Long-range monosynaptic inputs targeting apical and basal dendrites of primary motor cortex deep output neurons.

The primary motor cortex (M1) integrates various long-range signals from other brain regions for the learning and execution of goal-directed movements. How the different inputs target the distinct apical and basal dendrites of M1 pyramidal neurons is crucial in understanding the functions of M1, but the detailed connectivity pattern is still largely unknown. Here, by combining cre-dependent rabies virus tracing, layer-specific chemical retrograde tracing, optogenetic stimulation, and electrophysiological recording, we mapped all long-range monosynaptic inputs to M1 deep output neurons in layer 5 (L5) in mice. We revealed that most upstream areas innervate both dendritic compartments concurrently. These include the sensory cortices, higher motor cortices, sensory and motor thalamus, association cortices, as well as many subcortical nuclei. Furthermore, the dichotomous inputs arise mostly from spatially segregated neuronal subpopulations within an upstream nucleus, and even in the case of an individual cortical layer. Therefore, these input areas could serve as both feedforward and feedback sources albeit via different subpopulations. Taken together, our findings revealed a previously unknown and highly intricate synaptic input pattern of M1L5 neurons, which implicates that the dendritic computations carried out by these neurons during motor execution or learning are far more complicated than we currently understand.

Low Geriatric Nutritional Risk Index Is Associated with Poorer Prognosis in Elderly Diffuse Large B-Cell Lymphoma Patients Unfit for Intensive Anthracycline-Containing Therapy: A Real-World Study.

Nutritional assessments, including the Geriatric Nutritional Risk Index (GNRI), have emerged as prediction tools for long-term survival in various cancers. This study aimed to investigate the therapeutic strategy and explore the prognostic factors in the elderly patients (≥65 years) with diffuse large B cell lymphoma (DLBCL). The cutoff value of the GNRI score (92.5) was obtained using the receiver operating characteristic curve. Among these patients (n = 205), 129 (62.9%) did not receive standard R-CHOP chemotherapy. Old age (≥80 years), poor performance status, low serum albumin level, and comorbidities were the major factors associated with less intensive anti-lymphoma treatment. Further analysis demonstrated that a lower GNRI score (<92.5) was linked to more unfavorable clinical features. In the patients who received non-anthracycline-containing regimens (non-R-CHOP), multivariate analysis showed that a low GNRI can serve as an independent predictive factor for worse progression-free (HR, 2.85; 95% CI, 1.05-7.72; p = 0.039) and overall survival (HR, 2.98; 95% CI, 1.02-8.90; p = 0.045). In summary, nutritional evaluation plays a role in DLBCL treatment and the GNRI score can serve as a feasible predictive tool for clinical outcomes in frail elderly DLBCL patients treated with non-anthracycline-containing regimens.

Effects of Colloidal Oatmeal Lotion on Symptoms of Dermatologic Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors.

OBJECTIVE: The common adverse effects associated with targeted therapy for cancer, such as epidermal growth factor receptor inhibitors (EGFRIs), are dermatologic toxicities that cause the patient physical discomfort and affect treatment. Colloidal oatmeal lotion (COL) has been proven to help prevent dermatitis and xerosis. Evidence of its effect on EGFRI-induced dermatologic toxicities, however, is limited. The purpose of this study was to explore the effect of COL on EGFRI-induced dermatologic toxicities. DESIGN AND SETTING: This study used a 1-group pretest-posttest design with a convenience sample of 30 patients with cancer who developed EGFRI-induced dermatologic toxicities from a medical center in southern Taiwan. All participants applied topical COL 3 to 5 times a day for 4 consecutive weeks and received a pretest and 4 posttests. OUTCOME MEASURES: A generalized estimating equation was used to assess the impact of demographics, disease characteristics, and weeks of COL use on dermatologic toxicity severity, body surface area affected, and level of pruritus. MAIN RESULTS: Significant differences were found between the pretest and all posttests after using COL with regard to the severity, body surface area affected, and level of pruritus in participants who developed EGFRI-induced dermatologic toxicities (P < .05). There were no significant differences in demographics or disease characteristics on EGFRI-induced dermatologic toxicities. CONCLUSIONS: Based on the study results, COL could improve the symptoms of dermatologic toxicities in those receiving EGFRIs with no adverse effects. Therefore, the authors suggest the use of COL in clinical settings.

[An Experience Promoting the Interdisciplinary Care Model for Dengue Fever].

Emergency departments represent the first line in facing major healthcare events. During major epidemic outbreaks, patients crowding into the emergency departments increase the wait time for patients and overload the staffs that are on duty. The dengue fever outbreak in southern Taiwan during the summer 2015 presented a huge management challenge for physicians and nurses in local hospitals. We responded to this challenge by integrating resources from different hospital departments. This strategy successfully increased group cohesiveness among the medical team, ensuring that they could not only ultimately cope with the outbreak together but also effectively provide patient-centered care. This interdisciplinary care model may serve as a reference for medical professionals for the management of future epidemics and similar events.

L-cysteine protects intestinal integrity, attenuates intestinal inflammation and oxidant stress, and modulates NF-κB and Nrf2 pathways in weaned piglets after LPS challenge.

In this study we investigated whetherL-cysteine (L-cys) could alleviate LPS-induced intestinal disruption and its underlying mechanism. Piglets fed with anL-cys-supplemented diet had higher average daily gain.L-cys alleviated LPS-induced structural and functional disruption of intestine in weanling piglets, as demonstrated by higher villus height, villus height (VH) to crypt depth (CD) ratio, and transepithelial electrical resistance (TER) and lower FITC-dextran 4 (FD4) kDa flux in jejunum and ileum. Supplementation withL-cys up-regulated occludin and claudin-1 expression, reduced caspase-3 activity and enhanced proliferating cell nuclear antigen expression of jejunum and ileum relative to LPS group. Additionally,L-cys suppressed the LPS-induced intestinal inflammation and oxidative stress, as demonstrated by down-regulated TNF-α, IL-6 and IL-8 mRNA levels, increased catalase, superoxide dismutase, glutathione peroxidase activity, glutathione (GSH) contents and the ratio of GSH and oxidized glutathione in jejunum and ileum. Finally, a diet supplemented withL-cys inhibited NF-κB(p65) nuclear translocation and elevated NF erythroid 2-related factor 2 (Nrf2) translocation compared with the LPS group. Collectively, our results indicated the protective function ofL-cys on intestinal mucosa barrier may closely associated with its anti-inflammation, antioxidant and regulating effect on the NF-κB and Nrf2 signaling pathways.

Shikonin Inhibits Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts via lncRNA-NR024118.

Background. Shikonin is a major chemical component of zicao that possesses anti-inflammatory properties and the ability to mediate cellular and humoral immunity, especially in rheumatoid arthritis (RA). We investigated the impact of shikonin on inflammatory response in RA synovial fibroblasts using the CAIA model. Methods. Severe polyarticular arthritis was induced in Balb/c female mice. Expressions of lncRNA-NR024118, SOCS3, proinflammatory cytokines, and MMPs were evaluated using RT-RCR. Histone acetylation and SOCS3 protein expression were assessed by ChIP assay and western blot, respectively. Results. Mice treated with shikonin showed an abrogation of soft tissue and bone lesions. Shikonin remarkably enhanced the expression of NR024118 and SOCS3 and suppressed the secretion and expression of IL-6, IL-8, and MMPs. Proliferation of cultured RA synovial fibroblasts in the presence of IL-1ß was also significantly inhibited by shikonin. Moreover, shikonin dose-dependently increased acetylation of histone H3 at the promoter of NR024118. Finally, NR024118 overexpression and interference significantly changed SOCS3 expression and NR024118 interference could reverse regulation of shikonin on SOCS3, proinflammatory cytokines, and MMPs expression level in MH7A cells. Conclusion. Our results reveal that, in the CAIA mouse model of RA, shikonin has disease modifying activity that is attributable to the inhibition of inflammatory response via lncRNA-NR024118.

Zinc oxide influences mitogen-activated protein kinase and TGF-ß1 signaling pathways, and enhances intestinal barrier integrity in weaned pigs.

Weaning is the most significant event in the life of pigs and is always related with intestinal disruption. Although it is well known that zinc oxide (ZnO) exerts beneficial effects on the intestinal barrier, the mechanisms underlying these effects have not yet been fully elucidated. We examined whether ZnO protects the intestinal barrier via mitogen-activated protein kinases and TGF-ß1 signaling pathways. Twelve barrows weaned at 21 d of age were randomly assigned to two treatments (0 verus 2200 mg Zn/kg from ZnO) for 1 wk. The results showed that supplementation with ZnO increased daily gain and feed intake, and decreased postweaning scour scores. ZnO improved intestinal morphology, as indicated by increased villus height and villus height:crypt depth ratio, and intestinal barrier function, indicated by increased transepithelial electrical resistance and decreased mucosal-to-serosal permeability to 4-ku FITC dextran. ZnO decreased the ratios of the phosphorylated to total JNK and p38 (p-JNK/JNK and p-p38/p38), while it increased the ratio of ERK (p-ERK/ERK). Supplementation with ZnO increased intestinal TGF-ß1 expression. The results indicate that supplementation with ZnO activates ERK ½, and inhibits JNK and p38 signaling pathways, and increases intestinal TGF-ß1 expression in weaned pigs.

Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has "non-cholinergic" effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.

Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease.

Zinc oxide influences intestinal integrity, the expressions of genes associated with inflammation and TLR4-myeloid differentiation factor 88 signaling pathways in weanling pigs.

This study explored whether zinc oxide (ZnO) supplementation could alleviate weanling-induced intestinal injury through TLR and NOD-like receptor signaling pathways. Twelve early-weanling piglets were allotted to two dietary treatments (control vs 2200 mg Zn/kg from ZnO) for 1 wk. The results showed that supplemental ZnO improved daily gain and feed intake, decreased post weaning scour scores, increased villus height and villus height:crypt depth ratio at the jejunal mucosa, and decreased diamine oxidase activity and endotoxin concentration in plasma. The intestinal mRNA levels of TLR4 and its downstream signals, including MyD88, IL-1 receptor-associated kinase 1 and TNF-α receptor-associated factor 6, were decreased, and the expressions of intestinal pro-inflammatory cytokines and chemokines were decreased simultaneously in the ZnO-supplemented piglets. Although NF-κB p65 mRNA abundance was not affected by ZnO supplementation, NF-κB p65 protein expression was down-regulated by ZnO. However, ZnO supplementation had no effect on intestinal expressions of NOD1 and NOD2, and their adaptor molecule receptor-interacting serine/threonine-protein kinase 2, as well as protein expressions of caspase-3 and heat shock protein 70. The results indicated that the protective effects of ZnO on intestinal integrity were closely related to decreasing the expressions of genes associated with inflammation through inhibiting the TLR4-MyD88 signaling pathways.

[Study on in vitro release and percutaneous absorption for Zhitong cataplasm].

To evaluate in vitro release and transdermal behaviors of Zhitong cataplasm, modified Franz diffusion cell method was applied to investigate in vitro transdermal absorption of Zhitong cataplasm and the content of tetrahydropalmatine was determined by HPLC. In 24 hours, accumulative release rate of tetrahydropalmatine was 81. 9%, transmission rate was 2.26 microg x cm(-2) x h(-1). In 48 hours, accumulative transdermal rate and transmission rate of tetrahydropalmatine were 20.31%, 0.22 pg x cm(-2) x h(-1). So Zhitong cataplasm had a good release and transdermal properties and transdermal actions were consistent with zero-order kinetics process.

Study on in vitro release and percutaneous absorption for Zhitong cataplasm / 中国中药杂志

To evaluate in vitro release and transdermal behaviors of Zhitong cataplasm, modified Franz diffusion cell method was applied to investigate in vitro transdermal absorption of Zhitong cataplasm and the content of tetrahydropalmatine was determined by HPLC. In 24 hours, accumulative release rate of tetrahydropalmatine was 81. 9%, transmission rate was 2.26 microg x cm(-2) x h(-1). In 48 hours, accumulative transdermal rate and transmission rate of tetrahydropalmatine were 20.31%, 0.22 pg x cm(-2) x h(-1). So Zhitong cataplasm had a good release and transdermal properties and transdermal actions were consistent with zero-order kinetics process.

Hyperthermia conditioned astrocyte-cultured medium protects neurons from ischemic injury by the up-regulation of HIF-1 alpha and the increased anti-apoptotic ability.

It has been demonstrated that conditioned medium from astrocytes challenged by in vitro ischemia (oxygen-glucose deprivation, OGD) improved neuronal survival. In addition, preconditioning stimuli can be cross-tolerant, safeguarding against other types of injury. We therefore hypothesized that hyperthermia-conditioned astrocyte-cultured medium (ACM) might also have protective effect on neurons against ischemic injury. The cultured-media, named 38ACM and 40ACM respectively, were collected after astrocytes had been incubated at 38 °C or 40 °C for 6h, followed by incubation at 37 °C for 24h. It was found that ischemia for 6h induced a significant reduction in the number of neuronal cells and cell-viability, and an increase in lactate dehydrogenase (LDH) release and the percentage of apoptotic nuclei in neurons. Pre-treatment with 38ACM or 40ACM for 24h significantly diminished ischemia injury, enhanced cell viability, reduced LDH release and reversed apoptosis. Western blot analysis showed that treatment with 38ACM or 40ACM for 24h led to a significant increase in hypoxia-inducible factor-1 (HIF-1) alpha expression. The EMSA demonstrated that the ACM increased the binding activity of HIF-1 in ischemic neurons. The data implied that hyperthermia-conditioned ACM protects neurons from ischemic injury by up-regulating HIF-1 alpha, and the increased binding activity of HIF-1 and anti-apoptotic ability.

Ligustilide attenuates pain behavior induced by acetic acid or formalin.

Danggui is a popular traditional Chinese medicinal (TCM) herb, which has long been used clinically to treat primary dysmenorrhoea. In a recent study, we demonstrated that ligustilide (LIG), one of the main compounds of Danggui essential oil, has multiple effects on uterine smooth muscles and possesses a non-specific antispasmodic function, which suggests that LIG might play a major role in the therapeutic activity of Danggui in primary dysmenorrhoea. Since pain is the main syndrome of dysmenorrhea, the present investigation was carried out to evaluate the analgesic activity of LIG in vivo. LIG was intra-gastrically administered to animals. We demonstrated for the first time that LIG could cause a significant dose-related reduction of acetic acid-induced writhing response and formalin-induced licking time in both the early and late phases. These results showed that LIG possessed antinociceptive and anti-inflammatory activities. These findings plus the data we reported recently implied that LIG not only has an active dilatory effect on myometrium but also an effective role in reducing the neurogenic and inflammatory pain, thus having the potential to be developed into an effective drug for the treatment of various pain syndromes including primary dysmenorrhoea.

Ligustilide inhibits spontaneous and agonists- or K+ depolarization-induced contraction of rat uterus.

In the present study, the effects of ligustilide (LIG) on uterine contraction in vitro were investigated. In isolated rat uterine, LIG (2-8 microg/ml) inhibited the spontaneous periodic contraction in a concentration-dependent manner (EC(50)=4.4 microg/ml, 95% confidence interval 2.7-6.1 microg/ml), and attenuated prostaglandin F2alpha (PGF(2)alpha)- or acetylcholine chloride (Ach)-induced uterine contractions. At 8 microg/ml, LIG nearly completely blocked the PGF(2)alpha-induced contractions (95.3%). In the case of Ach-induced contraction, about 73.9% was inhibited by LIG at this dosage. It was also observed that LIG affected significantly oxytocin-induced increase in the contraction of uterine horns that were incubated not only in the Locke solution but also in a Ca(2+)-free solution. In addition, LIG caused concentration-dependent inhibition of uterine contraction induced by K(+) (56.3 Mm) depolarization, reaching the significant level at 2 microg/ml (EC(50)=3.3 microg/ml, 95% confidence interval 2.5-4.1 microg/ml). The findings clearly show that LIG has multiple effects on the uterine smooth muscles, suggesting that LIG possesses a non-specific antispasmodic function. The data also imply strongly that LIG is one of active ingredients of Danggui and has the potential to be developed into an effective drug for the prevention and treatment of primary dysmenorrhoea.