Rejected

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a broadly expressed neuropeptide which has diverse effects in both the peripheral and central nervous systems. While its neuroprotective effects have been shown in a variety of disease models, both animal and human data support the role of PACAP in migraine generation. Both PACAP and its truncated derivative PACAP(6-38) increased calcium influx in rat trigeminal ganglia (TG) primary sensory neurons in most experimental settings. PACAP(6-38), however, has been described as an antagonist for PACAP type I (known as PAC1), and Vasoactive Intestinal Polypeptide Receptor 2 (also known as VPAC2) receptors. Here, we aimed to compare the signaling pathways induced by the two peptides using transcriptomic analysis. Rat trigeminal ganglion cell cultures were incubated with 1 µM PACAP-38 or PACAP(6-38). Six hours later RNA was isolated, next-generation RNA sequencing was performed and transcriptomic changes were analyzed to identify differentially expressed genes. Functional analysis was performed for gene annotation using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. We found 200 common differentially expressed (DE) genes for these two neuropeptides. Both PACAP-38 and PACAP(6-38) treatments caused significant downregulation of NADH: ubiquinone oxidoreductase subunit B6 and upregulation of transient receptor potential cation channel, subfamily M, member 8. The common signaling pathways induced by both peptides indicate that they act on the same target, suggesting that PACAP activates trigeminal primary sensory neurons via a mechanism independent of the identified and cloned PAC1/VPAC2 receptor, either via another target structure or a different splice variant of PAC1/VPAC2 receptors. Identification of the target could help to understand key mechanisms of migraine.

We set out to explore the factors that may affect delayed disappearance (DD) of trigeminal neuralgia (TN) after percutaneous balloon compression (PBC).

Migraine is one of the major symptoms of many psychiatric and mental disorders like depression and anxiety. Eletriptan Hydrobromide (EH) is a well-tolerated drug in migraine treatment, but suffers from low oral bioavailability and low brain targeting after oral delivery. New nasal mucoadhesive EH-emulsomes development could be a new means to direct the drug from the nose-to-brain to achieve rapid onset of action and high drug concentration in the brain for acute migraine treatment. Eletriptan mucoadhesive emulsomes formulations were prepared using thin-film hydration method and 2 full factorial design was adopted to study different formulation factors' effect on the emulsomes characters. The emulsomes were characterized for entrapment efficiency (EE%), zeta potential (ZP), particle size (PS), morphology, and ex-vivo permeation through the nasal mucosa. The selected formula was evaluated in mice for its in-vivo bio-distribution in comparison with EH intranasal and intravenous solutions. Drug targeting efficacy (DTE%) and nose-to-brain direct transport percentage (DTP%) were calculated. The optimization formulation showed a nanoparticle size of 177.01 nm, EE 79.44%, and ZP = 32.12 ± 3.28 mV. In addition, in-vitro permeability studies revealed enhanced drug permeability with suitable mean residence time up to 120 ± 13 min. EH-emulsomes were stable under different storage conditions for three months. In vivo examination and pharmacokinetic drug targeting parameters revealed EH transport to the CNS after EH nanoparticle nasal administration. Histopathology study showed no ciliotoxic effect on the nasal mucosa. From the results, it can be confirmed that the emulsomes formulation of EH proved safe direct nose-to-brain transport of EH after nasal administration of EH emulsomes.

Pain is a complex sensory and emotional experience with nociceptive, nociplastic, and neuropathic components. An involvement of neurotropic B vitamins (B1 – thiamine, B6 – pyridoxine, and B12 – cyanocobalamin) as modulators of inflammation and pain has been long discussed. New evidence suggests their therapeutic potential in different pain conditions. In this review, we discuss the main role of neurotropic B vitamins on different nociceptive pathways in the nervous system and to describe their analgesic action mechanisms. The performed literature review showed that, through different mechanisms, these vitamins regulate several inflammatory and neural mediators in nociceptive and neuropathic pain. Some of these processes include aiming the activation of the descending pain modulatory system and in specific intracellular pathways, anti-inflammatory, antioxidative and nerve regenerative effects. Moreover, recent data shows the antinociceptive, antiallodynic, and anti-hyperalgesic effects of the combination of these vitamins, as well as their synergistic effects with known analgesics. Understanding how vitamins B1, B6, and B12 affect several nociceptive mechanisms can therefore be of significance in the treatment of various pain conditions.

Pentazocine (PTZ), a narcotic-antagonist analgesic, has been extensively used in the treatment of initial carcinogenic or postoperative pain. Hepatic first-pass metabolism results in low oral bioavailability and high dose wastage. Herein, 10 mg (-)-Pentazocine (HPLC-grade) was incorporated to solid lipid nanoparticles (SLNs) using a double water-oil-water (//) emulsion by solvent emulsification-evaporation technique, followed by high shear homogenization to augment its oral bioavailability, considering the lymphatic uptake. The resulting SLNs were characterized for zeta potential (ZP), particle size (PS), and polydispersity index (PDI) using a zetasizer. The entrapment efficiency (EE) and loading capacity (LC) were calculated. Chemical interactions, through the identification of active functional groups, were assessed by Fourier-transformed infrared (FTIR) spectroscopy. The nature (crystallinity) of the SLNs was determined by X-ray diffractometry (XRD). The surface morphology was depicted by transmission electron microscopy (TEM). In vitro (in Caco-2 cells) and in vivo (in male Wistar rats) investigations were carried out to evaluate the PTZ release behavior and stability, as well as the cellular permeation, cytotoxicity, systemic pharmacokinetics, antinociceptive, anti-inflammatory, and antioxidative activities of PTZ-loaded SLNs, mainly compared to free PTZ (marketed conventional dosage form). The optimized PTZ-loaded SLN2 showed significantly higher in vitro cellular permeation and negligible cytotoxicity. The in vivo bioavailability and pharmacokinetics parameters (t, Cmax) of the PTZ-loaded SLNs were also significantly improved, and the nociception and inflammation, following carrageenan-induced inflammatory pain, were markedly reduced. Concordantly, PTZ-loaded SLNs showed drastic reduction in the oxidative stress (e.g., malonaldehyde (MDA)) and proinflammatory cytokines (e.g., Interleukin (IL)-1β, -6, and TNF-α). The histological features of the paw tissue following, carrageenan-induced inflammation, were significantly improved. Taken together, the results demonstrated that PTZ-loaded SLNs can improve the bioavailability of PTZ by bypassing the hepatic metabolism via the lymphatic uptake, for controlled and sustained drug delivery.

The work performed by wildland firefighters (WFFs) is very demanding owing to the conditions in which they have to operate. It has been reported that these professionals walk long distances over unstable and steep terrain carrying heavy loads, handle tools manually and repeatedly and are subject to a high level of thermal stress. Under such conditions, the risk of developing chronic pain (CP) is high, although despite this, there are no available data pertaining to CP among WFFs, to the best of our knowledge. As such, the aim of this study is to describe CP in Spanish helitack crews, for which purpose 221 WFFs (203 men and 18 women) completed an online self-report questionnaire. Approximately 60% of WFFs reported suffering from CP, of which 45.5% had CP in more than one body region at the same time. Age and length of service were associated with the probability of suffering from CP. Likewise, the age and height of WFFs and weight of the protective equipment used increased the prevalence of CP. Lastly, gender and job position affected CP location, with women and forepersons reporting greater prevalence of CP in the lower limbs. To conclude, the results obtained suggest the major prevalence of CP among Spanish WFFs, with current data suggesting in turn the importance that age, stature, gender, length of service, weight of protective equipment and job position have on the prevalence and location of CP.

Migraine headache is a common disorder in pediatrics, sometimes leading to hospital admission. Psychiatric comorbidities are prevalent in adults with migraine headache, but there is limited evidence in the pediatric population. This study aimed to examine the prevalence of psychiatric comorbidity in children hospitalized for migraine headache and assess the association of this comorbid state on treatment interventions and outcomes.

Surgical site infections (SSIs), which are a potential complications in surgical procedures, are associated with prolonged hospital stays and increased postoperative mortality rates, and they also have a significant economic impact on health systems. Data in literature regarding risk factors for SSIs in pediatric age are scarce, with consequent difficulties in the management of SSI prophylaxis and with antibiotic prescribing attitudes in the various surgical procedures that often tend to follow individual opinions. The lack of pediatric studies is even more evident when we consider surgeries performed in subjects with underlying conditions that may pose an increased risk of complications. In order to respond to this shortcoming, we developed a consensus document to define optimal surgical antimicrobial prophylaxis (SAP) in neonates and children with specific high-risk conditions. These included the following: (1) colonization by methicillin-resistant (MRSA) and by multidrug resistant (MDR) bacteria other than MRSA; (2) allergy to first-line antibiotics; (3) immunosuppression; (4) splenectomy; (5) comorbidity; (6) ongoing antibiotic therapy or prophylaxis; (7) coexisting infection at another site; (8) previous surgery in the last month; and (9) presurgery hospitalization lasting more than 2 weeks. This work, made possible by the multidisciplinary contribution of experts belonging to the most important Italian scientific societies, represents, in our opinion, the most up-to-date and comprehensive collection of recommendations relating to behaviors to be undertaken in a perioperative site in the presence of specific categories of patients at high-risk of complications during surgery. The application of uniform and shared protocols in these high-risk categories will improve surgical practice with a reduction in SSIs and consequent rationalization of resources and costs, as well as being able to limit the phenomenon of antimicrobial resistance.

Chronic low back pain is one of the most common musculoskeletal disorders in different countries.