A spectroscopic and molecular dynamics study on the aggregation process of a long-acting lipidated therapeutic peptide: the case of semaglutide.

The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 µM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a ß-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs.

Deficits in temporal processing correlate with clinical progression in Huntington's disease.

OBJECTIVES: Precise temporal performance is crucial for several complex tasks. Time estimation in the second-to-minutes range-known as interval timing-involves the interaction of the basal ganglia and the prefrontal cortex via dopaminergic-glutamatergic pathways. Patients with Huntington's disease (HD) present deficits in cognitive and motor functions that require fine control of temporal processing. The objective of the present work was to assess temporal cognition through a peak-interval time (PI) production task in patients with HD and its potential correlation with the Unified Huntington's Disease Rating Scale (UHDRS). MATERIALS AND METHODS: Patients with molecular diagnosis of HD and controls matched by age, sex and educational level (n=18/group) were tested for interval timing in short- (3 seconds), medium- (6 seconds) and long (12 seconds)-duration stimuli. RESULTS: Significant differences were observed in the PI task, with worse performance in HD compared to controls. Patients underestimated real time (left-shifted Peak location) for 6- and 12-second intervals (P<.05) and presented decreased temporal precision for all the intervals evaluated (P<.01). Importantly, a significant correlation was found between time performance and the UHDRS (P<.01). Patients' responses also deviated from the scalar property. CONCLUSIONS: Our results contribute to support that timing functions are impaired in HD in correlation with clinical deterioration. Recordings of cognitive performance related to timing could be a potential useful tool to measure the neurodegenerative progression of movement disorder-related pathologies.

Unilateral condylar hyperplasia: diagnosis, clinical aspects and operative treatment. A case report.

BACKGROUND: Condylar hyperplasia of the mandible is an uncommon idiopathic disorder of the jaw characterised by increased volume of the condyle, unilaterally or bilaterally, leading to facial asymmetry, mandibular deviation, malocclusion and articular dysfunction. CASE REPORT: The authors present one case of unilateral condylar hyperplasia of a 16-year-old patient affected by severe facial asymmetry. Conventional X-rays examinations, multislice spiral CT and bone SPECT were used for the final diagnosis of primary condyle hyperplasia. The patient was treated with a combined orthodontic and surgical approach. CONCLUSION: Treatment of condylar hyperplasia with a combined orthodontic and surgical approach including condylectomy yield good aesthetic and functional outcomes.

Playing with peptides: how to build a supramolecular peptide nanostructure by exploiting helix···helix macrodipole interactions.

A novel method to build bicomponent peptide self-assembled monolayers (SAMs) has been developed, by exploiting helix···helix macrodipole interactions. In this work, a peptide-based self-assembled monolayer composed of two helical peptides was immobilized on a gold surface. Specifically, a pyrene-containing octapeptide, devoid of any sulfur atom (A8Pyr), and a hexapeptide, functionalized at the N-terminus with (S,R) lipoic acid, for binding to gold substrates (SSA4WA) via a Au-S linkage, have been employed. Both peptides investigated attain a helical structure, because they are almost exclusively formed by strongly folding inducer C(α)-tetrasubstituted α-amino acids. We demonstrate that the two peptides generate a stable supramolecular nanostructure (a densely packed bicomponent peptide monolayer), where A8Pyr is incorporated into the SSA4WA palisade by exploiting helix···helix macrodipole interactions. The presence of both peptides on the gold surface was investigated by spectroscopic and electrochemical techniques, while the morphology of the monolayer was analyzed by ultra high-vacuum scanning tunnelling microscopy. The composition of the bicomponent SAM on the surface was studied by a combination of electrochemical and spectroscopic techniques. In particular, the amount of Au-S linkages from the sulfur-containing peptides was quantified from reductive desorption of the peptide-based SAM, while the amount of A8Pyr was estimated by fluorescence spectroscopy. The antiparallel orientation of the A8Pyr and SSA4WA peptide chains minimizes the interaction energy between the helix dipoles, suggesting that this kind of electrostatic phenomenon is the driving force that stabilizes the bicomponent SAM.

[Identification of restless legs syndrome in polysomnography studies and its association with other variables]. / Identificación del síndrome de piernas inquietas en estudios polisomnográficos y su asociación con otras variables.

INTRODUCTION: Restless legs syndrome (RLS) is a movement disorder characterized by an uncontrollable urge to move the legs in response to an unpleasant sensation. The coexistence of RLS and other sleep and mood disorders may require adjustment in the therapeutic strategy. The objective of this study was to determine the prevalence of RLS in adults studied with polysomnography and to evaluate its association with other sleep and mood disorders. PATIENTS AND METHODS: Descriptive cross-sectional study. We included adults studied with polysomnography between 2015 and 2021. We collected information on their medical history, polysomnographic data and mood and sleep disorders using a self-administered written questionnaire which is part of the routine evaluation of all patients referred to this sleep unit. These variables were compared between patients with and without RLS. RESULTS: We included 406 patients. The prevalence of RLS was 36.7% (n = 149). The presence of fatigue (45.3%), moderate to severe insomnia (38.9%) and depression (45.6%) was higher in subjects with RLS. We did not find differences regarding daytime sleepiness and anxiety symptoms. Periodic Limb Movements (PLM) was not associated with RLS (p = 0.26) and its prevalence was low. CONCLUSION: The prevalence of RLS in subjects studied with Polysomnography is high and it was associated with clinically significant fatigue, insomnia and depression. These symptoms should be identified in order to establish an adequate therapeutic strategy. The prevalence of periodic limb movements was low and was not linked with RLS. These findings contrast with previous publications. Therefore, it requires additional studies to clarify the cause of this variation.

TITLE: Identificación del síndrome de piernas inquietas en estudios polisomnográficos y su asociación con otras variables.Introducción. El síndrome de piernas inquietas (SPI) es un trastorno del movimiento caracterizado por un impulso incontrolable de mover las piernas en respuesta a una sensación desagradable. La coexistencia de SPI junto con otros trastornos del sueño y del estado de ánimo puede modificar el enfoque terapéutico. El objetivo de este trabajo fue determinar la prevalencia de SPI en adultos estudiados con polisomnografía y evaluar su asociación con otros trastornos del sueño y del estado de ánimo. Pacientes y métodos. Estudio descriptivo transversal. Se incluyó a adultos estudiados con polisomnografía entre 2015 y 2021. Se recopiló información sobre sus antecedentes, datos polisomnográficos y trastornos del ánimo y del sueño mediante un cuestionario escrito autoadministrado que forma parte de la evaluación de todos los pacientes referidos a esta unidad de sueño. Se compararon estas variables en relación con la presencia de SPI. Resultados. Se incluyó a 406 pacientes. La prevalencia de SPI fue del 36,7% (n = 149). La presencia de fatiga (45,3%), insomnio moderado a grave (38,9%) y depresión (45,6%) fue mayor en sujetos con SPI. No se encontraron diferencias en relación con somnolencia diurna y síntomas de ansiedad. Los movimientos periódicos de las piernas no se asociaron con SPI (p = 0,26) y su prevalencia fue baja. Conclusión. La prevalencia de SPI en sujetos estudiados con polisomnografía fue elevada y se asoció a fatiga clínicamente significativa, insomnio y depresión. Estos síntomas deberían identificarse para establecer una estrategia terapéutica adecuada. La prevalencia de movimientos periódicos de las piernas fue baja y no se vinculó con SPI, hallazgo que contrasta con lo publicado previamente. Se requieren estudios adicionales para esclarecer la causa de esta asociación.

Influence of Cu nanoparticle size on the photo-electrochemical response from Cu-multiwall carbon nanotube composites.

We show that Cu metal nanoparticle-multiwall carbon nanotube (MWCNT) assemblies can act as a new hybrid photoactive layer in photo-electrochemical devices. The carbon nanotube (CNT) composites were formed by a controlled thermal deposition of copper which produced crystalline metal nanoparticles localized on the carbon tube outer walls. The photoresponse evaluated in terms of IPCE (incident photon-to-charge carrier generation efficiency) varied for different sized-Cu-MWCNT samples across all the visible and near ultraviolet photon energy range with respect to the response of bare MWCNTs. In the case of 0.2 nm Cu nominal thickness, the IPCE increased, reaching 15%, a value 2.5 times higher than that measured for bare MWCNTs. As the Cu nominal coverage thickened, the IPCE started to decrease and become totally ineffective after 1 nm deposited Cu. The IPCE increase found was interpreted as being the result of a remarkable charge transfer between the Cu metal nanoparticles and the CNTs due to the formation of a strong ionic bond at their interface. The results obtained prove that the metal nanoparticle-CNT composites have optical, electrical and structural properties that can be applied in a variety of nanoscale architectures for novel photo-electrochemical devices.

Tuning photoresponse through size control of Cu nanoparticles deposited on multi wall carbon nanotubes.

In this paper we illustrate a simple method for the production of multiwall carbon nanotubes thin films decorated with copper metal nanoparticles. The structural information obtained from the transmission electron microscopy study performed on samples differing in the quantity of deposited Copper was linked to the opto-electronic properties evaluated with photo-electrochemical measurements. The photo-response evaluated in terms of incident photon-to-charge carrier generation efficiency varied for different sized-Cu-multiwall carbon nanotubes samples across all the visible and near-ultraviolet photon energy range with respect to the response of bare carbon tubes. The photo-response from the sample covered with of 0.5 nm Cu nominal thickness, reached 10.2%, a value 2 times higher than that measured for bare carbon tubes of 5.9%. While this value decreased to 2.8% when the Cu nominal coverage thickened up to 3 nm. The increase in the photo-response found was interpreted as being the result of a remarkable charge transfer between the Cu metal nanoparticles and the carbon atoms in the tube due to the formation of a strong ionic bond at their interface. The results obtained prove that the metal nanoparticle-carbon nanotube composites have optical, electrical and structural properties that can be applied in a variety of nanoscale architectures for novel photo-electrochemical devices.

Fluorescence and computational studies of thymidine phosphorylase affinity toward lipidated 5-FU derivatives.

Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis. In this work, the intrinsic TP fluorescence has been investigated for the first time and exploited to study TP binding affinity for the unsubstituted 5-FU and for two 5-FU derivatives, designed to expose this molecule on liposomal membranes. These molecules were obtained by functionalizing the nitrogen atom with a chain consisting of six (1) or seven (2) units of glycol, linked to an alkyl moiety of 12 carbon atoms. Derivatives (1) and (2) exhibited an affinity for TP in the micromolar range, 10 times higher than the parent compound, irrespective of the length of the polyoxyethylenic spacer. This high affinity was maintained also when the compounds were anchored in liposomal membranes. Experimental results were supported by molecular dynamics simulations and docking calculations, supporting a feasible application of the designed supramolecular lipid structure in selective targeting of TP, to be potentially used as a drug delivery system or sensor device.

Chronic productive cough in young adults is very often due to chronic rhino-sinusitis.

BACKGROUND: Chronic productive cough is a common clinical problem; often potential causes outside the lower respiratory tract are forgotten or ignored. The aim of this study was to make a precise etiopathogenetic diagnosis of chronic productive cough in young adults. METHODS: In a clinical setting, 212 subjects (mean age 41+/-5 years) who had reported chronic productive cough in a previous postal survey of a young adult population underwent within two years clinical and functional investigations following a rational diagnostic approach. Two pulmonologists independently established the diagnosis using a clinically structured interview on nasal and respiratory symptoms, spirometry and other tests when appropriate (bronchodilator test or methacholine bronchial challenge, chest radiography); if rhino-sinusitis was suspected, subjects underwent an ENT examination with nasal endoscopy and/or sinus computed tomography. RESULTS: At the end of the diagnostic procedure, 87 subjects (41%) no longer had chronic productive cough and had normal function. Fifty-eight subjects (27%) had chronic rhino-sinusitis; seventeen subjects (8%) had asthma, and of these fourteen also had chronic rhino-sinusitis; 50 subjects (24%) had COPD stage 0+, of these seven also had chronic rhino-sinusitis. Chronic rhino-sinusitis was more frequent in females than in males (p<0.05). CONCLUSIONS: Both in clinical practice and in epidemiological studies, it is important to consider that the origin of chronic productive cough could be frequently outside the lower respiratory tract; a consistent percentage of young adults with persistent productive cough has indeed chronic rhino-sinusitis.

Identificación del síndrome de piernas inquietas en estudios polisomnográficos y su asociación con otras variables / Identification of restless legs syndrome in polysomnography studies and its association with other variables

Introducción: El síndrome de piernas inquietas (SPI) es un trastorno del movimiento caracterizado por un impulso incontrolable de mover las piernas en respuesta a una sensación desagradable. La coexistencia de SPI junto con otros trastornos del sueño y del estado de ánimo puede modificar el enfoque terapéutico. El objetivo de este trabajo fue determinar la prevalencia de SPI en adultos estudiados con polisomnografía y evaluar su asociación con otros trastornos del sueño y del estado de ánimo. Pacientes y métodos: Estudio descriptivo transversal. Se incluyó a adultos estudiados con polisomnografía entre 2015 y 2021. Se recopiló información sobre sus antecedentes, datos polisomnográficos y trastornos del ánimo y del sueño mediante un cuestionario escrito autoadministrado que forma parte de la evaluación de todos los pacientes referidos a esta unidad de sueño. Se compararon estas variables en relación con la presencia de SPI. Resultados: Se incluyó a 406 pacientes. La prevalencia de SPI fue del 36,7% (n = 149). La presencia de fatiga (45,3%), insomnio moderado a grave (38,9%) y depresión (45,6%) fue mayor en sujetos con SPI. No se encontraron diferencias en relación con somnolencia diurna y síntomas de ansiedad. Los movimientos periódicos de las piernas no se asociaron con SPI (p = 0,26) y su prevalencia fue baja. Conclusión: La prevalencia de SPI en sujetos estudiados con polisomnografía fue elevada y se asoció a fatiga clínicamente significativa, insomnio y depresión. Estos síntomas deberían identificarse para establecer una estrategia terapéutica adecuada. La prevalencia de movimientos periódicos de las piernas fue baja y no se vinculó con SPI, hallazgo que contrasta con lo publicado previamente. Se requieren estudios adicionales para esclarecer la causa de esta asociación.(AU)

Introduction: Restless legs syndrome (RLS) is a movement disorder characterized by an uncontrollable urge to move the legs in response to an unpleasant sensation. The coexistence of RLS and other sleep and mood disorders may require adjustment in the therapeutic strategy. The objective of this study was to determine the prevalence of RLS in adults studied with polysomnography and to evaluate its association with other sleep and mood disorders. Patients and methods: Descriptive cross-sectional study. We included adults studied with polysomnography between 2015 and 2021. We collected information on their medical history, polysomnographic data and mood and sleep disorders using a self-administered written questionnaire which is part of the routine evaluation of all patients referred to this sleep unit. These variables were compared between patients with and without RLS. Results: We included 406 patients. The prevalence of RLS was 36.7% (n = 149). The presence of fatigue (45.3%), moderate to severe insomnia (38.9%) and depression (45.6%) was higher in subjects with RLS. We did not find differences regarding daytime sleepiness and anxiety symptoms. Periodic Limb Movements (PLM) was not associated with RLS (p = 0.26) and its prevalence was low. Conclusion: The prevalence of RLS in subjects studied with Polysomnography is high and it was associated with clinically significant fatigue, insomnia and depression. These symptoms should be identified in order to establish an adequate therapeutic strategy. The prevalence of periodic limb movements was low and was not linked with RLS. These findings contrast with previous publications. Therefore, it requires additional studies to clarify the cause of this variation.(AU)

Evaluation of skin dose in a low dose spiral CT protocol.

AIM: The authors evaluated radiation and skin doses absorbed by the eye lens, as well as the parotid and thyroid glands, during a low dose maxillary spiral computed tomography (CT). METHODS: Three spiral CTs were carried out, one after the other, changing from time to time MAS, pitch factor, Kv and consequently, CTDI/Vol, until the minimum values detectable by the equipment were reached (MAS 28, Kv 80, CTDI/Vol 2.5, Pitch 1). The quality of the images was evaluated on the grounds of being able to visualise the anatomic structures considered. The amount of radiation effectively absorbed by the soft tissue (skin doses) can be measured with the help of dosimeters placed at the level of eye lens, parotid and thyroid glands. The spiral CTs were performed with a Siemens 16 CT sensation machine, using a tissue equivalent Head-Neck RT Humanoid phantom. RESULTS: From the results of this study, it appears possible to obtain high quality images, useful for diagnosing numerous skeletal pathologies in orthodontics, reducing of about 90% the radiation dose per unit of volume and, at the same time, reducing the soft tissue (skin) dose of about 85% when compared to pre-established settings. CONCLUSION: The authors conclude their research emphasizing the possibility of applying low dose protocols, not only in orthodontics but in any dental field, whenever a spiral CT is needed for a more detailed diagnosis.

Deposition of tetraferrocenylporphyrins on ITO surfaces for photo-catalytic O2 activation.

Tetraferrocenylporphyrins (TFcPs) are a class of compounds where the porphyrin macrocycle is functionalized with a ferrocenyl group at each of the four meso positions. TFcPs exhibit interesting electrochemical properties, mostly due to electronic communication between the ferrocenyl substituents and the porphyrin core. This leads to their capability to release and accept multiple electrons at distinct potentials through reversible and well distinguished processes. Synthesis of substituted-tetraferrocenylporphyrins containing a carboxylic acid functionality allowed to prepare well packed thin layers of TFcP on ITO electrodes using different deposition techniques. In this context, self-assembled monolayers (SAMs) and Langmuir-Blodgett mono- and multilayers (LBs) of TFcPs have been prepared on ITO surfaces. TFcP-functionalized ITO electrodes showed very high stability, and their application in photocatalytic oxygen activation has been tested.

The VITA project: phenotypic resistance to activated protein C and FV Leiden mutation in the general population. Vicenza Thrombophilia and Atherosclerosis.

Resistance to activated protein C (APC) has been recently identified as a common abnormality of the clotting system that significantly increases the risk of venous thromboembolism. The distribution of plasma response to APC in the general population and the variables potentially influencing it are however unknown. In this study, we analyzed the data from the first 4,000 subjects enrolled in the Vicenza Thrombophilia and Atherosclerosis (VITA) Project to identify the demographic and laboratory variables affecting the plasma response to APC. Plasma response to APC, expressed as APC-ratio, was significantly influenced not only by the presence of the FV Leiden mutation but also by the aPTT ratio, triglycerides, fibrinogen and cholesterol level and by pill use, ABO blood group, gender, smoke, body-mass index and age. The effect of these variables was independent of the presence of the FV Leiden mutation, and adjustment for their effect improved the discriminating efficiency of the APC-ratio for the presence of the FV Leiden mutation. Notwithstanding adjustment, the APC ratio was unsuitable for screening purposes in the general population (positive predictive value 82.7%).

Circulating plasma factors in Parkinson's disease enhance nitric oxide release of normal human neutrophils.

Nitric oxide (*NO)-mediated toxicity has been involved in neurodegenerative diseases, including Parkinson's disease (PD). We have recently reported an increase of about 50% in *NO production rate in PMA-activated polymorphonuclear leukocytes (PMN) from either newly diagnosed or chronically treated PD patients. As humoral factors in sera from PD patients could inhibit cell dopaminergic activity, the aim of this study was to determine whether a plasma circulating factor from PD patients could modify *NO metabolism in PMN from healthy control subjects. To this purpose, we determined simultaneously the maximal production rate of *NO and hydrogen peroxide (H2O2) of PMA-activated PMN isolated from healthy control subjects in the presence of aliquots of plasma of PD patients. The results showed that, after 30 min incubation, plasma from newly diagnosed (n=4) or from L-Dopa chronically treated (n=7) PD patients enhanced *NO release in neutrophils isolated from healthy controls by about 50% and 47% respectively, with respect to non-parkinsonian control plasma (n = 10); in the same condition, H2O2 production did not differ among the groups. These data suggest that an overproduction of *NO related to plasma circulating factors, already detected at initial stages of the disease, participates in the pathophysiology of Parkinson's disease.

Dopa-responsive dystonia masquerading as idiopathic kyphoscoliosis.

A 19-year-old girl with a long-standing history of kyphoscoliosis misdiagnosed as idiopathic was offered corrective surgery on several occasions but fortunately refused, since neurological examination later found evidence of mild dystonic posturing in the neck and right leg. Symptoms worsened toward evening but improved with rest. Treatment with low doses of levodopa led to total remission within a month. Our case illustrates that dopa-responsive dystonia can manifest spinal curvature as the major symptom and warrants its inclusion in the differential diagnoses of idiopathic kyphoscoliosis.

Continuous dopaminergic stimulation in cranial dystonia.

Meige's disease is a distressing complaint, the treatment of which often poses a challenge to the neurologist. The patient described here had blepharospasm-oromandibular dystonia, which responded transiently to oral lisuride. On three occasions, drug holidays successfully restored efficacy but thereafter further trials proved fruitless. Continuous subcutaneous lisuride administration in 0.35 mg doses per day, by means of a portable infusion pump, led to sustained improvement for 7 months. No major side effects were observed. Our findings suggest that this treatment deserves further trials.

Clenbuterol-induced tardive dyskinesia.

A 73-year-old man with a history of obstructive lung disease who received clenbuterol 20 mg b.i.d. over 5 years developed dyskinetic movements mainly of the respiratory muscles, closely resembling neuroleptic-induced dyskinesias. Despite drug withdrawal, abnormal movements persisted unchanged. Treatment with reserpine successfully controlled the dyskinetic movements. Clinicians should be aware of this potentially harmful effect of long-term clenbuterol therapy.

[An update on the role of fibrinogen in the atherothrombotic process]. / Un aggiornamento sul ruolo del fibrinogeno nel processo aterotrombotico.

The authors start from the clinical fact that fibrinogen shall be considered today as a major and independent cardiovascular risk factor. Based on this assumption, they re-examine the latest studies and the modern theories on the role that fibrinogen would play in the atherothrombotic process. Among the various theories taken into consideration, the authors particularly emphasize the lesion reaction theory which, revised and re-interpreted in the light of the recent acquisitions, seems to give the most plausible explanation to the events leading to atheromatous plate formation and to subsequent thrombosis. Furthermore, the various causes leading to hyperfibrinogenemia are taken into consideration. On this subject, the authors wonder which alternatives, can be adopted to reduce high fibrinogen levels. It is ascertained that no specific drugs are available for pharmacologic treatment of hyperfibrinogenemia. Instead, there are various active principles capable of reducing fibrinogen levels, in addition to their primary action. The authors stress that in the cardiovascular branch, for example, both ticlopidine and bezabifrate can help reduce hyperfibrinogenemia, in addition to their respective antiplatelet and anti-hyperlipoproteinemic action.

[Spinal myoclonus secondary to the intravenous administration of iodine contrast media]. / Mioclonus espinal secundario a la administración endovenosa de contraste iodado.

We describe a patient with a longstanding paraplegia who developed spinal myoclonus on 3 different occasions spanning one year, once after an enhanced CT scan and twice after excretory urographies, one of which was also followed by a generalized tonic-clonic seizure. To our knowledge only one case of spinal myoclonus secondary to the administration of intravenous contrast material in a patient with a spinal arteriovenous malformation has yet been reported. Taken together, the findings in these cases suggest that spinal myoclonus following intravenous iodine administration is indicative of an underlying spinal cord lesion.