Facial Stimulation Induces Long-Term Potentiation of Mossy Fiber-Granule Cell Synaptic Transmission via GluN2A-Containing N-Methyl-D-Aspartate Receptor/Nitric Oxide Cascade in the Mouse Cerebellum.

Long-term synaptic plasticity in the cerebellar cortex is a possible mechanism for motor learning. Previous studies have demonstrated the induction of mossy fiber-granule cell (MF-GrC) synaptic plasticity under in vitro and in vivo conditions, but the mechanisms underlying sensory stimulation-evoked long-term synaptic plasticity of MF-GrC in living animals are unclear. In this study, we investigated the mechanism of long-term potentiation (LTP) of MF-GrC synaptic transmission in the cerebellum induced by train of facial stimulation at 20 Hz in urethane-anesthetized mice using electrophysiological recording, immunohistochemistry techniques, and pharmacological methods. Blockade of GABAA receptor activity and repetitive facial stimulation at 20 Hz (240 pulses) induced an LTP of MF-GrC synapses in the mouse cerebellar cortical folium Crus II, accompanied with a decrease in paired-pulse ratio (N2/N1). The facial stimulation-induced MF-GrC LTP was abolished by either an N-methyl-D-aspartate (NMDA) receptor blocker, i.e., D-APV, or a specific GluNR2A subunit-containing NMDA receptor antagonist, PEAQX, but was not prevented by selective GluNR2B or GluNR2C/D subunit-containing NMDA receptor blockers. Application of GNE-0723, a selective and brain-penetrant-positive allosteric modulator of GluN2A subunit-containing NMDA receptors, produced an LTP of N1, accompanied with a decrease in N2/N1 ratio, and occluded the 20-Hz facial stimulation-induced MF-GrC LTP. Inhibition of nitric oxide synthesis (NOS) prevented the facial stimulation-induced MF-GrC LTP, while activation of NOS produced an LTP of N1, with a decrease in N2/N1 ratio, and occluded the 20-Hz facial stimulation-induced MF-GrC LTP. In addition, GluN2A-containing NMDA receptor immunoreactivity was observed in the mouse cerebellar granular layer. These results indicate that facial stimulation at 20 Hz induced LTP of MF-GrC synaptic transmission via the GluN2A-containing NMDA receptor/nitric oxide cascade in mice. The results suggest that the sensory stimulation-evoked LTP of MF-GrC synaptic transmission in the granular layer may play a critical role in cerebellar adaptation to native mossy fiber excitatory inputs and motor learning behavior in living animals.

Nicotine depresses facial stimulation-evoked molecular layer interneuron-Purkinje cell synaptic transmission via α7 nicotinic acetylcholine receptors in mouse cerebellar cortex.

Nicotine modulates cerebellar physiology function by interacting with nicotinic acetylcholine receptors (nAChRs) and is involved in modulation of cerebellar cortical circuitry functions. Here, we investigated the effect of nicotine on sensory stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission mouse cerebellar cortex using in vivo cell-attached recording technique and pharmacological methods. The results show that micro-application of nicotine to the cerebellar molecular layer significantly decreased sensory stimulation-evoked MLI-PC synaptic transmission in mouse cerebellar cortex. Nicotine-induced depression in sensory stimulation-evoked MLI-PC synaptic transmission was abolished by either a non-selective nAChR blocker, hexamethonium, or the α7-nAChR antagonist methyllycaconitine (MLA), but not the selective α4ß2-nAChR antagonist dihydro-ß-erythroidine. Notably, molecular layer micro-application of nicotine did not significantly affect the number of spontaneous or facial stimulation-evoked action potentials of MLIs. Moreover, nicotine produced significant increases in the amplitude and frequency of miniature inhibitory postsynaptic currents of PCs, which were abolished by MLA in cerebellar slices. These results indicate that micro-application of nicotine to the cerebellar molecular layer depresses facial stimulation-induced MLI-PC synaptic transmission by activating α7 nAChRs, suggesting that cholinergic inputs modulate MLI-PC synapses to process sensory information in the cerebellar cortex of mice in vivo.

Two cases of refractory erythrodermic psoriasis effectively treated with secukinumab and a review of the literature.

Erythrodermic psoriasis (EP), which accounts for 1 to 2.25% of all psoriatic cases, typically occurs in patients with poor control of existing psoriasis. Secukinumab yields rapid and sustained improvements of signs and symptoms in patients with plaque psoriasis. Currently, clinical data on the treatment of EP with secukinumab are scarce. We describe two adult patients with severe EP, including one male and one female who were both ineligible for or resistant to acitretin or methotrexate treatment and had additional diseases. The patients underwent treatment with secukinumab using the standard regimen. After 4 weeks of treatment, a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) was achieved in both patients. Secukinumab was well tolerated and was continued for at least 32 weeks of treatment. We report the clinical use of secukinumab in the treatment of EP and review its potential role in the management of this severe condition.

Propofol facilitates climbing fiber-Purkinje cell synaptic transmission via NMDA receptor in vitro in mice.

Propofol is generally used for the induction and maintenance of anesthesia in clinical procedures via activation of γ -aminobutyric acid A (GABAA) receptors. When administered at the clinical dose, propofol use is associated with movement disorders, including dystonia and ataxia, suggesting that propofol administration impacts the function of cerebellar neuronal circuitry. In this study, we investigated the effect of propofol on climbing fiber (CF)-Purkinje cell (PC) synaptic transmission in mouse cerebellar slices in the absence of GABAergic inhibition using a whole-cell recording technique and pharmacological methods. Our results showed that bath application of propofol enhanced CF-PC synaptic transmission, which was demonstrated by an increased amplitude and area under the curve (AUC) of the excitatory postsynaptic currents (EPSCs) accompanied by a decrease in the paired-pulse ratio (PPR). The propofol-induced increase in the amplitude of P1 was concentration-dependent with a half effective concentration (EC50) of 20.9 µM. The propofol-induced increases in the amplitude and AUC of CF-PC EPSCs were abolished by an N-Methyl-D-aspartate (NMDA) receptor blocker. Furthermore, the application of NMDA enhanced CF-PC EPSCs and overwhelmed the effect of propofol on CF-PC EPSCs. Moreover, intracellular blockade of NMDA receptors attenuated the propofol-induced enhancement of CF-PC synaptic transmission but strengthened the propofol-induced change in the PPR. These results indicate that propofol enhances CF-PC synaptic transmission by activation of NMDA receptors in the mouse cerebellar cortex, suggesting that propofol administration might be involved in propofol-induced dysfunction of the cerebellum via NMDA receptors.

Three cases report of idiopathic angiosarcoma of the head and neck and literature review.

Herein, we reported 3 cases of angiosarcoma (AS) of the head and neck in old patients, and the etiology, pathogenesis, histopathology, immunohistochemistry, diagnosis, differential diagnosis and prognosis were discussion. Case 1, a male patient aged 86 years old was admitted due to purplish erythema on the head and face and progressive purplish edema in the orbit of the eye for 3 years. He was misdiagnosed with connective tissue disease in another hospital, and a second biopsy and histopathological examination confirmed the AS of the head and neck. Case 2, a male patient aged 85 years were admitted due to erythemalike hyperplasia in the left anterior head with necrosis and scar formation at the center for 2 months. He was misdiagnosed with folliculitis in another hospital, and histopathological examination confirmed the AS of the head and neck. Case 3, a male patient aged 87 years were admitted due to large erythema in the right scalp with ulcer and scar formation for 1 month, and histopathological examination confirmed the AS of the head and neck. One of them was lost to follow, one died 5 months after confirmed diagnosis, and one achieved favorable outcome after radiotherapy and received further follow up. The early clinical manifestations of the three patients were different and lacked characteristics. The disease progressed rapidly and the prognosis was poor. At present, surgery combined with postoperative radiotherapy is the preferred treatment. Through this article, the following conclusions can be obtained: erythema in the head and face of the elderly, rapid progresses and painful, pathological examinations must be performed, and changes in blood vessels and vascular endothelial cells with or without crack formation and red blood cell extravasation should be carefully observed during pathological examinations in case of misdiagnosis. It is hoped that these three cases can serve as a reminder for clinicians, for reducing misdiagnosis and miss diagnosis, choosing appropriate treatment methods, and judging their prognosis. Therefore, early diagnosis and surgical treatment are extremely important to improve the prognosis of AS patients.

An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis.

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesity-related adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

Effects of Cyclosporine on Palmoplantar Pustulosis and Serum Expression of IL-17, IL-23, and TNF-α.

INTRODUCTION: This study aimed to investigate the effects of cyclosporine on palmoplantar pustulosis (PPP) and serum expression of IL-17, IL-23, and TNF-α. METHODS: Patients with PPP (n = 48) were recruited and treated with cyclosporine alone. The Palmoplantar Pustulosis Area and Severity Index score was obtained, and ELISA was employed to detect the serum IL-17, IL-23, and TNF-α expression before treatment and after 8 weeks of treatment. RESULTS: Complete remission was achieved in 16.7% of the patients, remission in 45.8%, an improvement in 31.3%, and the treatment was ineffective in 6.25%, yielding an overall effectiveness of 62.5%. Adverse effects included hypertension (n = 6), frequent urination and enuresis nocturna (n = 6), gastrointestinal discomfort (n = 6), hypertrichosis (n = 3), and increased creatinine (n = 1). While serum IL-17, IL-23, and TNF-α concentrations were reduced after 8 weeks of treatment, the reductions were greatest for IL-23 and TNF-α, whereas the reduction in IL-17 was not significant. CONCLUSION: Cyclosporine is a safe and effective treatment for PPP with few adverse effects, which might be related to the regulation of IL-23 and TNF-α.

Mechanisms of Spontaneous Climbing Fiber Discharge-Evoked Pauses and Output Modulation of Cerebellar Purkinje Cell in Mice.

Climbing fiber (CF) afferents modulate the frequency and patterns of cerebellar Purkinje cell (PC) simple spike (SS) activity, but its mechanism is unclear. In the present study, we investigated the mechanisms of spontaneous CF discharge-evoked pauses and the output modulation of cerebellar PCs in urethane-anesthetized mice using in vivo whole-cell recording techniques and pharmacological methods. Under voltage-clamp recording conditions, spontaneous CF discharge evoked strong inward currents followed by small conductance calcium-activated potassium (SK) channels that mediated outward currents. The application of a GABAA receptor antagonist did not significantly alter the spontaneous SS firing rate, although an AMPA receptor blocker abolished complex spike (CS) activity and induced significantly increased SS firing rates and a decreased coefficient of variation (CV) SS value. Either removal of extracellular calcium or chelated intracellular calcium induced a decrease in amplitude of CS-evoked after-hyperpolarization (AHP) potential accompanied by an increase in SS firing rate. In addition, blocking SK channels activity with a selective antagonist, dequalinium decreased the amplitude of AHP and increased SS firing rate. Moreover, we found repeated CF stimulation at 1 Hz induced a significant decrease in the spontaneous firing rate of SS, and accompanied with an increase in CV of SS in cerebellar slices, which was also abolished by dequalinium. These results indicated that the spontaneous CF discharge contributed to decreasing SS firing rate via activation of SK channels in the cerebellar PCs in vivo in mice.

Effect of FGF10 monoclonal antibody on psoriasis-like model in guinea pigs.

OBJECTIVE: To investigate the therapeutical effect of topical application of FGF10 monoclonal antibody on the guinea pig model with psoriasis. METHODS: Blank group, model group, hydrocortisone butyrate treatment group and high-dose (0.188 mg/ml), middle-dose (0.094 mg/ml) and low-dose (0.063 mg/ml) FGF10 antibody group were set, respectively. After two-week treatment, pathological changes of psoriasis-like models were observed by HE staining, and the difference in VEGF and PCNA expression levels among different groups was observed by immunohistochemical staining. RESULTS: All the test indicators of each treatment group were lower than those of the model group, and there was a significant difference (P<0.05). The inflammatory cell count of the high-dose FGF10 antibody group was not statistically different from those of the blank group (t=0.77, P=0.443), and the counts of the rest treatment groups were significantly higher than those of the blank group and the high-dose FGF10 antibody group (P<0.05). The epidermal thickness of each FGF10 antibody treatment group was significantly higher than that of hydrocortisone butyrate treatment group (P<0.05), while no statistical difference was found in the epidermal thickness among the FGF10 antibody treatment groups (P>0.05). FGF10 monoclonal antibodies can reduce the PCNA and VEGF expression in psoriasis-like model of guinea pig's ear. CONCLUSION: FGF10 monoclonal antibodies can affect keratinocyte proliferation and division and can also significantly inhibit the inflammatory response in the psoriasis model. Meanwhile, FGF10 monoclonal antibodies can produce a therapeutic effect on psoriatic lesions by inhibiting the abnormal epidermis cell proliferation and neovascularization of the dermis in the psoriasis model.

Combined treatment for cutaneous Rosai-Dorfman disease: a report of 2 cases.

We report 2 cases of cutaneous Rosai-Dorfman disease (CRDD). One was a 46-year-old Chinese woman who presented with a 10-year history of multiple papules and nodules on the left cheek. Another one was a 57-year-old Chinese woman who presented with a 7-month history of erythematous pruritic plaque on the Dorsum nasi. Their lesions consisted of proliferative large histiocytes occasionally showing emperipolesis. Immunohistochemistry showed these histiocytes were positive for CD68 and S-100, but negative for CD1a. A diagnosis of CRDD was made. Their lesions were improved after intralesional treatment with Compound Betamethasone, interferon and acitretin. To our knowledge, we for the first time reported the application of intralesional Compound Betamethasone and Lidocaine, intramuscular injection of interferon, and oral acitretin in the treatment of CRDD, and favorable outcome was achieved without recurrence over a 1-year follow-up period.