UNDULY ENHANCED RESPONSE TO TOLVAPTAN IN A WOMAN SHOWING SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION: AN INVESTIGATION OF POSSIBLE CAUSES

Objective: To investigate possible causes of an excessive response to tolvaptan in a woman with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Methods: A 32-year-old woman was admitted to our cardiologic unit 3 months after delivery for hypertension and severe hyponatremia (120 mEq/L). Two hyponatremic episodes had already been documented in her medical history. SIADH was diagnosed and treatment with tolvaptan, an arginine vasopressin (AVP) antagonist, was instituted. After the first 15-mg dose, excessive polyuria (1 L/ hour) and a rapid increase in serum sodium (13 mEq/L in 8 hours) occurred, so that therapy was stopped and restarted 2 days later at a reduced dose (5 mg). This level was effective and well tolerated. To explore the possible pharmacokinetic and pharmacodynamic mechanisms underlying the patient\u2019s hyperresponsiveness, the following tests were carried out: (1) in vivo phenotyping of CYP3A4 activity, the cytochrome responsible for tolvaptan metabolism, with two probe drugs (omeprazole and dextromethorphan); and (2) search for mutations in genes involved in AVP signaling (AVP, V2R, AQP2, OXT)

U.S.-Taliban negotiations and the Doha Agreement (2001-2020)

The article analyzes the negotiation process and the final agreement that ended the U.S. war in Afghanistan. While general attention was dedicated to the dramatic withdrawal and the Taliban takeover, less focus was directed towards the negotiations and the agreement between the U.S. and the insurgent group, signed in Doha on the 29th of February 2020. The paper underscores two pivotal observations. Firstly, despite the agreement's emphasis on peace, its primary objective is a strategic advantage for both parties. Secondly, the events of August 2021 were not unforeseen but were rooted in the negotiation process and the specific provisions outlined in the finalized agreement. Methodologically, the chronological proximity of these events necessitated the use of debates within the U.S. Congress, reports, and existing literature

Utility of MRI quantitative analysis in assessment of audio-vestibular impairment

Objectives. To quantify inner ear fluid changes in patients with audiovestibular deficits by measuring signal intensity values; to correlate the signal intensity values of inner ear structures and audio-vestibular impairment severity. Methods. 26 patients with unilateral vestibulocochlear deficits underwent hearing and vestibular assessments and were categorised into severity classes using audiological and vestibular deficit scores. Normalised signal intensity values of inner ear structures were extracted from 3D-T2WI-MRI scans (nT2mean, nT2Max, nT2min) and signal intensity ratios were calculated using the unaffected ear as a reference. Results. Asymmetry ratios of nT2Max and nT2mean volumetric intensity values from the cochlea and entire inner ear discriminated severe hearing impairment from lesser deficits and diagnostic performance of nT2mean values was excellent. Conclusions. Quantitative MRI analysis may be a useful tool to assess the severity of auditory deficits. Asymmetry ratios of nT2mean and nT2Max signal intensity values derived from the cochlea and entire inner labyrinth are surrogate indicators of unilateral cochlear-vestibular deficits and may have potential prognostic value

Type IV optic nerve and Onodi cell: is there a risk of injury during sphenoid sinus surgery?

Objective: This study aims to determine the prevalence and types of Onodi cell through computed tomography and investigate the relationship between Onodi cell and the surrounding structures, paying particular attention to the risky proximity to the optic nerve canal. Methods: In this study, 430 computed tomography scans of paranasal sinuses were analysed to establish the prevalence and different types of Onodi cell. Furthermore, the relationship between Onodi cell and different patterns of sphenoid sinus pneumatisation and surrounding structures were investigated. Special attention was paid to the relationship between Onodi cell and the optic nerve canal, particularly in cases when the optic nerve canal was bulging by more than 50% into Onodi cell (Type IV). Results: The Onodi cell was detected in 21.6% of cases, with the most common being Type I (48.5% right, 54.3% left). Type IV bulging of the optic nerve canal into the Onodi cell was observed in 47.1% of cases on the right side, 41.2% on the left side and bilateral in 11.7% of cases. Conclusions: In our series, we observed a high prevalence of Type IV optic nerve bulging into the Onodi cell. For this reason, we suggest that clinicians should always try to identify it in a pre-operative setting with computed tomography to avoid catastrophic consequences during endoscopic sinus surgery approaching the sphenoid area

A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report

Background Malan syndrome (MALNS) is a recently described ultrarare syndrome lacking guidelines for diagnosis, management and monitoring of evolutive complications. Less than 90 patients are reported in the literature and limited clinical information are available to assure a proper health surveillance. Results A multidisciplinary team with high expertise in MALNS has been launched at the "Ospedale Pediatrico Bambino Gesu", Rome, Italy. Sixteen Italian MALNS individuals with molecular confirmed clinical diagnosis of MALNS were enrolled in the program. For all patients, 1-year surveillance in a dedicated outpatient Clinic was attained. The expert panel group enrolled 16 patients and performed a deep phenotyping analysis directed to clinically profiling the disorder and performing critical revision of previously reported individuals. Some evolutive complications were also assessed. Previously unappreciated features (e.g., high risk of bone fractures in childhood, neurological/neurovegetative symptoms, noise sensitivity and Chiari malformation type 1) requiring active surveillance were identified. A second case of neoplasm was recorded. No major cardiovascular anomalies were noticed. An accurate clinical description of 9 new MALNS cases was provided. Conclusions Deep phenotyping has provided a more accurate characterization of the main clinical features of MALNS and allows broadening the spectrum of disease. A minimal dataset of clinical evaluations and follow-up timeline has been proposed for proper management of patients affected by this ultrarare disorder

Comparison of cerebellar grey matter alterations in bipolar and cerebellar patients: evidence from voxel-based analysis

The aim of this study was to compare the patterns of cerebellar alterations associated with bipolar disease with those induced by the presence of cerebellar neurodegenerative pathologies to clarify the potential cerebellar contribution to bipolar affective disturbance. Twenty-nine patients affected by bipolar disorder, 32 subjects affected by cerebellar neurodegenerative pathologies, and 37 age-matched healthy subjects underwent a 3T MRI protocol. A voxel-based morphometry analysis was used to show similarities and differences in cerebellar grey matter (GM) loss between the groups. We found a pattern of GM cerebellar alterations in both bipolar and cerebellar groups that involved the anterior and posterior cerebellar regions (p = 0.05). The direct comparison between bipolar and cerebellar patients demonstrated a significant difference in GM loss in cerebellar neurodegenerative patients in the bilateral anterior and posterior motor cerebellar regions, such as lobules I−IV, V, VI, VIIIa, VIIIb, IX, VIIb and vermis VI, while a pattern of overlapping GM loss was evident in right lobule V, right crus I and bilateral crus II. Our findings showed, for the first time, common and different alteration patterns of specific cerebellar lobules in bipolar and neurodegenerative cerebellar patients, which allowed us to hypothesize a cerebellar role in the cognitive and mood dysregulation symptoms that characterize bipolar disorder

Aberrant cerebello-cerebral connectivity in remitted bipolar patients 1 and 2: new insight into understanding the cerebellar role in mania and hypomania

Bipolar disorder (BD) is a major mental illness characterized by periods of (hypo) mania and depression with inter-episode remission periods. Functional studies in BD have consistently implicated a set of linked cortical and subcortical limbic regions in the pathophysiology of the disorder, also including the cerebellum. However, the cerebellar role in the neurobiology of BD still needs to be clarified. Seventeen euthymic patients with BD type1 (BD1) (mean age/SD, 38.64/13.48; M/F, 9/8) and 13 euthymic patients with BD type 2 (BD2) (mean age/SD, 41.42/14.38; M/F, 6/7) were compared with 37 sex- and age-matched healthy subjects (HS) (mean age/SD, 45.65/14.15; M/F, 15/22). T1 weighted and resting-state functional connectivity (FC) scans were acquired. The left and right dentate nucleus were used as seed regions for the seed based analysis. FC between each seed and the rest of the brain was compared between patients and HS. Correlations between altered cerebello-cerebral connectivity and clinical scores were then investigated. Different patterns of altered dentate-cerebral connectivity were found in BD1 and BD2. Overall, impaired dentate-cerebral connectivity involved regions of the anterior limbic network specifically related to the (hypo)manic states of BD. Cerebello-cerebral connectivity is altered in BD1 and BD2. Interestingly, the fact that these altered FC patterns persist during euthymia, supports the hypothesis that cerebello-cerebral FC changes reflect the neural correlate of subthreshold symptoms, as trait-based pathophysiology and/or compensatory mechanism to maintain a state of euthymia

Sclerotherapy with polidocanol microfoam in head and neck venous and lymphatic malformations

Objective. Polidocanol sclerotherapy of head and neck venous malformations (VMs) and lymphatic malformations (LMs) has been reported only in limited series. In this manuscript we evaluated the efficacy and safety of polidocanol sclerotherapy in a series of head and neck venous and lymphatic malformations. Methods. This retrospective observational study analysed data on 20 head and neck VMs and LMs that underwent to percutaneous or endoscopic intra-lesional 3% polidocanol microfoam sclerotherapy at our institution. Clinical response was ranked as excellent, moderate and poor based on volume reduction by MRI and resolution of symptoms. Results. The median volume decreased from 19.3 mL to 5.8 mL after sclerotherapy (mean volume reduction: 72.98 ± 16.1%). An excellent-moderate response was observed in 94.4% of cases. We observed a mean volume reduction of 79.5 ± 16.1 in macrocystic LMs, of 76.1 ± 13.0% in VMs, of 60.5 ± 10.9% in mixed lymphatic ones and 42.5% in microcystic lymphatic ones. Conclusions. Polidocanol sclerotherapy appears to be an effective and safe treatment for venous and lymphatic head and neck malformations. We observed the best responses in macrocystic LMs and VMs, whereas mixed lymphatic ones showed a moderate response and microcystic lymphatic ones a poor response

Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation

Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband's PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS

PELASeam survey: Pelagic dynamics and Biodiversity of Tyrrhenian Seamount Ecosystems. Cruise Report

The PELASeam survey is a multidisciplinary expedition conducted aboard the R/V Gaia Blu from July 23 to August 8, 2024 designed to explore the pelagic ecosystem of 2 seamounts in the Tyrrhenian Sea (Vavilov and Vercelli) with different topographic and environmental characteristics. The main goal was to investigate and assess the pelagic productivity, biodiversity, and ecological roles of these important ecosystems using various and innovative methods including net sampling, eDNA, visual, and acoustic observations. The results of this survey will help to better understand the unique features and potential ecological significance of the seamounts, providing valuable insights into their role in supporting marine life and contributing to the overall health of the marine ecosystem in the Tyrrhenian Sea