourea hemoglobin adducts: a possible indicator of exposure to ethylene bis dithiocarbamate pesticides.

Ethylenebisdithiocarbamates (EBDC) are an important class of fungicides used to control crop diseases and prevent mold. Ethylenethiourea (ETU), reported to be their main degradation and metabolic product in animals and man, may have teratogenic and carcinogenic properties. The feasibility of monitoring exposure to ETU on the basis of the formation of adducts to hemoglobin (Hb) was investigated. Rats given a single oral dose of ETU (from 62.5 to 500 mg/kg body wt) formed stable covalent ETU-Hb adducts. Mild acid hydrolysis of the protein regenerated ETU, allowing its detection by isotope dilution gas chromatography-mass spectrometry (GC-MS). The amount of released ETU increased with the dose. The dose-response curve fitted a linear model only between 62.5 mg/kg and 250 mg/kg. Acid-releasable ETU was also positively identified in the hemoglobin of workers exposed to Mancozeb, an EBDC formulation. In the exposed group, 40% had ETU-Hb adducts levels ranging from 0.5 to 1.42 pmol ETU/mg Hb. Such adducts might be useful for measuring EBDC exposure in humans.

[Transient idiopathic hyperphosphatasemia in a rotavirus infection]. / Iperfosfatasemia idiopatica transitoria in corso di infezione da rotavirus.

The paper reports two cases of transitory hyperphosphatasemia in two siblings of 13 and 29 months without modifications of the liver, kidney or bones. Laboratory data are given for hepatic and renal function and for the calcium/phosphorus metabolism. The paper underlines the observation of rotavirus and the consequent clinical symptoms in the two subjects. The hypothesised etiopathogenesis of transitory idiopathic hyperphosphatasemia is referred to a viral mechanism, and to rotavirus in particular.

Use of B.C.G. as loco-regional aspecific immunostimulator in cervical carcinoma.

This study concerns the possible use of BCG in oncologic gynecology for loco regional stimulation or loco aspecific active immunotherapy. The Authors administered BCG into the portio of 45 women affected by cervical cancer (stage I and stage II) immediately after the cytohistologic diagnosis and 21 days before the surgical intervention. The Authors conclude that the submucosal inoculation of BCG into the portio causes hyperplastic reactions in this area and in the locoregional lymphatic system with stimulation of the T-lymphocytes and with production of Interferon. Anyway this stimulation has a limited duration.