Wernicke Korsakoff Encephalopathy

Consideration for Wernicke encephalopathy should be given to patients with any evidence of long-term alco- hol abuse or malnutrition and any of the following: acute confusion, decreased conscious level, ataxia, ophthalmo- plegia, memory disturbance, hypothermia with hypoten- sion, and delirium tremens. Wernicke encephalopathy should be considered when any patient with long-term malnutrition presents with confusion or altered metal sta- tus. Signi cant overlap exists between Wernicke enceph- alopathy and Korsako psychosis, in which patients ex- perience delayed and potentially irreversible anterograde and retrograde amnesia. For this reason, the two entities have been described together as Wernicke-Korsako syn- drome. Bariatric surgery, human immunode ciency virus, hyperemesis gravidarum, and other disorders associated with grossly impaired nutritional status have been asso- ciated with Wernicke-Korsako syndrome. Additionally, infantile thiamine de ciency with manifestations of Wer- nicke syndrome has been reported in infants fed formula that was de cient in thiamine. Implementation therapy, with thiamine is a fun- damental approach for the treatment of WE: it must be avoided the administration of ev glucose, which may cause a precipitation of thiamine defects. No therapy has been validated for the treatment of Korsako amnestic syndrome. erefore, the clinicians should avoid any po- tential precipitating factor in speci c patients, more at risk to develop Wernicke-Korsako syndrome

Speech disorder and behavioral involvement in a thalamic stroke: a case report

Data from literature on clinical manifestation of thalamic strokes have been published for ages. First in 1906 Dejerine e Roussy have spoken about sensorymotor disturbances and have opened the door to new pathologic disorders that may occur after thalamic lesions. From 1925 behavior and speech disorders related with thalamic injury were described. Since then a classification of thalamic syndromes into four groups based on the four main arterial territories was accepted. As we know thalamic stroke account for 11% of vertebra basilar infarct. Inferolateral territory infarctions are the most common injury (45%), followed by the paramedian territory infarctions (35%) and the anterior territory lesions (12%), the posterior territory infarctions are less frequent (8%). Anyway lots of symptoms cannot still be classified easily and strictly into only one of this four groups and several variant topographic patterns of thalamic strokes with distinct manifestation and etiology have been proposed. Here we described the case of one young Caucasian man that was admitted to the emergency department for a sudden onset of dizziness with left lateropulsion, vertigo, visual impairment and speech disorder involving unpredictable topic shifts but grammatically correct. During recovery patient performed a typical behavior disorder consisting mainly in lack of emotion and memory long or short term loss. Magnetic resonance was performed and showed left thalamic infarction involving paramedian territory. The complex cognitive and behavioral disorders described can be explaned only supporting the already described different topographic patterns of thalamic infarctio

Pulmonary arterial hypertension: role of miRNAs in animal models and pathological samples

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries (PAs), characterized by an increase in pulmonary arterial pressure and vascular remodelling leading to a progressive increase in pulmonary vascular resistance. The consequence of vascular obliteration is right heart failure and high mortality. Germline mutations in the gene coding for the bone morphogenetic protein (BMP) type-2 receptor (BMPR2), a receptor for the transforming growth factor (TGF)-beta super-family, have been identified in approximately 70% of patients with the heritable form of PAH (HPAH). Moreover, BMPR2 expression is markedly reduced in PAH cases in the absence of mutations in this gene (idiopathic PAH, IPAH). In pulmonary artery smooth muscle cells (PASMCs) mutations in BMPR2 are associated with an abnormal growth response to BMPs and TGF-beta. In endothelial cells (PAECs), these mutations increase the susceptibility of cells to apoptosis. The absence of BMPR2 mutations in some families and in the majority of IPAH cases suggests that further pathological mechanisms still need to be identified. The serotonin system has also been implicated in both experimental and human PAH. In fact, an additional genetic risk factor for the development of this pathology has been identified in the serotonin transporter (SERT), dysregulated in IPAH patients. Mice over-expressing SERT (SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH. Although different advanced PAH therapies are currently available, they can only provide a symptomatic relief, and mortality rates remain high. Therefore, the identification of novel therapeutic approaches for the treatment of this pathology is urgently required. MicroRNAs (miRNAs) are a class of small, endogenous and non-coding RNAs able to negatively regulate gene expression by targeting specific messenger RNAs (mRNAs) and inducing their degradation or translational repression. These non-coding sequences are transcribed from endogenous loci as long precursors, converted in single-stranded molecules of approximately 20 nucleotides after a series of enzymatic maturation steps. miRNAs carry out their activity in association with the RNA-induced silencing complex (RISC), interacting with the 3’ untranslated region (3’UTR) of specific target mRNAs which they bind with imperfect complementarity. Several recent studies have assessed the direct role of miRNAs in vascular inflammation and in the development of cardiovascular pathologies. The aim of this project was to investigate the role of miRNAs in the development of PAH. In Chapter 3, two distinct and well established rat models (hypoxic and monocrotaline) of PAH were used to determine the regulation of miRNAs during disease initiation and progression. We demonstrate time and insult-dependent changes in a specific group if miRNAs and this dysregulation was also confirmed in vitro in rat and human PA cells exposed to chronic hypoxia. Moreover, the stimulation of rat cells with TGF-beta and BMP4 mimicked the alteration of miRNA expression observed in vivo. An analysis of the expression level of the main enzymes involved in miRNA maturation (i.e. Dicer, Drosha, DGCR8 and Exp5) revealed the significant down-regulation of Dicer in response to chronic hypoxia both in vivo and in vitro, suggesting that the manipulation of this enzyme could re-establish a normal miRNA expression level in pathological samples. We also identified selective targets altered in response to miRNA dysregulation, suggesting the possibility of future interventional studies. In Chapter 4 the specific role of miR-143 and miR-145 in the development of PAH was evaluated. We report the significant up-regulation of these miRNAs in WT mice exposed to chronic hypoxia and that genetic ablation of miR-145 is protective against the development of PAH (with no effects on miR-143 expression), assessed via measurement of systolic right ventricular pressure (sRVP), pulmonary vascular remodelling and right ventricular hypertrophy (RVH). miR-145 KO has also an effect on the expression of specific targets, including kruppel-like factor 4 and 5 (KLF4 and 5), which are regulators of smooth muscle proliferation and differentiation. Further, both miR-143 and miR-145 are up-regulated in mice heterozygous for a BMPR2 mutation. In human tissues we confirm the elevated expression of the miR-143/145 cluster observed in hypoxic mice in pathological samples compared with unaffected controls, suggesting a conserved regulation of these miRNAs in the two species. The study described in this chapter is the first to report a critical role for miR-145 in the development of PAH in vivo. Finally, in Chapter 5 a preliminary study focused on miR-21 regulation and function on PAH development is shown. An analysis of the expression of this miRNA in WT mice revealed its up-regulation in response to chronic hypoxia, whereas the genetic ablation of miR-21 induced an exaggerated hypoxia-induced PAH phenotype. However, the analysis of human pathological samples showed a reduced expression of this miRNA in comparison with unaffected controls, suggesting its differential regulation in hypoxic mice and patients, although the differences observed between the animal and the human pathology could be the cause of this different phenothipe. The identification of dysregulated targets in both the species will give more informations about the effect of miR-21 alteration in the development of PAH. In summary, the results presented in this thesis support a role for defined miRNAs in the development of PAH, both in animal models and patients. Whether this specific alteration of selective miRNAs can be used as a novel therapeutical approach still need to be evaluated, but represent an attractive possibility to assess in the longer term

R-spondin 1/Dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis

Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1. The latter experiments allowed us to observe that DKK1 administration also perturbs the expression level of the Pdgf-b chain, which is consistent with some authors' observations relating this factor with prenatal testicular patterning and angiogenesis. Interestingly, the DKK1 induced inhibition of testicular angiogenesis was rescued by the co-administration of R-spondin 1. In addition, R-spondin 1 alone was sufficient to enhance, in culture, testicular angiogenesis

Very High-Resolution Ultrasound of the Distal Median Nerve

Objective: A very high-resolution (70 MHz) ultrasound device (VHRUS) has recently been approved for use in humans. The aim of this study was to use VHRUS to collect data on healthy subjects to propose some reference values for the digital branches of the median nerves of the hand. Methods: A VHRUS with 70 MHz linear array transducer was used to measure the cross sectional area of the median nerve at the wrist (CSAw) and digital branches (CSAf), largest and smallest fascicles, the fascicles number (Nfasc), the fascicle density (FD), the flattening ratio (FR) and CSAw/CSAf. Results: Data from 20 healthy subjects were obtained for both hands. The median nerve at the wrist and digital branches were properly identified without anatomical alterations. No differences were found between the right and the left hand. In the dominant hand, CSAw was 9.35 mm2 (4.57-12.35) and Nfasc was 24 (18-38). FD and FR were respectively 2.94 (2.47-4.91) and 2.74 (1.70-4.90). Conclusion: VHRUS technology can visualize the median nerves at the wrist, their internal structure and their small branches at the fingers, providing both a qualitative and quantitative assessment. Results from this study provide preliminary reference values in a young healthy sample. Significance: Most conventional ultrasound devices are not able to properly visualize the distal branches of the median nerve. In contrast, VHRUS allows to detect and measure smaller structures of the nerve, assisting in clinical practice

Induction of neutralizing antibodies in CLL patients after SARS-CoV-2 mRNA vaccination: a monocentric experience

Vaccination represents the best strategy to fight COVID-19 pandemics, especially in immune compromised subjects. In chronic lymphatic leukemia patients, a marked impairment of the immune response to mRNA SARS-CoV-2 vaccine was observed. In this report, we analyzed anti-RBD and neutralizing antibodies in CLL patients after two doses of mRNA SARS CoV 2 vaccine and evaluated the impact of Bruton kinase inhibitory agents. Twenty-seven CLL patients vaccinated with mRNA vaccines against SARS CoV-2 were recruited. Serum IgG, IgM and IgA anti-RBD antibodies and neutralizing antibodies were detected, and antibody avidity was measured. Peripheral blood leukocytes subsets were evaluated by flow cytometry. After two vaccine doses anti-RBD IgG were produced in 11/27 (40.5%) of patients and levels of IgG and IgA anti RBD in CLL patients were sensibly lower than in controls. Neutralizing antibodies were detectable in 12/27 (44.5%) of the patients and their level was lower than that observed in controls. Disease burden and treatment with Bruton kinases inhibitors markedly impaired vaccine induced antibody response. However, in responder patients, antibody avidity was comparable to normal subjects, indicating that the process of clonal selection and affinity maturation takes place as expected. Taken together, these data confirm the impact of disease burden and therapy on production of anti-RBD and neutralizing antibodies and support the current policy of vaccinating CLL patients

Efficient isolation on Vero.DogSLAMtag cells and full genome characterization of Dolphin Morbillivirus (DMV) by next generation sequencing

The Dolphin Morbillivirus (DMV) genome from the frst Mediterranean epidemic (1990-\u201992) is the only cetacean Morbillivirus that has been completely sequenced. Here, we report the frst application of next generation sequencing (NGS) to morbillivirus infection of aquatic mammals. A viral isolate, representative of the 2006-\u201908 Mediterranean epidemic (DMV_IZSPLV_2008), efciently grew on Vero.DogSLAMtag cells and was submitted to whole genome characterization by NGS. The fnal genome length was 15,673 nucleotides, covering 99.82% of the DMV reference genome. Comparison of DMV_IZSPLV_2008 and 1990-\u201992 DMV strain sequences revealed 157 nucleotide mutations and 47 amino acid changes. The sequence similarity was 98.7% at the full genome level. Whole-genome phylogeny suggested that the DMV strain circulating during the 2006-\u201908 epidemics emerged from the 1990-\u201992 DMV strain. Viral isolation is considered the \u201cgold standard\u201d for morbillivirus diagnostics but efcient propagation of infectious virus is difcult to achieve. The successful cell replication of this strain allowed performing NGS directly from the viral RNA, without prior PCR amplifcation. We therefore provide to the scientifc community a second DMV genome, representative of another major outbreak. Interestingly, genome comparison revealed that the neglected L gene encompasses 74% of the genetic diversity and might serve as \u201chypervariable\u201d target for strain characterization

Autophagy processes are dependent on EGF receptor signaling

Autophagy is a not well-understood conserved mechanism activated during nutritional deprivation in order to maintain cellular homeostasis. In the present study, we investigated the correlations between autophagy, apoptosis and the MAPK pathways in melanoma cell lines. We demonstrated that during starvation the EGF receptor mediated signaling activates many proteins involved in the MAPK pathway. Our data also suggest a previously unidentified link between the EGFR and Beclin-1 in melanoma cell line. We demonstrated that, following starvation, EGFR binds and tyrosine-phosphorylates Beclin-1, suggesting that it may play a key inhibitory role in the early stage of starvation, possibly through the Beclin-1 sequestration. Furthermore, EGFR releases Beclin-1 and allows initiating steps of the autophagic process. Interestingly enough, when the EGFR pathway was blocked by anti-EGF antibodies, immunoprecipitated Beclin-1 did not bind the phospho-EGFR. In addition, an extended binding of p-Bcl2 either with Beclin-1 or with Bax was observed with a decreased activation of the stress-induced JNK kinase, thus avoiding the transduction pathways that activate autophagy and apoptosis, respectively. For this reason, we advance the hypothesis that the activation of the EGFR is a necessary event that allows the ignition and progression of the autophagic process, at least in melanoma cells

Zero-point energy of massless scalar fields in the presence of soft and semihard boundaries in D dimensions

The renormalized energy density of a massless scalar field defined in a D-dimensional flat spacetime is computed in the presence of "soft" and "semihard" boundaries, modeled by some smoothly increasing potential functions. The sign of the renormalized energy densities for these different confining situations is investigated. The dependence of this energy on $D$ for the cases of "hard" and "soft/semihard" boundaries are compared.Comment: 36 pages, LaTeX, 4 figure

Early Recovery of Aphasia through Thrombolysis: The Significance of Spontaneous Speech

Aphasia in one of the most devastating stroke-related consequences for social interaction and daily activities. Aphasia recovery in acute stroke depends on the degree of reperfusion after thrombolysis or thrombectomy. As aphasia assessment tests are often time-consuming for patients with acute troke, physicians have been developing rapid and simple tests. The aim of our study is to evaluate the improvement of language functions in the earliest stage in patients treated with thrombolysis and in nontreated patients using our rapid screening tes