Clozapine-Induced Severe Toxicity: Exploring the Pharmacokinetic Profile of Clozapine and Its Significance in Hemodynamic Instability - A Case Report.

Hemodynamic instability in patients with clozapine intoxication can indirectly reflect the serum concentration of clozapine.We have described a case of a 32-year-old pregnant woman who developed life-threatening clozapine toxicity at 28 weeks of gestation. The levels of clozapine and norclozapine in the serum were high. We initiated hemoperfusion(HP) and other detoxification therapies to remove the drug. The patient had severely dilated peripheral blood vessels, which led to cardiac symptoms such as fatal hypotension and uncontrollable tachycardia, resulting in very high cardiac output and elevated Central venous oxygen saturation (ScvO2). Pharmacological intervention significantly improved the hemodynamics.In light of our observations in the ongoing case, we posit that evaluating hemodynamic parameters before and after blood detoxification could serve as a valuable means to gauge effectiveness and provide guidance for treatment.

Global, Regional, and National Burden of Road Injuries from 1990 to 2019.

(1) Background: Understanding occurrence can help formulate effective preventative laws and regulations. However, the most recent global burden and road injuries (RIs) trends have not been reported. This study reports the burden of RIs globally from 1990 to 2019. (2) Methods: RIs data were downloaded from the Global Burden of Disease 2019. Incidence, deaths, and disability-adjusted life years (DALYs) described the trend and burden of RIs. We calculated age-standardized rates (ASRs) and estimated annual percentage change (EAPC) for the above indexes to evaluate the temporal trend of RIs. We evaluated the social-demographic index (SDI) with epidemiological RI parameters and reported proportions of age-standardized rates due to RI. (3) Results: In 2019, the global incidence of RIs reached 103.2 million. The EAPC of RI incidence increased, whereas deaths and DALYs decreased. Age-standardized incident rate (ASIR) was highest in low-middle SDI regions, age-standardized death rate (ASDR) was high in middle SDI regions, and age-standardized DALYs increased in low SDI regions. The highest accident rates were found in those aged 20-24 years old. Cyclist injuries were the leading RIs (34%), though pedestrian and motor vehicle accidents were the leading cause of death (37.4%, 37.6%) and DALYs (35.7%, 32.3%), respectively. (4) Conclusions: Over the past 30 years, RIs incidence increased annually, though death and DALY rates decreased. RIs places a considerable burden on public health in low SDI countries. Data should be used to develop and implement effective measures to reduce the burden of RIs.

Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines.

Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.

Nanotechnology Assisted Targeted Drug Delivery for Bone Disorders: Potentials and Clinical Perspectives.

Nanotechnology and its allied modalities have brought revolution in tissue engineering and bone healing. The research on translating the findings of the basic and preclinical research into clinical practice is ongoing. Advances in the synthesis and design of nanomaterials along with advances in genomics and proteomics, and tissue engineering have opened a bright future for bone healing and orthopedic technology. Studies have shown promising outcomes in the design and fabrication of porous implant substrates that can be exploited as bone defect augmentation and drug-carrier devices. However, there are dozens of applications in orthopedic traumatology and bone healing for nanometer-sized entities, structures, surfaces, and devices with characteristic lengths ranging from tens 10s of nanometers to a few micrometers. Nanotechnology has made promising advances in the synthesis of scaffolds, delivery mechanisms, controlled modification of surface topography and composition, and biomicroelectromechanical systems. This study reviews the basic and translational sciences and clinical implications of the nanotechnology in tissue engineering and bone diseases. Recent advances in NPs assisted osteogenic agents, nanocomposites, and scaffolds for bone disorders are discussed.

Recent developments in strontium-based biocomposites for bone regeneration.

Recent advances in biomaterial designing techniques offer immense support to tailor biomimetic scaffolds and to engineer the microstructure of biomaterials for triggering bone regeneration in challenging bone defects. The current review presents the different categories of recently explored strontium-integrated biomaterials, including calcium silicate, calcium phosphate, bioglasses and polymer-based synthetic implants along with their in vivo bone formation efficacies and/or in vitro cell responses. The role and significance of controlled drug release scaffold/carrier design in strontium-triggered osteogenesis was also comprehensively described. Furthermore, the effects of stem cells and growth factors on bone remodeling are also elucidated.

Spinal cord regeneration using dental stem cell-based therapies.

Spinal cord injury (SCI) is traumatic central nervous system damage resulting in a motor and sensory dysfunction that usually causes a severe and permanent paralysis. Today, the treatment of SCI principally includes surgical treatment, pharmacological treatments and rehabilitation therapies, which target secondary events determining only some clinical improvements in patients. SCI is still a worldwide problem in the clinic and remains a big challenge for neuroscientists and neurologists throughout the world. Therefore, new therapies able to restore the function of the injured spinal cord are urgently needed for SCI patients. An interesting approach to overcome the growth inhibiting properties present in the injured spinal cord is to transplant cells with reparative and protective properties such as mesenchymal stem cells. In this context, human dental-derived stem cells represent a promising new cell source for cell-based therapies. It has been shown that dental-derived stem cells isolated from dental pulp, named dental pulp stem cells or stem cells from human exfoliated deciduous teeth induce functional improvement after SCI in animal models. This review summarises the current state of the literature regarding the use of dental-derived stem cells for spinal cord repair and regeneration and highlights the neuroprotective effects of these cells when administered after spinal cord injury.

Mesenchymal stem cell sheets: a new cell-based strategy for bone repair and regeneration.

Mesenchymal stem cells (MSCs), a class of adult stem cells, are considered a promising source for bone regeneration. Although combining MSCs with biomaterial scaffolds offers an interesting clinical strategy for bone tissue engineering, the presence of the scaffolds could induce an undesirable effect on cell-cell interactions. Moreover, before the application of scaffold materials in bone tissue reconstruction, cells must be manipulated with proteolytic enzymes, such as trypsin or dispase that degrade extracellular matrix (ECM) molecules and cell surface proteins, which can result in the cell damage and loss of cellular activity. Therefore, the development of alternative strategies for bone regeneration is required to solve these problems. Recently, a novel tissue engineering technology named 'cell sheet' has been efficaciously utilized in the regeneration of bone, corneal, cardiac, tracheal and periodontal ligament-like tissues. The cell sheet is a layer of cells, which contains intact ECM and cell surface proteins such as growth factor receptors, ion channels and cell-to-cell junction proteins. MSC sheets can be easily fabricated by layering the recovered cell sheets without any scaffolds or complicated manipulation. This review summarizes the current state of the literature regarding the use of MSCs to produce cell sheets and assesses their applicability in bone tissue regeneration and repair.

Long non-coding RNA THOR promotes human osteosarcoma cell growth in vitro and in vivo.

Long non-coding RNA (LncRNA) dysregulation is associated with human osteosarcoma (OS) cell progression. Recent studies have characterized a novel but ultra-conserved LncRNA THOR ("Lnc-THOR") as a cancer-specific LncRNA, mediating cell growth. In the current study, we show that Lnc-THOR is expressed in established and primary human OS cells. It is also detected in human OS tissues, but not in the surrounding normal bone tissues. siRNA-induced knockdown or CRSIPR/Cas9-mediated knockout Lnc-THOR significantly inhibited human OS cell survival and proliferation. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) target mRNAs, including IGF2, GLI1 and CD44, were downregulated in Lnc-THOR-silenced OS cells as well. Conversely, forced over-expression of Lnc-THOR enhanced IGF2BP1 target mRNA expression, promoting OS cell survival and proliferation. In vivo, xenograft tumors of Lnc-THOR-knockout U2OS cells grew significantly slower than the control U2OS tumors. Together, these results show that Lnc-THOR expression is essential for human OS cell growth. Lnc-THOR could be a novel therapeutic target and/or diagnosis marker for human OS.

The anti-osteosarcoma cell activity by a mTORC1/2 dual inhibitor RES-529.

mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation. Significantly, RES-529 induced reactive oxygen species (ROS) production and mitochondrial depolarization in U2OS cells as well. RES-529-induced anti-OS cell activity was more potent than other known Akt-mTOR inhibitors. In vivo, RES-529 intraperitoneal injection significantly inhibited U2OS xenograft tumor growth in severe combined immunodeficiency (SCID) mice. mTORC1/2 activation in RES-529-treated tumor tissues was largely inhibited. Collectively, the mTOR inhibitor RES-529 efficiently inhibits human OS cell growth in vitro and in vivo.