Objectives: To evaluate the association of illicit drug use with bone mineral density (BMD) and hip geometric parameters at the narrow neck. Methods: This is a cross-sectional matched cohort study conducted in the Hong Kong Chinese population. Associations with illicit drug use were estimated using linear regression for BMD (lumbar spine and femoral neck) and hip geometrical parameters (cross-sectional area [CSA], cross-sectional moment of inertia [CSMI], section modulus [SM], average cortical thickness [ACT] and BMD at the narrow neck) after adjusting for age, body mass index (BMI), smoking status, drinking status, physical activity, and history of antipsychotic and antidepressant use. Mean difference and 95% confidence intervals (95% CI) were calculated between 108 illicit drug users and 108 controls using an adjusted linear model and cluster-robust standard errors after matching by age and sex. The false discovery rate was used to correct for multiple testing. Results: Illicit drug users had a significantly lower BMD (g/cm2 ) at the lumbar spine (mean difference: -0.062; 95% CI: -0.108 to − 0.015), and femoral neck (mean difference: -0.058; 95% CI: -0.106 to − 0.010) in the fully adjusted model. Illicit drug users also had a significantly lower CSA (mean difference: -0.238 cm2 ; 95% CI: -0.462 to − 0.013), ACT (mean difference: -0.018 cm; 95% CI: -0.030 to − 0.006) and BMD (mean difference: -0.070 g/ cm2 ; 95% CI: -0.128 to − 0.012) at the narrow neck. Conclusions Illicit drug use is associated with lower BMD and bone strength. Future studies evaluating the risk of illicit drug use with fragility fracture are warranted.

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

While most types of malignancies remain recalcitrant to treatment, application of natural products or their analogs in daily life has offered some hopes as an effective prophylaxis against cancer onset and progression in the past decades. Emerging evidence supports a link between garlic consumption and decreased cancer incidence. Notably, aged garlic extract (AGE) exhibits stronger anti-cancer activities than that of fresh garlic, by virtue of enrichment of several AGE-specific organosulfur compounds, including S-allylmercaptocysteine (SAMC). In this review, we summarize the up-to-date mechanistic pathways associated with the anti-proliferative, anti-metastatic and pro-apoptotic effects of SAMC in various cancer models. Based upon the proven safety and improved understanding on its anti-neoplastic properties, SAMC has gained recognition as a promising daily food supplement for cancer prevention or management.
Animals ; Antineoplastic Agents, Phytogenic ; chemistry ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Cysteine ; analogs & derivatives ; chemistry ; pharmacology ; therapeutic use ; Disease Models, Animal ; Garlic ; chemistry ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; metabolism ; Signal Transduction ; drug effects

No abstract available.
Hong Kong* ; Rehabilitation* ; Stroke*

PURPOSE: The aim of this study was to validate a computational fluid dynamics (CFD) simulation of flow-diverter treatment through Doppler ultrasonography measurements in patient-specific models of intracranial bifurcation and side-wall aneurysms. METHODS: Computational and physical models of patient-specific bifurcation and sidewall aneurysms were constructed from computed tomography angiography with use of stereolithography, a three-dimensional printing technology. Flow dynamics parameters before and after flow-diverter treatment were measured with pulse-wave and color Doppler ultrasonography, and then compared with CFD simulations. RESULTS: CFD simulations showed drastic flow reduction after flow-diverter treatment in both aneurysms. The mean volume flow rate decreased by 90% and 85% for the bifurcation aneurysm and the side-wall aneurysm, respectively. Velocity contour plots from computer simulations before and after flow diversion closely resembled the patterns obtained by color Doppler ultrasonography. CONCLUSION: The CFD estimation of flow reduction in aneurysms treated with a flow-diverting stent was verified by Doppler ultrasonography in patient-specific phantom models of bifurcation and side-wall aneurysms. The combination of CFD and ultrasonography may constitute a feasible and reliable technique in studying the treatment of intracranial aneurysms with flow-diverting stents.
Aneurysm ; Angiography ; Computer Simulation ; Endovascular Procedures ; Hydrodynamics ; Intracranial Aneurysm* ; Stents ; Ultrasonography ; Ultrasonography, Doppler* ; Ultrasonography, Doppler, Color

Epstein-Barr virus (EBV) infection is closely associated with undifferentiated nasopharyngeal carcinoma (NPC), strongly implicating a role for EBV in NPC pathogenesis; conversely, EBV infection is rarely detected in normal nasopharyngeal epithelial tissues. In general, EBV does not show a strong tropism for infecting human epithelial cells, and EBV infection in oropharyngeal epithelial cells is believed to be lytic in nature. To establish life-long infection in humans, EBV has evolved efficient strategies to infect B cells and hijack their cellular machinery for latent infection. Lytic EBV infection in oropharyngeal epithelial cells, though an infrequent event, is believed to be a major source of infectious EBV particles for salivary transmission. The biological events associated with nasopharyngeal epithelial cells are only beginning to be understood with the advancement of EBV infection methods and the availability of nasopharyngeal epithelial cell models for EBV infection studies. EBV infection in human epithelial cells is a highly inefficient process compared to that in B cells, which express the complement receptor type 2 (CR2) to mediate EBV infection. Although receptor(s) on the epithelial cell surface for EBV infection remain(s) to be identified, EBV infection in epithelial cells could be achieved via the interaction of glycoproteins on the viral envelope with surface integrins on epithelial cells, which might trigger membrane fusion to internalize EBV in cells. Normal nasopharyngeal epithelial cells are not permissive for latent EBV infection, and EBV infection in normal nasopharyngeal epithelial cells usually results in growth arrest. However, genetic alterations in premalignant nasopharyngeal epithelial cells, including p16 deletion and cyclin D1 overexpression, could override the growth inhibitory effect of EBV infection to support stable and latent EBV infection in nasopharyngeal epithelial cells. The EBV episome in NPC is clonal in nature, suggesting that NPC develops from a single EBV-infected nasopharyngeal epithelial cell, and the establishment of persistent and latent EBV infection in premalignant nasopharyngeal epithelium may represent an early and critical event for NPC development.
Carcinoma ; Cell Transformation, Neoplastic ; Cells, Cultured ; Epithelial Cells ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; Humans ; Nasopharyngeal Neoplasms ; Nasopharynx ; Precancerous Conditions

The availability of human stem cells heralds a new era for in vitro cell-based modeling of neurodevelopmental and neurodegenerative diseases. Adding to the excitement is the discovery that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells that carry the disease genotype can be derived. These in vitro cell-based models of neurological diseases hold promise for monitoring of disease initiation and progression, and for testing of new drug treatments on the patient-derived cells. In this review, we focus on the prospective applications of different stem cell types for disease modeling and drug screening. We also highlight how the availability of patient-specific induced pluripotent stem cells (iPS cells) offers a unique opportunity for studying and modeling human neurodevelopmental and neurodegenerative diseases in vitro and for testing small molecules or other potential therapies for these disorders. Finally, the limitations of this technology from the standpoint of reprogramming efficiency and therapeutic safety are discussed.
Drug Evaluation, Preclinical ; Humans ; Induced Pluripotent Stem Cells ; cytology ; pathology ; Models, Neurological ; Nervous System Diseases ; physiopathology ; Neural Stem Cells ; pathology ; Neurodegenerative Diseases ; physiopathology

The capability of the central vestibular system in utilizing cues arising from the inner ear determines the ability of animals to acquire the sense of head orientations in the three-dimensional space and to shape postural movements. During development, neurons in the vestibular nucleus (VN) show significant changes in their electrophysiological properties. An age-dependent enhancement of membrane excitability is accompanied by a progressive increase in firing rate and discharge regularity. The coding of horizontal and vertical linear motions also exhibits developmental refinement in VN neurons. Further, modification of cell surface receptors, such as glutamate receptors, of developing VN neurons are well-orchestrated in the course of maturation, thereby regulating synaptic efficacy and spatial coding capacity of these neurons in local circuits. Taken together, these characteristic features of VN neurons contribute to developmental establishment of space-centered coordinates within the brain.
Animals ; Ear, Inner ; physiology ; Electrophysiological Phenomena ; Movement ; Neurons ; physiology ; Rats ; Receptors, Cell Surface ; physiology ; Vestibular Nuclei ; physiology

OBJECTIVETo establish an assay for screening chromosome 22q11 microdeletion efficiently, and apply it for detecting del22q11 in patients with non-syndromic congenital heart defects (CHD).

METHODSSeventy nine patients with non-syndromic CHD and 84 normal controls were genotyped for 8 short tandem repeat (STR) markers located in 22q11 region, by using quantitative fluorescence polymerase chain reaction (QF-PCR).

RESULTSThe average heterozygosity of the STR markers in patients and controls was 0.76 and 0.79, respectively. One patient with Tetralogy of Fallot (TOF) from the 79 CHD cases (1.3%) was found to have a deletion within chromosome 22q11.2, which was confirmed by multiplex ligation-dependent probe amplification (MLPA).

CONCLUSIONThe QF-PCR assay developed in this study was a reliable and an efficient alterative approach to screen for 22q11 microdeletion in clinical diagnosis and genetic counseling.

Case-Control Studies ; Chromosome Deletion ; Chromosomes, Human, Pair 22 ; genetics ; Fluorescence ; Heart Defects, Congenital ; diagnosis ; genetics ; Humans ; Microsatellite Repeats ; Polymerase Chain Reaction ; instrumentation ; methods

BACKGROUNDThe neurogenesis in retina of adult mammals is generally abolished, and this renders the retina lack of regenerative capacity. Despite this, there is a small population of nestin-positive cells in the ciliary epithelium which retains neurogenic potential. The present study aimed at investigating the effect of two drugs, corticosterone and paroxetine, on the cell proliferation of the ciliary body.

METHODSAdult Sprague-Dawley rats were given vehicle, corticosterone, paroxetine, or both corticosterone and paroxetine treatment for 14 days. Cell proliferation in the ciliary body was quantified using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. Co-labelling of BrdU and stem cell marker was used to phenotype the BrdU immunoreactive cells.

RESULTSCorticosterone treatment suppressed while paroxetine treatment increased the cell proliferation of the ciliary body. Co-labelling with cell markers revealed that the BrdU positive cells also showed nestin expression but not glial fibrillary acidic protein (GFAP).

CONCLUSIONSThe results illustrate that proliferation of retinal progenitor cells situated in ciliary body are subjected to regulation by selective serotonin reuptake inhibitors (SSRI) and corticosteroid, which is similar to our previous findings in neurogenic regions in central nervous system (CNS). Paroxetine treatment could reverse the suppressive effect of corticosterone on ciliary body cell proliferation. This provides information for future investigation of retinal stem cell biology and potential treatment of retinal degenerative diseases.

Adrenal Glands ; drug effects ; pathology ; Animals ; Body Weight ; drug effects ; Cell Proliferation ; drug effects ; Ciliary Body ; cytology ; drug effects ; Corticosterone ; pharmacology ; Immunohistochemistry ; In Vitro Techniques ; Male ; Organ Size ; drug effects ; Paroxetine ; pharmacology ; Rats ; Rats, Sprague-Dawley