Rejected

Voltage-gated sodium channels (Na) are closely associated with epilepsy, cardiac and skeletal muscle diseases, and neuropathic pain. Several toxic compounds have been isolated from the marine sponge ; however, toxic substances that modulate Na are yet to be identified. This study aimed to identify Na inhibitors from two snake venoms and using mouse neuroblastoma Neuro-2A cells (N2A), which primarily express the specific Na subtype Na1.7, using whole-cell patch-clamp recordings. We successfully isolated arachidonic acid (AA, ) from the hexane extract of , and then the fatty acid-mediated modulation of Na in N2A was investigated in detail for the first time. Octanoic acid (), palmitic acid (), and oleic acid () showed no inhibitory activity at 100 μM, whereas AA (), dihomo-γ-linolenic acid (DGLA, ), and eicosapentaenoic acid (EPA, ) showed IC values of 6.1 ± 2.0, 58 ± 19, and 25 ± 4.0 μM, respectively ( = 4, mean ± SEM). Structure and activity relationships were investigated for the first time using two ω-3 polyunsaturated fatty acids (PUFAs), EPA () and eicosatetraenoic acid (ETA, ), and two ω-6 PUFAs, AA () and DGLA (), to determine their effects on a resting state, activated state, and inactivated state. Steady-state analysis showed that the half inactivation potential was largely hyperpolarized by 10 μM AA (), while 50 μM DGLA (), 50 μM EPA (), and 10 μM ETA () led to a slight change. The percentages of the resting state block were 24 ± 1, 22 ± 1, 34 ± 4, and 38 ± 9% in the presence of AA (), DGLA (), EPA (), and ETA (), respectively, with EPA () and ETA () exhibiting a greater inhibition than both AA () and DGLA (), and their inhibitions did not increase in the following depolarization pulses. None of the compounds exhibited the use-dependent block. The half recovery times from the inactivated state for the control, AA (), DGLA (), EPA (), and ETA () were 7.67 ± 0.33, 34.3 ± 1.10, 15.5 ± 1.10, 10.7 ± 0.31, and 3.59 ± 0.18 ms, respectively, with AA () exhibiting a distinctively large effect. Overall, distributed binding to the resting and the inactivated states of Na would be significant for the inhibition of Na, which presumably depends on the active structure of each PUFA.

The sphenoid bone is a complex structure in terms of its embryological origin. At birth, the sphenoid sinus is nonpneumatized. Arrested pneumatization of the sphenoid sinus is considered a normal anatomic variant but may be mistaken for disease in imaging studies. We report 2 cases of arrested pneumatization of the sphenoid sinus, a normal variant commonly misdiagnosed as a serious disease of the skull base. A 29-year-old man with a complaint of dizziness visited a local clinic for assessment. Computed tomography (CT) of the paranasal sinuses (PNS) showed a noneroding, nonexpansile, and nonhomogenous lesion in the sphenoid bone. Magnetic resonance imaging (MRI) of the brain revealed a high-signal lesion on both T1-weighted and T2-weighted images. Given these typical findings in the CT of PNS and MRI of the brain, the lesion was diagnosed as arrested pneumatization of the sphenoid sinus. In the second case, a 60-year-old woman with a complaint of headache visited a local clinic for assessment. CT of PNS showed a fibro-osseous lesion (with features of sclerosis and osteolysis) in the skull base. Brain MRI revealed a low-signal lesion on a T1-weighted image containing a high-signal intensity around the sphenoid bone, thereby suggesting internal fat contents. A precise interpretation of CT of PNS and brain MRI is essential to distinguish arrested pneumatization of the sphenoid sinus and to help establish a differential diagnosis and avoid needless biopsy.

mRNA COVID-19 vaccination was initiated worldwide in late 2020, and its efficacy has been well reported. However, studies about vaccine-related side effects are sparse. A total of 262 health care workers who received mRNA COVID-19 vaccine BNT162b2 were recruited, and their vaccine-related side effects were investigated. Impact of sex and age on the side effects was statistically analyzed. A higher number of vaccine-related side effects among females versus males was identified (median 3 versus 2,  < 0.05, after the first dose, and 5 versus 2.5,  < 0.01, after the second dose). General fatigue, headache, chills, and fever were the culprit adverse symptoms. In multivariate analysis, females had an increasing number of side effects after receiving their first (B = 0.7; 95% confidence interval [CI], 0.2 to 1.2) and second (B = 1.5; 95% CI, 0.7 to 2.2) vaccine doses compared to that of males. In age analysis, the older group (≥60 years old) had a lower number of side effects than the younger group (B = -0.5 with a 95% CI of -1.1 to -0.02 after the first vaccine dose, and B = -2.1 with a 95% CI of -2.9 to -1.2 after the second vaccine dose). Additionally, prolonged time to recovery was found among females ( = 0.003 after the first dose;  = 0.008 after the second dose). Specifically, symptoms of general fatigue, headache, itching, swelling at the injection site, and dizziness were the culprit symptoms affecting recovery time. Several cutaneous and membranous symptoms, including "COVID arm," were identified among females. These results highlight the impact of sex and age on side effects from mRNA COVID-19 vaccine and will aid in creating a safer vaccine. We demonstrate sex- and age-related impact on mRNA COVID-19 vaccine-related side effects, with a higher number and frequency of side effects and prolonged time to recovery in females compared to males and negative correlation between age and vaccine-related side effects. Identification of unique age- and sex-specific adverse symptoms will provide the opportunity to better understand the nature of sex- and age-associated immunological differences and develop safer and more efficacious vaccines.

Coronavirus disease 2019 (COVID-19) is frequently associated with neurological deficits, but how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces these effects remains unclear. Here, we show that astrocytes are readily infected by SARS-CoV-2, but surprisingly, neuropilin-1, not angiotensin-converting enzyme 2 (ACE2), serves as the principal receptor mediating cell entry. Infection is further positively modulated by the two-pore segment channel 2 (TPC2) protein that regulates membrane trafficking and endocytosis. Astrocyte infection produces a pathological response closely resembling reactive astrogliosis characterized by elevated type I interferon (IFN) production, increased inflammation, and the decreased expression of transporters of water, ions, choline, and neurotransmitters. These combined events initiated within astrocytes produce a hostile microenvironment that promotes the dysfunction and death of uninfected bystander neurons. SARS-CoV-2 infection primarily targets the lung but may also damage other organs, including the brain, heart, kidney, and intestine. Central nervous system (CNS) pathologies include loss of smell and taste, headache, delirium, acute psychosis, seizures, and stroke. Pathological loss of gray matter occurs in SARS-CoV-2 infection, but it is unclear whether this is due to direct viral infection, indirect effects associated with systemic inflammation, or both. Here, we used induced pluripotent stem cell (iPSC)-derived brain organoids and primary human astrocytes from the cerebral cortex to study direct SARS-CoV-2 infection. Our findings support a model where SARS-CoV-2 infection of astrocytes produces a panoply of changes in the expression of genes regulating innate immune signaling and inflammatory responses. The deregulation of these genes in astrocytes produces a microenvironment within the CNS that ultimately disrupts normal neuron function, promoting neuronal cell death and CNS deficits.

To provide pharmacists and other health care professionals with the knowledge required to minimize the risk of prolonged opioid use following total hip arthroplasty (THA) and total knee arthroplasty (TKA).

To investigate whether the delay between onset of neurological signs and spinal cord decompression affects the time to recovery in non-ambulatory paraparetic/paraplegic dogs with deep pain perception affected by thoracolumbar intervertebral disc extrusion.

Chronic traumatic neck pain has a high prevalence of post-traumatic stress symptoms (PTSS). However, whether PTSS moderates treatment effects is unknown. This study investigated: 1) whether PTSS was associated with patient-reported outcomes and clinical test results at baseline; 2) whether PTSS moderated the effect of a multimodal physiotherapy intervention of exercise therapy and patient education; and 3) whether adherence to the intervention differed across PTSS groups.

Recent studies have indicated that long-term neurological sequelae after COVID-19 are not accompanied by an increase of canonical biomarkers of central nervous system injury in blood, but subgroup stratifications are lacking. This is a particular concern in chronic headache, which can be a leading symptom of Post-COVID diseases associated with neuronal damage such as vasculitis or autoimmune encephalitis. We here compared patients with mild Post-COVID-19 syndrome and persistent headache (persistent Post-COVID-19 headache) lasting longer than 12 weeks after the initial serological diagnosis, to patients with mild and severe COVID-19 and COVID-19-negative controls. Levels of neurofilament light chain and glial fibrillary astrocytic protein, i.e. markers of neuronal damage and reactive astrogliosis, were lower in blood from patients with persistent Post-COVID-19 headache compared to patients with severe COVID-19. Hence, our pilot serological study indicates that long-term Post-COVID-19 headache may not be a sign of underlying neuronal damage or neuroinflammation.

Osteoarthritis (OA) is a degenerative disease that leads to the progressive destruction of articular cartilage. Current clinical therapeutic strategies are moderately effective at relieving OA-associated pain but cannot induce chondrocyte differentiation or achieve cartilage regeneration. We investigated the ability of wedelolactone, a biologically active natural product that occurs in Eclipta alba (false daisy), to promote chondrogenic differentiation.

Homozygous familial hypercholesterolaemia (HoFH) is a disorder affecting low-density lipoprotein (LDL) receptor genes. Patients typically have a triad of elevated LDL-cholesterol (LDL-C), xanthomatosis and premature atherosclerotic cardiovascular disease. Our patient, a preteen boy, presented with signs of hypertensive encephalopathy. Physical examination showed arcus cornealis, planar xanthomas and tuberous xanthomas. After appropriate investigations, a direct aetiology of the hypertension could not be elucidated; however, our patient's hypertension resolved with the reduction in serum lipid levels. β-hydroxy β-methylglutaryl coenzyme A reductase and cholesterol absorption inhibitors were administered as first-line treatment. A significant proportion of patients with HoFH continue to have elevated LDL-C levels, thereby requiring second-line agents, such as proprotein convertase subtilisin/kexin type inhibitors (evolocumab), microsomal triglyceride transfer protein inhibitors (lomitapide) and angiopoietin-like protein inhibitors (evinacumab). This case report aimed to raise awareness among paediatricians to consider HoFH as a possible aetiology in a child presenting with hypertension and suggestive physical findings.