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Ageing Research Reviews Feb 2024Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2 A (SV2A) enables quantification of synaptic density in the living...
Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2 A (SV2A) enables quantification of synaptic density in the living human brain. Assessing the regional distribution and severity of synaptic density loss will contribute to our understanding of the pathological processes that precede atrophy in neurodegeneration. In this systematic review, we provide a discussion of in vivo SV2A PET imaging research for quantitative assessment of synaptic density in various dementia conditions: amnestic Mild Cognitive Impairment and Alzheimer's disease, Frontotemporal dementia, Progressive supranuclear palsy and Corticobasal degeneration, Parkinson's disease and Dementia with Lewy bodies, Huntington's disease, and Spinocerebellar Ataxia. We discuss the main findings concerning group differences and clinical-cognitive correlations, and explore relations between SV2A PET and other markers of pathology. Additionally, we touch upon synaptic density in healthy ageing and outcomes of radiotracer validation studies. Studies were identified on PubMed and Embase between 2018 and 2023; last searched on the 3rd of July 2023. A total of 36 studies were included, comprising 5 on normal ageing, 21 clinical studies, and 10 validation studies. Extracted study characteristics were participant details, methodological aspects, and critical findings. In summary, the small but growing literature on in vivo SV2A PET has revealed different spatial patterns of synaptic density loss among various neurodegenerative disorders that correlate with cognitive functioning, supporting the potential role of SV2A PET imaging for differential diagnosis. SV2A PET imaging shows tremendous capability to provide novel insights into the aetiology of neurodegenerative disorders and great promise as a biomarker for synaptic density reduction. Novel directions for future synaptic density research are proposed, including (a) longitudinal imaging in larger patient cohorts of preclinical dementias, (b) multi-modal mapping of synaptic density loss onto other pathological processes, and (c) monitoring therapeutic responses and assessing drug efficacy in clinical trials.
Topics: Humans; Alzheimer Disease; Brain; Cognitive Dysfunction; Neurodegenerative Diseases; Positron-Emission Tomography
PubMed: 38266660
DOI: 10.1016/j.arr.2024.102197 -
Cephalalgia : An International Journal... Jan 2024Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM...
BACKGROUND
Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP.
METHODS
We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers.
RESULTS
MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations.
CONCLUSIONS
These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine. Not Applicable.
Topics: Humans; Male; Adult; Female; Mice; Animals; Receptors, Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide; Mice, Inbred C57BL; Migraine Disorders; Motion Sickness; Nausea
PubMed: 38215227
DOI: 10.1177/03331024231223971 -
Orphanet Journal of Rare Diseases Jan 2024Fabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities,...
BACKGROUND
Fabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review.
RESULTS
One-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20-81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1-629). Pain in the hands and abdominal pain were significantly higher (p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes.
CONCLUSIONS
We demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies.
Topics: Male; Female; Humans; Middle Aged; Fabry Disease; Mobile Applications; alpha-Galactosidase; Gastrointestinal Diseases; Neuralgia
PubMed: 38212814
DOI: 10.1186/s13023-023-02999-6 -
Biochemistry and Biophysics Reports Mar 2024Breast cancer (BC) remains the foremost cause of cancer-related mortality, with an estimated 2.3 million new cases anticipated globally. The timely diagnosis of BC is...
Breast cancer (BC) remains the foremost cause of cancer-related mortality, with an estimated 2.3 million new cases anticipated globally. The timely diagnosis of BC is pivotal for effective treatment. Currently, BC diagnosis predominantly relies on Immunohistochemistry (IHC), a method known for its sluggishness, expense, and dependence on proficient pathologists for confident cancer typing. In this study, we introduce a novel approach to enhance the accuracy, speed, and cost-effectiveness of BC diagnosis. We employ multiplex Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) with touch-down methods, which consistently yield significantly lower Cycle Threshold (CT) values. The study evaluates gene expression profiles of HER2, PGR, ESR, and Ki67 genes across 61 samples representing four BC subtypes, using RPL13A as the endogenous control gene. The results demonstrate that our method offers remarkable precision, nearly equivalent to IHC, in detecting gene expressions vital for BC diagnosis and subtyping. Moreover, we explore the gene expression of Hif1A, ANG, and VEGFR genes involved in angiogenesis, shedding light on the metastatic potential of the tested BC tumours. Notably, numerous samples exhibit elevated levels of Hif1A and VEGFR, indicating their potential as valuable biomarkers for assessing metastatic status. Collectively, our RT-qPCR methodology emerges as a powerful diagnostic tool for swiftly identifying BC subtypes and can be complemented with other essential tumorigenic biomarker assessments, such as angiogenesis, to further refine cancer characterisation and inform personalised therapeutic strategies for BC patients. This innovation holds the promise of revolutionising BC diagnosis and treatment, offering expedited and reliable insights for improved patient care.
PubMed: 38205186
DOI: 10.1016/j.bbrep.2023.101615 -
Molecular Pain 2024Ultraviolet B (UVB) radiation induces cutaneous inflammation, leading to thermal and mechanical hypersensitivity. Here, we examine the mechanical properties and profile...
Ultraviolet B (UVB) radiation induces cutaneous inflammation, leading to thermal and mechanical hypersensitivity. Here, we examine the mechanical properties and profile of tactile and nociceptive peripheral afferents functionally disrupted by this injury and the role of oxytocin (OXT) as a modulator of this disruption. We recorded intracellularly from L4 afferents innervating the irradiated area (5.1 J/cm) in 4-6 old week male mice (C57BL/6J) after administering OXT intraperitoneally, 6 mg/Kg. The distribution of recorded neurons was shifted by UVB radiation to a pattern observed after acute and chronic injuries and reduced mechanical thresholds of A and C- high threshold mechanoreceptors while reducing tactile sensitivity. UVB radiation did not change somatic membrane electrical properties or fiber conduction velocity. OXT systemic administration rapidly reversed these peripheral changes toward normal in both low and high-threshold mechanoreceptors and shifted recorded neuron distribution toward normal. OXT and V1aR receptors were present on the terminals of myelinated and unmyelinated afferents innervating the skin. We conclude that UVB radiation, similar to local tissue surgical injury, cancer metastasis, and peripheral nerve injury, alters the distribution of low and high threshold mechanoreceptors afferents and sensitizes nociceptors while desensitizing tactile units. Acute systemic OXT administration partially returns all of those effects to normal.
Topics: Mice; Male; Animals; Oxytocin; Nociception; Mice, Inbred C57BL; Touch; Skin; Mechanoreceptors; Nociceptors
PubMed: 38172079
DOI: 10.1177/17448069241226553 -
BMC Complementary Medicine and Therapies Jan 2024In addition to curative care, supportive care is beneficial in managing the anxiety symptoms common in patients in sterile hematology unit. We hypothesize that personal... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of the practice of touch-massage® by a nurse on the anxiety of patients with hematological disorders hospitalized in a sterile environment, a randomized, controlled study.
CONTEXT
In addition to curative care, supportive care is beneficial in managing the anxiety symptoms common in patients in sterile hematology unit. We hypothesize that personal massage can help the patient, particularly in this isolated setting where physical contact is extremely limited. The main objective of this study was to show that anxiety could be reduced after a touch-massage® performed by a nurse trained in this therapy.
METHODS
A single-center, randomized, unblinded controlled study in the sterile hematology unit of a French university hospital, validated by an ethics committee. The patients, aged between 18 and 65 years old, and suffering from a serious and progressive hematological pathology, were hospitalized in sterile hematology unit for a minimum of three weeks, patients were randomized into either a group receiving 15-minute touch-massage® sessions or a control group receiving an equivalent amount of quiet time once a week for three weeks. In the treated group, anxiety was assessed before and after each touch-massage® session, using the State-Trait Anxiety Inventory questionnaire with subscale state (STAI-State). In the control group, anxiety was assessed before and after a 15-minute quiet period. For each patient, the difference in the STAI-State score before and after each session (or period) was calculated, the primary endpoint was based on the average of these three differences. Each patient completed the Rosenberg Self-Esteem Questionnaire before the first session and after the last session.
RESULTS
Sixty-two patients were randomized. Touch-massage® significantly decreased patient anxiety: a mean decrease in STAI-State scale score of 10.6 [7.65-13.54] was obtained for the massage group (p ≤ 0.001) compared with the control group. The improvement in self-esteem score was not significant.
CONCLUSION
This study provides convincing evidence for integrating touch-massage® in the treatment of patients in sterile hematology unit.
TRIAL REGISTRATION
NCT02343965.
Topics: Humans; Anxiety; Anxiety Disorders; Massage; Surveys and Questionnaires; Touch; Adolescent; Young Adult; Adult; Middle Aged; Aged
PubMed: 38167315
DOI: 10.1186/s12906-023-04302-3 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons,... (Review)
Review
Itch (pruritus) is a sensation in the skin that provokes the desire to scratch. The sensation of itch is mediated through a subclass of primary afferent sensory neurons, termed pruriceptors, which express molecular receptors that are activated by itch-evoking ligands. Also expressed in pruriceptors are several types of Transient Receptor Potential (TRP) channels. TRP channels are a diverse class of cation channels that are responsive to various somatosensory stimuli like touch, pain, itch, and temperature. In pruriceptors, TRP channels can be activated through intracellular signaling cascades initiated by pruritogen receptors and underly neuronal activation. In this review, we discuss the role of TRP channels TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPC3/4 in acute and chronic pruritus. Since these channels often mediate itch in association with pruritogen receptors, we also discuss Mas-related G-protein-coupled receptors (Mrgprs) and protease-activated receptors (PARs). Additionally, we cover the exciting therapeutic targets amongst the TRP family, as well as Mrgprs and PARs for the treatment of pruritus.
PubMed: 38139833
DOI: 10.3390/ph16121707 -
International Journal of Molecular... Dec 2023Extracellular vesicles (EVs)/exosomes are nanosized membrane-bound structures that are released by virtually all cells. EVs have attracted great attention in the... (Review)
Review
Extracellular vesicles (EVs)/exosomes are nanosized membrane-bound structures that are released by virtually all cells. EVs have attracted great attention in the scientific community since the discovery of their roles in cell-to-cell communication. EVs' enclosed structure protects bioactive molecules from degradation in the extracellular space and targets specific tissues according to the topography of membrane proteins. Upon absorption by recipient cells, EV cargo can modify the transcription machinery and alter the cellular functions of these cells, playing a role in disease pathogenesis. EVs have been tested as the delivery system for the mRNA COVID-19 vaccine. Recently, different therapeutic strategies have been designed to use EVs as a delivery system for microRNAs and mRNA. In this review, we will focus on the exciting and various platforms related to using EVs as delivery vehicles, mainly in gene editing using CRISPR/Cas9, cancer therapy, drug delivery, and vaccines. We will also touch upon their roles in disease pathogenesis.
Topics: Humans; COVID-19 Vaccines; Extracellular Vesicles; Exosomes; MicroRNAs; RNA, Messenger
PubMed: 38138963
DOI: 10.3390/ijms242417134 -
Medicina (Kaunas, Lithuania) Dec 2023Although acupuncture is listed as a beneficial treatment for neck/shoulder stiffness, which has increased with the spread of information technology, to date, evidence... (Randomized Controlled Trial)
Randomized Controlled Trial
Although acupuncture is listed as a beneficial treatment for neck/shoulder stiffness, which has increased with the spread of information technology, to date, evidence of its efficacy under double-blind conditions has not been shown. This study aimed to assess whether acupuncture treatment with superficial skin piercing is superior to placebo treatment. A randomized, double-blind (practitioner-patient) placebo-controlled trial was performed at a single center with four arms (ISRCTN76896018). Four hundred patients with essential neck/shoulder stiffness were randomly assigned to penetrating needle treatment (acupuncture ritual and skin penetration), skin-touch needle treatment (acupuncture ritual and skin touch), no-touch needle treatment (acupuncture ritual alone), and no-treatment control. Each of the six acupuncturists applied a needle to each of the four acupoints in the neck/shoulder of 50 patients. Each of the three treatments significantly ( = 0.01) improved neck/shoulder stiffness compared with the no-treatment control immediately and 24 h after treatment. There was a significant improvement in penetrating needle treatment over no-touch needle treatment 24 h later. However, there was no significant difference between the penetrating and skin-touch and skin-touch vs. no-touch. All treatments that received the ritual of acupuncture were better than the no-treatment control. Only genuine acupuncture involves the specific effects of needle insertion into the body. The acupuncture ritual had a significant impact on the subjective improvement of neck/shoulder stiffness; however, improvement with ritual alone versions of placebo acupuncture was not maintained as with superficial skin piercing. Our study provides important evidence of acupuncture efficacy and information regarding inert no-touch placebo control in acupuncture research.
Topics: Humans; Neck Pain; Double-Blind Method; Japan; Acupuncture Therapy; Skin
PubMed: 38138244
DOI: 10.3390/medicina59122141 -
Clinical Pharmacokinetics Feb 2024Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. This study assessed the...
BACKGROUND AND OBJECTIVE
Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5'-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter.
METHODS
Thirty-two patients received a single oral dose of a probe drug on Day - 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed.
RESULTS
Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration-time curve from time zero to infinity (AUC) and maximum (peak) plasma drug concentration (C) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC and C of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively.
CONCLUSIONS
Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT.
CLINICALTRIALS
gov: NCT01970865.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP2C9; Lung Neoplasms; Cytochrome P-450 CYP2B6; ATP Binding Cassette Transporter, Subfamily B, Member 1; Uridine; Glucuronosyltransferase; Drug Interactions; Lactams, Macrocyclic; Aminopyridines; Lactams; Pyrazoles
PubMed: 38079095
DOI: 10.1007/s40262-023-01309-4