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The presented study investigates the functional role of GABA in somatosensory processing, using a combined neuropharmacological-neuroimaging approach. Three different GABA agonists (GABA A : alprazolam, ethanol; GABA B : baclofen) were investigated in a double blind cross-over design in 16 male participants, accomplishing a tactile perception task. Somatosensory evoked magnetic fields modulated by GABAR-agonists and placebo were recorded using whole-head magnetoencephalography. Peak latencies and amplitudes of primary (SI) and secondary (SII) somatosensory cortex source activities confirmed the previously reported role of GABA as a modulator of somatosensory processing. Significant inhibitory effects on the latency of SII and on the amplitude of SI and SII were found exclusively for alprazolam, a positive allosteric modulator at GABA A receptors. The GABA B agonist baclofen did not have any modulatory effect. Moreover, we investigated whether the observed effects of alprazolam on the level of SII were explainable by the mere propagation of activity from SI to SII modulated by GABA A receptors, independently from any further GABA A -mediated inhibition in SII. By estimating the transfer function between SI and SII activation under placebo conditions, we were able to predict SII activity for the administration of GABA receptors agonists under the assumption that GABA exclusively acts at the level of SI. By comparing measured and predicted data, we propose a model in which the initial activation of SI is modulated through GABA A receptors and subsequently propagated to SII, without any significant further inhibition. In addition, initial GABA A effects in SI appear to be strongly potentiated with time, selectively in SI but not in SII. • The study investigated the role of GABA as a mechanism controlling the processing of sensory information in SI, and SII. • Our results evidence GABA-ergic modulation on the level of SI involving the GABA A receptors sensitive to alprazolam. • Inhibitory effects on the level of SII appear to be the consequence of propagated inhibited activation of SI to SII. • The current study allowed us to disclose the temporal dynamics of inhibitory processes within SI and between SI and SII. [ABSTRACT FROM AUTHOR]

Polyphosphoinositides (PPIns) are a family of seven lipid messengers that regulate a vast array of signalling pathways to control cell proliferation, migration, survival and differentiation. PPIns are differentially present in various sub-cellular compartments and, through the recruitment and regulation of specific proteins, are key regulators of compartment identity and function. Phosphoinositides and the enzymes that synthesise and degrade them are also present in the nuclear membrane and in nuclear membraneless compartments such as nuclear speckles. Here we discuss how PPIns in the nucleus are modulated in response to external cues and how they function to control downstream signalling. Finally we suggest a role for nuclear PPIns in liquid phase separations that are involved in the formation of membraneless compartments within the nucleus. [ABSTRACT FROM AUTHOR]

Evidence suggests that subcortical structures play a role in high-level cognitive functions such as the allocation of spatial attention. While there is abundant evidence in humans for posterior alpha band oscillations being modulated by spatial attention, little is known about how subcortical regions contribute to these oscillatory modulations, particularly under varying conditions of cognitive challenge. In this study, we combined MEG and structural MRI data to investigate the role of subcortical structures in controlling the allocation of attentional resources by employing a cued spatial attention paradigm with varying levels of perceptual load. We asked whether hemispheric lateralization of volumetric measures of the thalamus and basal ganglia predicted the hemispheric modulation of alpha-band power. Lateral asymmetry of the globus pallidus, caudate nucleus, and thalamus predicted attention-related modulations of posterior alpha oscillations. When the perceptual load was applied to the target and the distractor was salient caudate nucleus asymmetry predicted alpha-band modulations. Globus pallidus was predictive of alpha-band modulations when either the target had a high load, or the distractor was salient, but not both. Finally, the asymmetry of the thalamus predicted alpha band modulation when neither component of the task was perceptually demanding. In addition to delivering new insight into the subcortical circuity controlling alpha oscillations with spatial attention, our finding might also have clinical applications. We provide a framework that could be followed for detecting how structural changes in subcortical regions that are associated with neurological disorders can be reflected in the modulation of oscillatory brain activity., Competing Interests: TG, CM, KG, TG, OJ No competing interests declared, (© 2023, Ghafari et al.)

In this paper we propose a neurogeometrical model of the behaviour of cells of the arm area of the primary motor cortex (M1). We will mathematically express as a fiber bundle the hypercolumnar organization of this cortical area, first modelled by Georgopoulos (Georgopoulos et al., 1982; Georgopoulos, 2015). On this structure, we will consider the selective tuning of M1 neurons of kinematic variables of positions and directions of movement. We will then extend this model to encode the notion of fragments introduced by Hatsopoulos et al. (2007) which describes the selectivity of neurons to movement direction varying in time. This leads to consider a higher dimensional geometrical structure where fragments are represented as integral curves. A comparison with the curves obtained through numerical simulations and experimental data will be presented. Moreover, neural activity shows coherent behaviours represented in terms of movement trajectories pointing to a specific pattern of movement decomposition Kadmon Harpaz et al. (2019). Here, we will recover this pattern through a spectral clustering algorithm in the subriemannian structure we introduced, and compare our results with the neurophysiological one of Kadmon Harpaz et al. (2019)., (© 2023. The Author(s).)

While pharmacological treatment with methylphenidate (MPH) is a first line intervention for ADHD, its mechanisms of action have yet to be elucidated. We here seek to identify the white matter tracts that mediate MPH's effect on beta oscillations. We implemented a double-blind placebo-controlled crossover design, where boys diagnosed with ADHD underwent behavioral and MEG measurements during a spatial attention task while on and off MPH. The results were compared with an age/IQ-matched control group. Estimates of white matter tracts were obtained using diffusion tensor imaging (DTI). Via a stepwise model selection strategy, we identified the fiber tracts (regressors) significantly predicting values of the dependent variables of interest (i.e., oscillatory power, behavioral performance, and clinical symptoms): the anterior thalamic radiation (ATR), the superior longitudinal fasciculus ("parietal endings") (SLFp), and superior longitudinal fasciculus ("temporal endings") (SLFt). ADHD symptoms severity was associated with lower fractional anisotropy (FA) within the ATR. In addition, individuals with relatively higher FA in SLFp compared to SLFt, led to stronger behavioral effects of MPH in the form of faster and more accurate responses. Furthermore, the same parietotemporal FA gradient explained the effects of MPH on beta modulation: subjects with ADHD exhibiting higher FA in SLFp compared to SLFt also displayed greater effects of MPH on beta power during response preparation. Our data suggest that the behavioral deficits and aberrant oscillatory modulations observed in ADHD depend on a possibly detrimental structural connectivity imbalance within the SLF, caused by a diffusivity gradient in favor of parietal rather than temporal, fiber tracts., (© 2022 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Giardiasis, the disease caused by the flagellate Giardia duodenalis (syn. G.lamblia, G. intestinalis ), is the most commonly reported among the five food- and waterborne parasitic diseases under mandatory surveillance in 24 EU countries. From November 2018 to April 2019, an outbreak of giardiasis occurred in a municipality of the Bologna province, in north-eastern Italy. Microscopy and immunochromatography identified cysts and antigens, respectively, of the parasite in stool samples of 228 individuals. Molecular typing of 136 stool samples revealed a vast predominance (95%) of G. duodenalis assemblage B. Investigations into potential sources indicated tap water as the most likely vehicle of infection, although cysts were not detected in water samples. Control measures mostly aimed at preventing secondary transmission by informing citizens about the outbreak, and by treatment of patients with anti-parasitic drugs. This is the first documented human outbreak of giardiasis in Italy; its investigation has highlighted the difficulties in the timely detection and management of this parasite, which is often overlooked as a cause of human gastroenteritis. The long and variable incubation time, absence of specific symptoms and a general lack of awareness about this pathogen contributed to delay in diagnosis.

Cannabidiol (CBD) has become a buzzword in many products that have bloomed on the market. The scientific community and some authorities have recently raised concerns on the quality of these products. In particular, the discrepancy between the labelled and the real content of cannabidiol in liquids for e-cigarettes seems to be emerging as a major issue. Furthermore, to-date no studies have been carried out on the chemical stability upon storage of these type of products. The aim of this work was to investigate the accuracy in labelling of thirteen commercially e-liquids containing CBD and the effects of different storage conditions on their quality. The results showed that only 38% of samples were labelled within a ±10% variance from their labels. Stability tests showed a maximum degradation of CBD when samples were stored at 37 °C for 30 days with average values up to 20%. The effect of light was lower but still significant with averages values up to 15% degradation after 30 days. In conclusion, we believe that health authorities should regulate and control this market more stringently to protect customers and their health. Furthermore, our stability tests have shown that if clear indications are provided on the best storage conditions, the quality of these products can be mostly preserved.

Whereas subcortical structures such as the basal ganglia have been widely explored in relation to motor control, recent evidence suggests that their mechanisms extend to the domain of attentional switching. We here investigated the subcortical involvement in reward related top-down control of visual alpha-band oscillations (8-13 Hz), which have been consistently linked to mechanisms supporting the allocation of visuospatial attention. Given that items associated with contextual saliency (e.g., monetary reward or loss) attract attention, it is not surprising that the acquired salience of visual items further modulates. The executive networks controlling such reward-dependent modulations of oscillatory brain activity have yet to be fully elucidated. Although such networks have been explored in terms of corticocortical interactions, subcortical regions are likely to be involved. To uncover this, we combined MRI and MEG data from 17 male and 11 female participants, investigating whether derived measures of subcortical structural asymmetries predict interhemispheric modulation of alpha power during a spatial attention task. We show that volumetric hemispheric lateralization of globus pallidus (GP) and thalamus (Th) explains individual hemispheric biases in the ability to modulate posterior alpha power. Importantly, for the GP, this effect became stronger when the value saliency parings in the task increased. Our findings suggest that the GP and Th in humans are part of a subcortical executive control network, differentially involved in modulating posterior alpha activity in the presence of saliency. Further investigation aimed at uncovering the interaction between subcortical and neocortical attentional networks would provide useful insight in future studies. SIGNIFICANCE STATEMENT Whereas the involvement of subcortical regions into higher level cognitive processing, such as attention and reward attribution, has been already indicated in previous studies, little is known about its relationship with the functional oscillatory underpinnings of said processes. In particular, interhemispheric modulation of alpha band (8-13 Hz) oscillations, as recorded with magnetoencephalography, has been previously shown to vary as a function of salience (i.e., monetary reward/loss) in a spatial attention task. We here provide novel insights into the link between subcortical and cortical control of visual attention. Using the same reward-related spatial attention paradigm, we show that the volumetric lateralization of subcortical structures (specifically globus pallidus and thalamus) explains individual biases in the modulation of visual alpha activity., (Copyright © 2019 the authors.)

In 1955, Allen and Masters describe a painful syndrome which associates traumatic delivery to laceration found on the posterior leaf of the broad ligament. Herniation through this defect is a rare entity, accounted for about 4-7% of all internal hernias. Normally, it involves the small bowel. The authors present the case of a multiparous woman admitted at emergency for constipation and abdominal pain. The CT scan showed an extremely rare case of internal hernia of the sigmoid colon, fallopian tube and left ovary through a large defect of the broad ligament. The patient underwent a full laparoscopic surgery that allowed the reduction of the hernia and the suture of the defect with very good outcome.

Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2X7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML.

In previous studies, we have reported that phospholipase C (PLC)-β1 plays a crucial role in myogenic differentiation and we determined the importance of its catalytic activity for the initiation of this process. Here we define the effectors that take part to its signaling pathway. We show that the Inositol Polyphosphate Multikinase (IPMK) is able to promote myogenic differentiation since its overexpression determines the up-regulation of several myogenic markers. Moreover, we demonstrate that IPMK activates the same cyclin D3 promoter region targeted by PLC-β1 and that IPMK-induced promoter activation relies upon c-jun binding to the promoter, as we have shown previously for PLC-β1. Furthermore, our data shows that IPMK overexpression causes an increase in β-catenin translocation and accumulation to the nuclei of differentiating myoblasts resulting in higher MyoD activation. Finally, we describe that PLC-β1 overexpression determines too an increase in β-catenin translocation and that PLC-β1, IPMK and β-catenin are mediators of the same signaling pathway since their overexpression results in cyclin D3 and myosin heavy chain (MYH) induction.

Introduction: TransAnal Minimally Invasive Surgery (TAMIS) has generated interest and attracted research in the last decade. This approach is used to treat primary benign and malignant diseases, but it can also be adopted to resolve colorectal complications, such as leak and fistula, bleeding and stenosis. A new reusable transanal platform formed by a new port and monocurved instruments has been invented and here presented., Materials and Methods: The first experience included 13 patients submitted to TAMIS for rectal adenocarcinoma (8), immediate colorectal leak (1), early rectovaginal fistula (1), late colorectal fistula (1), immediate colorectal bleeding (1), and benign stenosis (1). Mean age was 62.3 years (38-74), and mean BMI was 25.2 kg/m2 (20.5-32.1)., Results: Mean operative time for transanal total mesorectal excision (TME) was 149.2 minutes (96-193) and for the other procedures 80.6 minutes (15-163). Mean operative bleeding was 51.1 cc (0-450). Mean hospital stay was 5.0 days (2-8). The 3 patients with coloanal anastomosis presented diarrhea postoperatively. No other early postoperative complications were registered. Pathologic report in the oncologic diseases showed that a mean number of 14.7 nodes (16-20) were removed. After a mean follow-up of 8 months (1-14), there were no late complications in any of the 13 patients treated., Conclusion: TAMIS is a feasible alternative approach to treat rectal cancer and a completely new technique to manage colorectal complications. Moreover, this new transanal platform offers surgeons a satisfactory working ergonomy, with no increase in cost of the procedures, because entirely reusable materials are adopted.

Lantibiotics, an abbreviation for "lanthionine-containing antibiotics", interfere with bacterial metabolism by a mechanism not exploited by the antibiotics currently in clinical use. Thus, they have aroused interest as a source for new therapeutic agents because they can overcome existing resistance mechanisms. Starting from fermentation broth extracts preselected from a high-throughput screening program for discovering cell-wall inhibitors, we isolated a series of related class I lantibiotics produced by different genera of actinomycetes. Analytical techniques together with explorative chemistry have been used to establish their structures: the newly described compounds share a common 24 aa sequence with the previously reported lantibiotic planosporicin (aka 97518), differing at positions 4, 6, and 14. All of these compounds maintain an overall -1 charge at physiological pH. While all of these lantibiotics display modest antibacterial activity, their potency can be substantially modulated by progressively eliminating the negative charges, with the most active compounds carrying basic amide derivatives of the two carboxylates originally present in the natural compounds. Interestingly, both natural and chemically modified lantibiotics target the key biosynthetic intermediate lipid II, but the former compounds do not bind as effectively as the latter in vivo. Remarkably, the basic derivatives display an antibacterial potency and a killing effect similar to those of NAI-107, a distantly related actinomycete-produced class I lantibiotic which lacks altogether carboxyl groups and which is a promising clinical candidate for treating Gram-positive infections caused by multi-drug-resistant pathogens.

Background: In the last years the incidence of gastric cancer is changed as the complementary therapy to surgical treatment especially about the advanced stage gastric cancer., Materials and Methods: We have analyzed the patients treated at Unit of General Surgery and Organ Transplantation of University Hospital of Parma from 1/1/2009 to 30/9/2012. The cases surgically treated after neoadiuvant therapy were compared to patients not treated with neoadiuvant therapy.The choice to neoadiuvant therapy was decided on locally advanced disease and low comorbidity., Results: The cases surgically treated were 93, in 9 cases were treated with neoadiuvant therapy. The histotype in neoadiuvant cases was an intestinale type 3 cases, a diffuse type 3 cases and no classificable sec. Lauren 3 cases. The average of number of lymphnodes removed was 22.5 in total gastrectomy and 15.7 nodes in partial gastrectomy. On RECIST criteria the response to neoadiuvant chemotherapy were in 2 cases a partial response and in the others 7 cases the disease remained stable., Conclusion: In our experience as in literature, the neoadiuvant therapy can reduce staging, increases the R0 resection, should proposed in young patients with low comorbidity.

Aim: Our objective is to describe a case of hypothermic politrauma management in our country., Material of Study: We report the case of a 29-year-old male who was a beating victim and fell off from 4 meters, and was afterwards found after an unknown time interval. The patient came to our DEA in cardiac arrest and underwent to a aggressive and prolonged resuscitation which included sternotomy and extracorporeal circulation., Results: The patient was discharged in 40th postoperative day without neurologic complications and complete recovery., Discussion: Even without a dedicated protocol for the hypothermic politrauma the correct multidisciplinary approach lead to the complete recovery of the patient. In literature many papers describe the aggressive resuscitation of hypothermic patients underlining that the politrauma management must be multidisciplinar., Conclusion: We want to underline the importance of the "Damage control strategy" in a politrauma team in the major hospitals in our country., Key Words: Cardiopulmonary resuscitation, Extracorporeal circulation, Hypothermia, Polytrauma, Trauma team.

Two new members of the spirotetronate class, nai414-A and nai414-B, were discovered and isolated from an Actinoallomurus sp. Their structures were established by 1D and 2D NMR, UV, and MS analyses and by chemical degradation. They showed antimicrobial and antitumor activity against Gram-positive bacteria and against human microvascular endothelial cells, respectively. Substituting bromide for chloride ions in the growth medium afforded mono- and dibrominated derivatives.

Two different strategies for the synthesis of functionalised γ-lactones from δ-lactones are described and used in a convergent synthesis of (+)-mupirocin H. The total synthesis is versatile and may be readily adapted for the preparation of further truncated metabolites from Pseudomonas fluorescens., (This journal is © The Royal Society of Chemistry 2012)

In the search for novel antibiotics, natural products continue to represent a valid source of bioactive molecules. During a program aimed at identifying previously unreported taxa of actinomycetes as potential source of novel compounds, we isolated hundreds of different representatives of a new group, initially designated as 'Alpha' and independently described as Actinoallomurus. We report on a PCR-specific method for the detection of this taxon, on appropriate growth conditions and on a pilot-screening program on 78 strains. The strains produce antibacterial or antifungal compounds at a relatively high frequency. Four strains were characterized in further detail: one produced the aromatic polyketide benanomicin B and its dexylosyl derivative; a second strain produced N-butylbenzenesulfonamide; a third strain was an efficient converter of soymeal isoflavonoids from soymeal constituents; and a fourth strain produced several coumermycin-related aminocoumarins, with coumermycin A2 as the major peak, and with some new congeners as minor components of the complex. These data suggest that Actinoallomurus strains possess several pathways for secondary metabolism and represent an attractive source in the search for novel antibiotics.

We present a case of a patient who developed a metachronous splenic metastasis from renal clear cell carcinoma, for which he has undergone a left nephrectomy 14 years earlier. During his routine follow up a CT scan showed a splenic mass which was considered an isolated metastasis possibly originating from the renal cancer. A splenectomy was performed and histopatological examination of the spleen confirmed the presence of clear cell carcinoma with infiltration of the capsule. Splenic metastases are uncommon and from the reported literature we understand that splenic metastasis from renal cell carcinoma is extremely rare. The optimal treatment seems to be splenectomy with a good long term outcome. With this report the authors would like to discuss the possibility that it could be a case of local recurrence rather than a real metastasis. A revision of previous reports in the literature is performed too., (Published by Elsevier Ltd.)

A common feature of the mupirocin and other gene clusters of the AT-less polyketide synthase (PKS) family of metabolites is the introduction of carbon branches by a gene cassette that contains a beta-hydroxy-beta-methylglutaryl CoA synthase (HMC) homologue and acyl carrier protein (ACP), ketosynthase (KS) and two crotonase superfamily homologues. In vivo studies of Pseudomonas fluorescens strains in which any of these components have been mutated reveal a common phenotype in which the two major isolable metabolites are the truncated hexaketide mupirocin H and the tetraketide mupiric acid. The structure of the latter has been confirmed by stereoselective synthesis. Mupiric acid is also the major metabolite arising from inactivation of the ketoreductase (KR) domain of module 4 of the modular PKS. A number of other mutations in the tailoring region of the mupirocin gene cluster also result in production of both mupirocin H and mupiric acid. To explain this common phenotype we propose a mechanistic rationale in which both mupirocin H and mupiric acid represent the products of selective and spontaneous release from labile points in the pathway that occur at significant levels when mutations block the pathway either close to or distant from the labile points.

Postoperative nausea and vomiting (PONV) are among the most common complications in surgical patients. In this prospective, double blind, parallel group study we compare the prophylactic antiemetic efficacy of ondansetron versus placebo in 90 patients undergoing general balanced anaesthesia. The patients were stratified according to the kind of surgery and randomly allocated to three treatment groups: 30 patients (Group A) received ondansetron 4 mg i.v. 1 hour before the induction of anaesthesia and placebo 1 hour before the end of surgery; 30 patients (Group B) received placebo 1 hour before the end of anaesthesia and ondansetron 4 mg i.v. 1 hour before the end of surgery; 30 patients (Group C-control group) received placebo in both the administrations. Data were analyzed by Student t test and chi 2 test; significance was taken at p < 0.05. The three groups proved comparable with respect to demographic characteristics, duration of anaesthesia and fentanyl consumption. Analysis of the results showed that PONV had a significantly lower incidence in treated patients (Groups A and B) than in the control group patients (Group C): postoperative nausea occurred in 13%, 30% and 67% of patients in Group A, B and C respectively and it was associated with vomiting in 3%, 7% and 57% of patients in Group A, B and C respectively. Although the patients in Group A showed a lower incidence of PONV in comparison to the patients in Group B, such differences proved to be not statistically significant. No adverse effects in relation to drug administration were observed. We conclude that ondansetron 4 mg i.v. is safe and effective in preventing PONV in the surgical patients, particularly when administered before the induction of anaesthesia.