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Charles Veltri,1 Oliver Grundmann1,21Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ 85308, USA; 2Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32611, USAAbstract: The leaves from the tree Mitragyna speciosa, commonly known as Kratom, in the coffee plant family (Rubiaceae) are commonly used in their native habitat of Southeast Asia as a stimulant to sustain energy during hard day labor and as an opioid-like analgesic and sedative. Traditional and modern uses overlap based on the effects of the leaf extract which has also gained popularity in the United States and Europe in the last two decades. Kratom has and is being used for the mitigation of opioid withdrawal symptoms and as a harm reduction agent with a minority of users subsequently developing a dependence on the extract. The respective demographic use patterns of Kratom differ between Southeast Asia and the Western world. While pure Kratom is primarily used by day laborers and misused in conjunction with cough medicine by youth in Southeast Asia, a majority of users in the United States is middle-aged, has at least middle income, private health insurance, and completed some college. Deaths attributed to the use of Kratom have been reported in Europe and the United States but not in Southeast Asia. Although Kratom was detected as the alkaloid mitragynine in the blood of the decedents, causality could not be established in almost all cases because of poly-drug exposures. It is notable that Kratom can cause herb–drug interactions, especially with other central nervous system -active substances. Given the mostly unregulated market for Kratom products in Western countries, consumers may be exposed to adulterated or contaminated products, especially if purchased through websites or the darknet. A number of countries have scheduled Kratom because of its stimulant- and opioid-like effects and the established interaction of the alkaloid mitragynine with opioid receptors.Keywords: Kratom, Mitragyna speciosa, use pattern, Southeast Asia, substance dependence

Examines the molecular genetic characterization of the goat s&sub2;-casein E allele in Italy. Occurrence of protein variant E allele; Amplification of the 18 exons of the gene using primers; Confirmation of nucleotide substitution by amplified cDNA.

Objective: To analyse work participation among patients with inflammatory rheumatic musculoskeletal diseases (iRMDs), namely rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV)., Methods: A cross-sectional sample of 16 421 patients from the National Database of the German Collaborative Arthritis Centers, aged <65 years were analysed. For each diagnosis, yearly rates of absenteeism, employment and disability pensions were analysed from 2010 to 2022. Population data were used to calculate standardised employment ratios (SERs), adjusted for age, sex, federal state and vocational qualification. The analysis was additionally stratified by sex, adjusting for other factors., Results: Over the observed time span, large employment increases were found across all diagnoses, namely in RA (54%-68%), PsA (58%-72%), SSc (47%-66%), AAV (43%-61%), SLE (48%-60%) and axSpA (65%-73%). SERs were for RA 0.88 (95% CI 0.86 to 0.90), axSpA (0.88 (0.84 to 0.91)), PsA (0.88 (0.85 to 0.91)), SSc (0.83 (0.75 to 0.91)), SLE (0.76 (0.72 to 0.80)) and AAV (0.73 (0.63 to 0.83)). In RA, axSpA, PsA and AAV, SERs were higher in men while in SLE and SSc men had lower SER. Median of yearly absenteeism due to the disease decreased by 5 (RA), 1 (axSpA), 6 (PsA), 11 (SLE), 4 (SSc) and 10 days (AAV) in the time span. Except for SSc, the proportion of disability pension receivers decreased for all diagnoses., Conclusion: Since 2010, work participation has improved for patients with iRMDs, as reflected in higher employment, reduced absenteeism and less disability retirement. However, patients have not reached population employment rates., Competing Interests: Competing interests: CAGV, KA, DM-O, UK and KT declared nothing. JC has received speaker honoraria from Janssen, Pfizer, Idorsia. SS has received speaker honoraria from Abbvie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Galapagos, GSK, Lilly, MSD, Novartis, Pfizer, Sanofi and UCB. AS has received speaker honoraria from AbbVie, Amgen, BMS, Celltrion, MSD, Lilly, Pfizer, Roche and UCB., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Atlantoaxial injuries pose a significant threat to morbidity and mortality. This retrospective study aims to analyze clinical and radiologic results, failure rates, and complications in a series of patients treated with a halo vest, validating the effectiveness of this device through long-term follow-up., Methods: This study reviewed adult patients with acute upper cervical spine injuries treated with halo vest immobilization from 1994 to 2022. Fracture types were classified based on computed tomography characteristics. Clinical and radiologic follow-up was performed at the end of treatment and 3 months after the removal of the system., Results: Most treated patients were male (70%), with a mean age of 38 years. Car accidents were the primary cause of injury (63%). Among 161 patients, 134 had a C2 fracture, 20 had a C1 fracture, 5 had a C1-C2 rotational dislocation, and 2 had other unclassified combined C1/C2 fractures. Patients without additional injuries or neurologic deficits had significantly shorter hospitalization (8 vs. 16 days and 12 vs. 22 days, respectively) compared with those with additional injuries (P < 0.00001) or neurologic deficits (P = 0.00164). At 6 months follow-up, radiologic and clinical outcomes were available for 147 patients. Radiography in 139 cases showed fracture fusion (94.6%). Clinical follow-up showed a normal or slightly reduced range of motion in 144 cases (98%). Pain was absent or episodic in all the patients except one. In 131 patients (89%), an excellent or good clinical result was achieved. Complications did not affect treatment., Conclusions: Based on our results, the halo vest is a valid treatment for atlantoaxial injuries in selected patients. These patients include young and middle-aged individuals (up to 65 years old) with C1 and/or C2 fractures. Halo vest treatment is associated with minor complications and yields a high percentage of excellent/good clinical results., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives : Metastatic spinal cord compression represents a substantial risk to patients, given its potential for spinal cord and/or nerve root compression, which can result in severe morbidity. This study aims to evaluate the effectiveness of a diagnostic-therapeutic algorithm developed at our hospital to mitigate the devastating consequences of spinal cord compression in patients with vertebral metastases. Materials and Methods : The algorithm, implemented in our practice in January 2022, is based on collective clinical experience and involves collaboration between emergency room physicians, oncologists, spine surgeons, neuroradiologists, radiation oncologists, and oncologists. To minimize potential confounding effects from the COVID-19 pandemic, data from the years 2019 and 2021 (pre-protocol) were collected and compared with data from the years 2022 and 2023 (post-protocol), excluding the year 2020. Results : From January 2022 to December 2023, 488 oncological patients were assessed, with 45 presenting with urgency due to suspected spinal cord compression. Out of these, 44 patients underwent surgical procedures, with 25 performed in emergency settings and 19 cases in elective settings. Comparatively, in 2019 and 2021, 419 oncological patients were evaluated, with 28 presenting with urgency for suspected spinal cord compression. Of these, 17 underwent surgical procedures, with 10 performed in emergency scenarios and 7 in elective scenarios. Comparing the pre-protocol period (years 2019 and 2021) to the post-protocol period (years 2022 and 2023), intrahospital consultations (commonly patients neurologically compromised) for spine metastasis decreased (105 vs. 82), while outpatient consultations increased remarkably (59 vs. 124). Discussion : Accurate interpretation of symptoms within the context of metastatic involvement is crucial for patients with a history of malignancy, whether presenting in the emergency room or oncology department. Even in the absence of a cancer history, careful interpretation of pain characteristics and clinical signs is crucial for diagnosing vertebral metastasis with incipient or current spinal cord compression. Early surgical or radiation intervention is emphasized as it provides the best chance to prevent deficits or improve neurological status. Preliminary findings suggest a notable increase in both the number of patients diagnosed with suspected spinal cord compression and the proportion undergoing surgical intervention following the implementation of the multidisciplinary protocol. The reduced number of intrahospital consultations (commonly patients neurologically compromised) and the increased number of visits of outpatients with vertebral metastases indicate a heightened awareness of the issue, leading to earlier identification and intervention before neurological worsening necessitating hospitalization. Conclusions : A comprehensive treatment planning approach is essential, and our multidisciplinary algorithm is a valuable tool for optimizing patient outcomes. The protocol shows potential in improving timely management of spinal cord compression in oncological patients. Further analysis of the factors driving these changes is warranted. Limitations: This study has limitations, including potential biases from the retrospective nature of data collection and the exclusion of 2020 data due to COVID-19 impact. To enhance the robustness of our results, long-term studies are required. Moreover, the single-center study design may limit the validity of the findings. Further multicenter studies would be beneficial for validating our results and exploring underlying factors in detail.

Kratom ( Mitragyna speciosa Korth., Rubiaceae) is native to and has traditional use in Southeast Asia. The number of kratom users outside of Southeast Asia has increased significantly in recent decades with use spreading to the Unites States (US) and Europe. Because of its reputed opioid-like psychoactive effects at higher doses, kratom has been regulated in several countries and is subject to an import ban by the US Food and Drug Administration. Nonetheless, in the US it is estimated that 10-15 million people consume kratom primarily for the self-treatment of pain, psychiatric disorders, to mitigate withdrawal from or dependence on opioids, and to self-treat opioid use disorder or other substance use disorders (SUDs). Due to the global COVID-19 pandemic, a shortage in the supply of kratom products may place unexpected burdens on kratom users, potentially influencing some who use kratom for SUD self-treatment to regress to harmful drug use, hence increasing the likelihood of adverse outcomes, including overdose. Inadequate treatment, treatment barriers, and increases in the sales of adulterated kratom products on the internet or in convenience stores could exacerbate circumstances further. Although there are currently no verified indications of kratom scarcity, researchers and clinicians should be aware of and remain vigilant to this unanticipated possibility., Competing Interests: JH is an employee of Pinney Associates which provides consulting services on the development and regulation of pharmaceuticals, cannabinoids, and dietary supplements including kratom and advises the American Kratom Association on Kratom science. PB provides scientific guidance on dietary supplement manufacture and regulatory compliance to companies, associations, and government and in her capacity as Director of Applied Research at BCIT engages in contract research on medicinal plants, including Kratom. AG-R serves as a scientific advisor for ETHA Natural Botanicals, a distributor of kratom supplements. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor and two of the reviewers, JC and SC, declared a shared affiliation, though no collaboration, with two of the authors, EC and OC, at the time of review., (Copyright © 2020 Singh, Brown, Cinosi, Corazza, Henningfield, Garcia-Romeu, McCurdy, McMahon, Prozialeck, Smith, Swogger, Veltri, Walsh and Grundmann.)

Among the symptoms of COVID-19 fever, general malaise, pain and aches, myalgia, fatigue, and headache can affect the quality of life of patients, even after the end of the acute phase of the infection and can be long lasting. The current treatment of these symptoms, also because COVID-19 patients have been asked not to use non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen are often unsatisfactory. Among the above mentioned symptoms malaise and fatigue seem the most difficult to treat. In this case report we describe the use of kratom ( Mitragyna speciosa ) by a patient with confirmed COVID-19 infection. What we observed was a fast and sustained relieve of the above mentioned symptoms., (Copyright © 2020 Metastasio, Prevete, Singh, Grundmann, Prozialeck, Veltri, Bersani and Corazza.)

Fertilization is a complex and multiphasic process, consisting of several steps, where egg-coating envelope's glycoproteins and sperm surface receptors play a critical role. Sperm-associated β-N-acetylglucosaminidases, also known as hexosaminidases, have been identified in a variety of organisms. Previously, two isoforms of hexosaminidases, named here DmHEXA and DmHEXB, were found as intrinsic proteins in the sperm plasma membrane of Drosophila melanogaster. In the present work, we carried out different approaches using solid-phase assays in order to analyze the oligosaccharide recognition ability of D. melanogaster sperm hexosaminidases to interact with well-defined carbohydrate chains that might functionally mimic egg glycoconjugates. Our results showed that Drosophila hexosaminidases prefer glycans carrying terminal β-N-acetylglucosamine, but not core β-N-acetylglucosamine residues. The capacity of sperm β-N-acetylhexosaminidases to bind micropylar chorion and vitelline envelope was examined in vitro assays. Binding was completely blocked when β-N-acetylhexosaminidases were preincubated with the glycoproteins ovalbumin and transferrin, and the monosaccharide β-N-acetylglucosamine. Overall, these data support the hypothesis of the potential role of these glycosidases in sperm-egg interactions in Drosophila., (© 2017 Wiley Periodicals, Inc.)

Purpose: The purpose of this retrospective analysis is to determine whether disc prosthesis replacement can be equivalent or superior compared with the disc interbody fusion., Methods: Between January, 2005 and June, 2011 we performed microdiscetomy by the anterior approach in 176 patients. We subdivided the total set of patients into two groups. Group A is made up of 84 patients in whom the prosthetic disc was implanted; Group B is made up of 92 patients in whom disc fusion was performed., Results: In both groups, the radicular pain disappeared and the signs of spinal cord compression improved or remained stable. Patients of Group A required significantly fewer days of hospitalization and shorter absence from work, and had significant lower scores in the Neck Disability Index (NDI) at 12 months., Conclusions: Our experience demonstrates that the use of disc prosthesis is a safe and effective alternative to interbody fusion.

Aim: Neurogenic low urinary tract dysfunctions unresponsive to medical and conservative therapy are difficult to manage. Nowadays they can be treated with Sacral Nerve Stimulation (SNS), even if clinical experiences reported in literature are still limited., Methods: We performed SNS in 6 patients with neurogenic bladder: 3 patients had incontinence-urgency (1 myelitis, 1 multiple sclerosis, 1 autonomic polineuropathy) and 3 patients had urinary retention (1 incomplete spinal cord lesion, 1 operation for discal hernia T5-T6, 1 hysterectomy)., Results: Among cases with incontinence-urgency we achieved complete control of the bladder in 2 patients while in 1 patient the number of urinary losses was reduced of the 80%. In 2 patients with urinary retention we obtained complete recovery of the bladder function, while in 1 patient the number of cateterisms/die reduced of 50%, the urinary volume for micturion increased and residual urinary volume decreased. Results were unchanged during the follow-up (maximum 26 months), except for 1 patient in which a partial loss of effectiveness occurred., Conclusions: Chronic electric stimulation of S3 sacral roots via an implanted neuroprotesis is therefore an effectiveness, save and promising therapeutic option in treatment of neurogenic bladder dysfunctions.

The alphas1-casein (alphas1-Cas) locus in the goat is characterized by a polymorphism, the main feature of which is to be qualitative as well as quantitative. A systematic analysis performed in an autochthon southern Italy breed identified a new rare allele (M), which was characterized at both the protein and genomic level. The M protein displays the slowest electrophoretic mobility of the alphas1-Cas variants described so far. MS and automated Edman degradation experiments showed that this behavior was due to the loss of two phosphate residues in the multiple phosphorylation site (64SP-SP-SP-SP-SP-E-70E) consecutively to a Ser-->Leu substitution at position 66 of the peptide chain (64S-SP-L-SP-SP-E-70E). This was confirmed by sequencing a genomic DNA fragment encompassing exon 9 where the 8th codon (TCG) was shown to be mutated to TTG. Sequencing of amplified genomic DNA segments spanning the 5' and 3' flanking regions of each exon allowed us to identify 23 single nucleotide polymorphisms and two insertion/deletion events in the coding as well as the noncoding regions. A comparison of specific haplotypes defined for each of the alphas1-CasF, A and M alleles indicates that the M allele probably arises from interallelic recombination between alleles A and B2, followed by a C-->T transition at nucleotide 23 of the ninth exon. The region encompassing the recombination break point was putatively located between nucleotide 86 upstream and nucleotide 40 downstream of exon 8. Interallelic recombination therefore appears to be a possible means of generating allelic diversity at the alphas1-Cas locus, at least in the goat. The previously proposed molecular phylogeny must now be revised, possibly starting from two ancestral allelic lineages.

Although dependence on afferent synaptic activity has been shown for central neurons in every sensory system, the mechanisms of afferent maintenance of target sensory neurons are not understood. Neurons in the cochlear nucleus (CN) require afferent activity for maintenance and survival. One of the earliest changes seen after activity deprivation is an increase in intracellular calcium that leads to the death of 30% of the neuronal population. Sixty minutes after deafferentation, the surviving neurons show increased phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). CREB phosphorylation in activity-deprived CN neurons is dependent on increased intracellular calcium resulting from influx through AMPA receptors and is mediated by calcium/calmodulin-dependent kinases and protein kinase A. We conclude that in CN neurons, the deafferentation-induced increase in calcium activates at least two kinase pathways that phosphorylate CREB in surviving neurons. We hypothesize that this phosphorylation results in the transcription of genes containing the calcium/cAMP response element within their promoter regions, and these genes code for proteins that allow the neurons to compensate for their hypercalcemic, activity-deprived state.

The nucleoside conformation of pseudouridine (psi) was investigated in a series of RNA oligonucleotides and compared with the same sequences containing the parent, unmodified uridine nucleoside. 1H NMR spectroscopy was used to determine the glycosyl conformational preference in pseudouridine systems at the nucleoside level; these experiments were extended to trimers, and ultimately to RNA tetraloop hairpins that are models for the codon-anticodon interaction in tRNA. ROESY 1D and 2D NMR experiments were used to measure the nucleoside conformational preference as a function of temperature. The thermodynamic stability of the RNA tetraloops was also analyzed using UV monitored Tm experiments which established that pseudouridine has a very strong stabilizing effect on double-stranded, base pairing interactions when the modification is located within a base-paired region. This was shown for a tetraloop hairpin model of the codon-anticodon interaction in tRNA(Tyr) which contains a psi at position 35. Pseudouridine also stabilizes double-stranded RNA when the psi modification is in a single-stranded region adjacent to a duplex region as occurs for psi at positions 38 or 39 in tRNA(Lys) and tRNA(His). These results establish that pseudouridine modification of RNA is a powerful and versatile mechanism for stabilizing local RNA structure in both single-stranded and double-stranded regions. Previously postulated roles for pseudouridine as a "conformational switch" are unlikely in light of the increased barrier to rotation about the glycosyl bond upon modification of uridine to pseudouridine. The Tm and NMR data show that local RNA stacking stabilization as a result of psi will stabilize adjacent double-stranded RNA regions such as the codon-anticodon interaction in tRNA.