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Department of Pharmacology

 

Current status of neurotrauma management in resource-limited settings

Thu, 20/03/2025 - 10:00

Ann Med Surg (Lond). 2025 Jan 7;87(2):673-683. doi: 10.1097/MS9.0000000000002901. eCollection 2025 Feb.

ABSTRACT

Over the last several decades neurotrauma has become recognized as a significant contributor to poor health outcomes, with growing physical, cognitive, social, and economic burdens. Although it serves as a significant contributor globally, it disproportionately affects low- and middle-income countries (LMIC). In this manuscript, we will be comparing how neurotrauma is managed across the globe with special consideration on how variations in environment, resources, infrastructure, and access can influence patient care and outcomes. Moreover, we will be examining the challenges faced by health care systems in LMIC and exploring strategies for quality improvement.

PMID:40110290 | PMC:PMC11918690 | DOI:10.1097/MS9.0000000000002901

Multi-channel MRI reconstruction using cascaded Swinμ transformers with overlapped attention

Wed, 19/03/2025 - 10:00

Phys Med Biol. 2025 Mar 19;70(7). doi: 10.1088/1361-6560/adb933.

ABSTRACT

Objective.Deep neural networks have been shown to be very effective at artifact reduction tasks such as magnetic resonance imaging (MRI) reconstruction from undersampled k-space data. In recent years, attention-based vision transformer models have been shown to outperform purely convolutional models at a wide variety of tasks, including MRI reconstruction. Our objective is to investigate the use of different transformer architectures for multi-channel cascaded MRI reconstruction.Approach.In this work, we explore the effective use of cascades of small transformers in multi-channel undersampled MRI reconstruction. We introduce overlapped attention and compare it to hybrid attention in shifted-window (Swin) transformers. We also investigate the impact of the number of Swin transformer layers in each architecture. The proposed methods are compared to state-of-the-art MRI reconstruction methods for undersampled reconstruction on standard 3T and low-field (0.3T) T1-weighted MRI images at multiple acceleration rates.Main results.The models with overlapped attention achieve significantly higher or equivalent quantitative test metrics compared to state-of-the-art convolutional approaches. They also show more consistent reconstruction performance across different acceleration rates compared to their hybrid attention counterparts. We have also shown that transformer architectures with fewer layers can be as effective as those with more layers when used in cascaded MRI reconstruction problems.Significance.The feasibility and effectiveness of cascades of small transformers with overlapped attention for MRI reconstruction is demonstrated without incorporating pre-training of the transformer on ImageNet or other large-scale datasets.

PMID:40105018 | DOI:10.1088/1361-6560/adb933

A comprehensive review of the clinical presentation, diagnosis, and treatment of calcineurin inhibitor-induced pain syndrome

Mon, 17/03/2025 - 10:00

Eur J Med Res. 2025 Mar 17;30(1):177. doi: 10.1186/s40001-025-02357-1.

ABSTRACT

Calcineurin inhibitor-induced pain syndrome (CIPS), a rare but recognized complication of calcineurin inhibitor (CNI) therapy in transplant recipients, presents as severe bilateral lower extremity pain. This syndrome, first described in 1989, primarily affects patients receiving tacrolimus or cyclosporine. Proposed mechanisms include intraosseous vasoconstriction, bone marrow edema, and altered bone metabolism, possibly involving TRSK channels and NFAT signaling. The diagnosis relies on clinical history, characteristic pain patterns, and imaging findings such as bone marrow edema on MRI. The management of CIPS revolves around reducing or discontinuing the offending CNI while maintaining immunosuppression. Alternative immunosuppressants like mammalian target rapamycin (mTOR) inhibitors or mycophenolate mofetil are considered to mitigate symptoms. Symptomatic relief includes calcium channel blockers, bisphosphonates, and analgesics like NSAIDs or opioids. Physical therapy and close monitoring are also integral to improving outcomes and managing chronic pain effectively in affected transplant recipients. This review synthesizes current knowledge on CIPS, highlighting diagnostic challenges, treatment options, and areas for future research to optimize clinical management and enhance patient outcomes.

PMID:40091077 | DOI:10.1186/s40001-025-02357-1

Molybdenum-Catalyzed Asymmetric Amination of α-Hydroxy Esters: Synthesis of α-Amino Acids

Mon, 10/03/2025 - 10:00

Adv Sci (Weinh). 2025 Mar 10:e2403437. doi: 10.1002/advs.202403437. Online ahead of print.

ABSTRACT

Unnatural α-amino acids are found in a wide variety of bioactive compounds ranging from proteins to pharmaceutical agents to materials science. As a result, the investigation of efficient and simple methods for their synthesis is a major purpose in reaction development. In this study, it is found that a catalyst based on molybdenum, an earth-abundant transition metal, can facilitate the amination of readily accessible α-hydroxy esters to afford N-protected unnatural α-amino acid esters in high yield. This simple process also enables enantioselective amination, which proceeds through cooperative catalysis of chiral molybdenum complex with chiral phosphoric acid (CPA), and complements earlier procedures to the catalytic synthesis of this important class of compounds. The obtained protected α-amino acid ester products are directly useful or further utilized for the synthesis of commercially available drugs and analogs.

PMID:40063505 | DOI:10.1002/advs.202403437

Catalytic Asymmetric Synthesis of β-Amino α-Tertiary Alcohol through Borrowing Hydrogen Amination

Thu, 06/03/2025 - 11:00

Org Lett. 2025 Mar 6. doi: 10.1021/acs.orglett.5c00283. Online ahead of print.

ABSTRACT

The first enantioconvergent transition-metal-catalyzed amination of racemic α-tertiary 1,2-diols providing access to vicinal β-amino α-tertiary alcohols is disclosed. The iridium-catalyzed amination reaction proceeds through a chiral phosphoric acid-mediated borrowing hydrogen pathway with excellent yields and enantioselectivities for a range of amine nucleophiles and α-tertiary 1,2-diols. An array of β-amino α-tertiary alcohols were obtained with high yields and enantioselectivities (50 examples with up to 91% yield and up to 99% ee). These important chiral amino alcohol products can be easily converted into chiral ligands and bioactive skeletons. Mechanistic investigations proposed a dynamic kinetic resolution pathway involving imine formation and then imine reduction as the enantiodetermining step.

PMID:40048559 | DOI:10.1021/acs.orglett.5c00283

Long-term outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer

Thu, 06/03/2025 - 11:00

BMJ Oncol. 2025 Feb 25;4(1):e000574. doi: 10.1136/bmjonc-2024-000574. eCollection 2025.

ABSTRACT

OBJECTIVES: To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.

METHODS AND ANALYSIS: We used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery. Long-term health outcomes were selected from both datasets. Multivariable Cox regression was used to examine the associations, with BSO modelled as a time-dependent covariate. The associations were investigated separately by age at BSO.

RESULTS: We identified 568 883 women, 23 401 of whom had BSO after the breast cancer diagnosis. There was an increased risk of total cardiovascular diseases with an HR of 1.10 (95% CI 1.04 to 1.16) in women who had BSO<55 years and 1.07 (95% CI 1.01 to 1.13) for women who had BSO≥55 years. There was an increased risk of ischaemic heart diseases, but there was no association with cerebrovascular diseases. BSO at any age was associated with an increased risk of depression (HR 1.20, 95% CI 1.12 to 1.28) and increased risk of second non-breast cancer in older women (HR 1.21, 95%CI 1.08 to 1.35). BSO in older women was associated with reduced risk of all-cause mortality (HR 0.92, 95% CI 0.87 to 096), but not in women who had BSO<55 years.

CONCLUSION: In women with a personal history of breast cancer, BSO before and after the age of 55 years is associated with an increased risk of long-term outcomes. BSO after 55 years is associated with reduced all-cause mortality. Family history or genetic predisposition may confound these associations.

PMID:40046828 | PMC:PMC11880784 | DOI:10.1136/bmjonc-2024-000574

Women in academic nephrology: have we bridged the gender gap?

Thu, 06/03/2025 - 11:00

Clin Kidney J. 2025 Jan 28;18(3):sfaf019. doi: 10.1093/ckj/sfaf019. eCollection 2025 Mar.

NO ABSTRACT

PMID:40046819 | PMC:PMC11879463 | DOI:10.1093/ckj/sfaf019

Analysis of the factors associated with sexual health improvement in patients who underwent surgical management for adult spine deformity

Mon, 03/03/2025 - 11:00

Eur Spine J. 2025 Mar 4. doi: 10.1007/s00586-025-08746-8. Online ahead of print.

ABSTRACT

BACKGROUND: Spinal deformity can have a severe impact on the patient's sexual health. Eventually, this can lead to depression and relationship distress. Spinal surgical management is suggested to improve sexual function, however, the literature concerning these aspects is still scarce. This study evaluated which factors predicted improvement in sexual health in patients with adult spinal deformity (ASD) who underwent surgical treatment.

METHODS: Multicentric retrospective study based on a prospectively collected ASD database. Data of patients who underwent surgical correction and had a 2-year follow-up were collected. The association between different patient-reported outcome measures and ODI question 8 (Q8, sexual health) was explored with Pearson correlations and Principal Component Analysis (PCA). Improvement in sexual health was evaluated through a 1-point decrease on Q8. Comparisons between improved and non-improved patients and the non-response to the preoperative Q8 were assessed.

RESULTS: Data from 880 patients were collected. Moderate correlations were revealed between ODI and COMI-back, SRS-22, and SF-36 items and confirmed with PCA. The main factors associated to a non-response to Q8 were being of an older age, having worse sagittal imbalance, and having a specific nationality. Patients with an improvement in sexual health at 2 years were the ones with a worse baseline quality of life, older patients with a greater sagittal correction, and a better improvement of the level of physical activity.

CONCLUSION: Non-response to Q8 was correlated to age and nationality. Long-segment ASD surgery could improve sexual health, which was correlated to physical activity improvement, severe deformity with worse preoperative quality of life, and better postoperative sagittal correction.

PMID:40032697 | DOI:10.1007/s00586-025-08746-8

Pro-inflammatory mediators sensitise Transient Receptor Potential Melastatin 3 cation channel (TRPM3) function in mouse sensory neurons

Sun, 02/03/2025 - 11:00

Neuropharmacology. 2025 Feb 28:110391. doi: 10.1016/j.neuropharm.2025.110391. Online ahead of print.

ABSTRACT

Pro-inflammatory mediators can directly activate pain-sensing neurons, known as nociceptors. Additionally, these mediators can sensitise ion channels and receptors expressed by these cells through transcriptional and post-translational modulation, leading to nociceptor hypersensitivity. A well-characterised group of ion channels that subserve nociceptor sensitisation is the transient receptor potential (TRP) superfamily of cation channels. For example, the roles of TRP channels vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in nociceptor sensitisation and inflammatory pain have been extensively documented. In the case of TRP melastatin 3 (TRPM3), however, despite the increasing recognition of this channel's role in inflammatory pain, the mediators driving its sensitisation during inflammation remain poorly characterised. Here, using Ca2+ imaging, we found that an inflammatory soup of bradykinin, interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) sensitised TRPM3 function in isolated mouse sensory neurons; IL-1β and TNFα, but not bradykinin, independently potentiated TRPM3 function. TRPM3 expression and translocation to the membrane remained unchanged upon individual or combined exposure to these inflammatory mediators, which suggests that post-translational modification might occur. Finally, using the complete Freund's adjuvant-induced model of knee inflammation, we found that systemic pharmacological blockade of TRPM3 does not alleviate inflammatory pain (as assessed through evaluation of digging behaviour and dynamic weight bearing), which contrasts with previous reports using different pain models. We propose that the nuances of the immune response may determine the relative contribution of TRPM3 to nociceptive signalling in different neuro-immune contexts. Collectively, our findings improve insight into the role of TRPM3 sensitisation in inflammatory pain.

PMID:40024472 | DOI:10.1016/j.neuropharm.2025.110391