Base-promoted triple cleavage of CCl2Br: a direct one-pot synthesis of unsymmetrical oxalamide derivatives.

We present a novel, eco-friendly and one-pot approach for synthesizing unsymmetrical oxalamides with the aid of dichloroacetamide and amine/amides in the presence of CBr4 in a basic medium. The use of water as a potent supplement for the oxygen atom source and the detailed mechanism have been disclosed. Moreover, the protocol involves triple cleavage of CCl2Br and the formation of new C-O/C-N bonds, with the advantage of achieving selective bromination using CBr4 with good to excellent yield under mild conditions. The method also demonstrates promise for industrial use, as proven by its effective implementation in gram-scale synthesis conducted in a batch process, along with its utilization in a continuous-flow system.

Alkaloids from Fritillaria przewalskii Bulbs and Their Anti-Alzheimer's Disease Activities.

Three undescribed isosteroidal alkaloids, przewalskines A-C (1-3), as well as seven known alkaloids (4-10) were obtained from Fritillaria przewalskii bulbs. Their structures were deduced by extensive HRESIMS, 1D NMR, and 2D NMR analyses, and their bioactivities were evaluated involving the anti-inflammatory and inhibitory potencies on AChE, BChE, and Aß aggregation. Compound 4 revealed the potent effect on inhibiting Aß aggregation activity with IC50 value of 33.1 µM, AChE activity with IC50 value of 6.9 µM, and also showed NO release inhibitory acitivity with IC50 value of 32.6 µM. These findings contribute new multi-.target anti-AD agents and embody the chemical diversity of F. przewalskii.

The effect of radiotherapy on patients with pathological stage IIB breast cancer after breast-conserving surgery or mastectomy: A cohort study.

BACKGROUND: Breast cancer is one of the most common cancers in women, and treatment options include surgery, systemic therapies, and radiotherapy (RT). While postoperative RT plays an important role in reducing local recurrence rates and improving survival outcomes, its exact impact on patients with pathological stage IIB breast cancers remains unidentified. METHODS: In this retrospective cohort study, patients with newly diagnosed pathological stage IIB breast cancer who underwent surgery and postoperative RT were included. The data were collected from medical records, and survival outcomes were assessed using the Kaplan-Meier method, log-rank tests, and Cox regression models. RESULTS: In total, 350 patients participated in this study. Overall survival, locoregional recurrence-free survival, event-free survival, and distant metastasis-free survival rates did not significantly differ between those who received RT and those who did not. Multivariate analyses revealed that patients who received anthracycline or taxane chemotherapy had better survival outcomes. CONCLUSION: Our findings demonstrated that postoperative RT had no significant effect on overall survival, locoregional recurrence, event-free survival, or distant metastasis rates in patients with pathological stage IIB breast cancer. However, anthracycline- and taxane-based chemotherapies were associated with improved outcomes. These findings demonstrated the complexities of treating such patient populations with multimodal therapies. Further research is needed to ensure optimal postoperative RT in patients with pathological stage IIB breast cancer. Clinicians must consider individual patient characteristics and incorporate comprehensive treatment approaches to ensure successful outcomes in this population.

Bioactive Isoquinoline Alkaloids with Diverse Skeletons from Fissistigma polyanthum.

Six new isoquinoline alkaloids, including aporphine alkaloids (2, 3, 9, and 10), a benzylisoquinoline alkaloid (13), and a protoberberine alkaloid (17), were isolated from the roots of Fissistigma polyanthum, along with a new furanone (20) and 13 known isoquinoline alkaloids (1, 4-8, 11, 12, 14-16, 18, and 19). The structures of the new compounds were elucidated by the analysis of spectroscopic data. Compounds 1 and 2 are rare oxalyl-fused dehydroaporphine alkaloids. Compound 12 presented the most potent dual-target activities on AChE inhibition and Aß aggregation inhibition, while compounds 13 and 19 simultaneously exhibited discernible AChE and BChE inhibitions with antioxidant activities. The activity results indicate that F. polyanthum alkaloids have a potential of inhibition and prevention of Alzheimer's disease mainly through both ChEs and ß-amyloid pathways in addition to antioxidant activity.

Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

BACKGROUND: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). METHODS: BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. RESULTS: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. CONCLUSION: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Antimicrobial activity effects of electrolytically generated hypochlorous acid-treated pathogenic microorganisms by isothermal kinetic simulation.

This study involves isothermal kinetic simulation to evaluate the parameters of inhibition conditions for Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) of high-risk pathogens. This is because the new type of the 2019 novel coronavirus (2019-nCoV) is continuously spreading and the importance of public health issues. Environmental disinfection and personal wearing of masks have become important epidemic prevention measures. Selection of concentration kinetics could be estimated best for E. coli and S. aureus of pathogens, 2.74 × 104 and 105 and 2.44 × 104 and 105 colony-forming units (CFU mL-1), by isothermal micro-calorimeter (TAM Air) tests, respectively. Comparisons were made of different doses of 0-70 ppm (in 20 mL test ampoule) hypochlorous acid treatment for conducting nth-order and autocatalytic reaction simulation to evaluate the inhibition reaction parameters, which determined the autocatalytic kinetic model that was beneficially applied on the E. coli and S. aureus. We developed the inhibition reaction parameters of the pathogens, which included the activation energy (E a), the natural logarithm of pre-exponential factor (lnk 0), the enthalpy of inhibition microbial growth reaction (∆H), inhibition microbial growth, and the inhibition growth analysis. Overall, we conducted isothermal kinetic simulation to understand the antimicrobial activity effects of electrolytically generated hypochlorous acid-treated pathogenic microorganisms, which will provide reference for public health and medical-related fields for SDG3, and can contribute to ensuring human health and hygiene.

The clinical relative biological effectiveness and prostate-specific antigen kinetics of carbon-ion radiotherapy in low-risk prostate cancer.

BACKGROUND: To evaluate the clinical relative biological effectiveness (RBE) of carbon-ion radiotherapy (C-ion RT) for prostate cancer. METHODS: The records of 262 patients with low-risk prostate cancer (median age, 65 [47-80] years) treated with C-ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000-2018 were reviewed retrospectively. Four different protocol outcomes and prostate-specific antigen (PSA) responses were evaluated. The median follow-up was 8.4 years. The Kaplan-Meier method was used to estimate the biochemical or clinical failure-free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. RESULTS: The 5-, 7-, and 10-year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10-year BCFFRs of patients who received C-ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow-up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18-2.24), 2.16 (2.14-2.23), and 2.12 (2.09-2.21), respectively. CONCLUSIONS: Using clinical data from low-risk prostate cancer patients, we showed the clinical RBE of C-ion RT decreased with increasing dose per fraction.

Combined modality therapy for patients with esophageal squamous cell carcinoma: Radiation dose and survival analyses.

BACKGROUND: We aimed to analyze the radiation dose and compare survival among combined modality therapy using modern radiation techniques for patients with esophageal squamous cell carcinoma (ESCC). METHODS: This retrospective study included patients with clinically staged T1-4N0-3M0 ESCC from 2014 to 2018. Patients who received combined modality therapies with curative intent were enrolled. The overall survival (OS) rates among combined modality therapy were compared. The clinical variables and impacts of radiation dose on survival were analyzed by the Kaplan-Meier method and Cox regression model. RESULTS: Of the 259 patients, 141 (54.4%) received definitive concurrent chemoradiotherapy (DCCRT); 67 (25.9%) underwent neoadjuvant chemoradiotherapy followed by surgery (NCRT+S); 51 (19.7%) obtained surgery followed by adjuvant chemoradiotherapy (S+ACRT). Two-year OS rates of the DCCRT, NCRT+S and S+ACRT group were 48.9, 61.5 and 51.2%. In the subgroup analysis of DCCRT group, the 2-year OS of patients receiving radiation dose 55-60 Gy was 57.1%. Multivariate analyses showed that clinical stage (p = 0.004), DCCRT with 55-60 Gy (p = 0.043) and NCRT+S with pathological complete response (pCR) (p = 0.014) were significant prognostic factors for better OS. The radiation dose-survival curve demonstrated a highly positive correlation between higher radiation dose and better survival. CONCLUSION: Our results suggest that NCRT+S can provide a favorable survival for patients with ESCC, especially in patients who achieved pCR. The optimal radiation dose might be 55-60 Gy for patients receiving DCCRT via modern radiation techniques. Further randomized clinical studies are required to confirm the survival benefits between NCRT+S and DCCRT with escalated dose.

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups.

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC50 values of 1.94 ± 0.13 µM and 28.37 ± 1.85 µM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC50 values of 9.07 ± 1.34 µM and 6.05 ± 1.17 µM, respectively, which were superior to the control, Trolox (IC50 = 11.03 ± 0.76 µM). It is worth noting that 3-aminoquinoline derivatives 12a-12d exhibited better drug-like properties.

Study on the sleep quality of women pregnant with a second child and the influencing factors.

OBJECTIVES: To investigate the sleep quality of women pregnant with a second child and the influencing factors and provide a scientific basis for health care guidance to clinically improve the sleep quality of pregnant women. METHODS: A total of 162 women pregnant with a second child at a first-class tertiary hospital in Changsha from January to August 2018 were selected as the research subjects. General demographic characteristics were collected, and the Pittsburgh Sleep Quality Index (PSQI) scale was used to assess their sleep quality. Multivariate logistic regression analysis was used to explore the influencing factors of the sleep quality of women pregnant with a second child. RESULTS: The PSQI score (except hypnotic drugs) and total score of pregnant women with second birth were higher than those of normal female population, and the difference was statistically significant (P < 0.05). Univariate analysis showed statistically significant differences in sleep quality among women pregnant with a second child of different ages, marital relationships, gender expectations, education levels, monthly family incomes, planned or unplanned pregnancy, and gestational weeks (P < 0.05). The results of the multi-factor analysis showed that the low education level (OR = 0.224, P = 0.001), low family monthly income (OR = 3.035, P = 0.014), expectation of gender (OR = 0.065, P = 0.038), and dissatisfaction with marital relationship (OR = 0.275, P = 0.001) were the primary risk factors of poor sleep quality of in women with second pregnant. CONCLUSIONS: The overall sleep quality of women pregnant with a second child is poor, and 37.65% have sleep quality problems. Low education levels, low family monthly incomes, fetal gender expectations, and poor relationship between husband and wife are the main factors affecting the sleep quality of women pregnant with a second child. Pregnant women with the above factors should pay attention to their sleep quality and take necessary measures for intervention and guidance to improve the level of health care during pregnancy.

Isosteroidal alkaloids of Fritillaria taipaiensis and their implication to Alzheimer's disease: Isolation, structural elucidation and biological activity.

Four undescribed and five known isosteroidal alkaloids were isolated from the bulbs of Fritillaria taipaiensis and their structures were elucidated on the basis of HR-ESI-MS, 1D and 2D NMR spectroscopic data analyses. The undescribed compounds were designated taipainines A-D. Of these, taipainine D presented a unique structure having the D/E trans (H-13α/H-17ß) and E/F cis (ß-axial lone pair of the N atom/H-22ß) ring junctions. Possible biosynthetic pathway to taipainine D is proposed. Four compounds showed significant BChE inhibitory activities similar or better than the positive control galantamine. In addition, the preliminary structure-activity relationships (SARs) of these isosteroidal alkaloids were also investigated.

Discovery of Guanidine Derivatives from Buthus martensii Karsch with Metal-Binding and Cholinesterase Inhibition Properties.

Two rare guanidine-type alkaloids, Buthutin A (1) and Buthutin B (2), along with two other compounds (3, 4), were isolated from Buthus martensii Karsch, and determined using extensive spectroscopic data analysis and high resolution-mass spectrometry. Compound 1 showed the most potent inhibition on AChE and BChE with IC50 values of 7.83 ± 0.06 and 47.44 ± 0.95 µM, respectively. Kinetic characterization of compound 1 confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows its interaction with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of compound 1 to PAS domain of AChE was also confirmed experimentally. Moreover, compounds 1 and 3 exhibited satisfactory biometal binding abilities toward Cu2+, Fe2+, Zn2+ and Al3+ ions. These results provide a new evidence for further development and utilization of B. martensii in health and pharmaceutical products.

Positive Effects of Preventive Nutrition Supplement on Anticancer Radiotherapy in Lung Cancer Bearing Mice.

(1) Background: Radiotherapy (RT) is one of the major treatments for non-small cell lung cancer, but RT-associated toxicities usually impede its anticancer effect. Nutrient supplementation has been applied for cancer prevention or a complementary measure to anticancer therapy. Here, we explored the influence of total nutrition supplementation before and after cancer occurrence on the anticancer benefit and side effects of RT. (2) Methods: C57BL/6JNarl mice were inoculated with Lewis lung carcinoma cells and then treated with radiotherapy. TNuF, a total nutrition formula, was prescribed by oral gavage. In the preventive groups, TNuF supplementation started from seven days before tumor inoculation. In the complementary groups, TNuF supplementation began after tumor inoculation. (3) Results: TNuF successfully enhanced the anticancer effect of RT against primary tumor and lung metastasis. Additionally, the complementary supplement improved the high serum TNF-α level and the wasting of sartorius muscle in mice receiving RT. In histologic and molecular analysis, TNuF was observed to modulate EGFR, apoptosis, and VEGF and PD-1/PD-L1 pathways. Furthermore, the anticancer benefit of the preventive supplement was comparable to that of the complementary administration. (4) Conclusions: Our results demonstrated that the prescription of the TNuF total nutrition formula before and after cancer diagnosis attains similar benefits in testing subjects with typical anticancer RT. TNuF is also a potential sensitizer to anti-PD-1 immune therapy.

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome.

BACKGROUND: This study aimed to investigate the clinical relevance of the immune microenvironment in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-ICC). PATIENTS AND METHODS: The density of tumor-infiltrating CD3+ , CD8+ , CD163+ , and Foxp3+ immune cells, as well as Programmed cell death 1, Programmed cell death-ligand 1, and Tumor necrosis factor receptor superfamily member 4, was measured in the peritumor liver, tumor invasive margin, and intratumor subregions of 56 cHCC-ICC by immunohistochemistry. The immune index was established to stratify patients. Prognostic significance of immune cell subsets and immune indices was evaluated. RESULTS: The distribution of immune cells was highly heterogeneous among different subregions of cHCC-ICC. As compared with the hepatocellular carcinoma (HCC) component, the lower density of CD8+ T cells and higher intensity of Foxp3+ Tregs and immune checkpoints in the intrahepatic cholangiocarcinoma (ICC) component may indicate a stronger immune evasive ability of ICC. Based on clustering classification or a combination of random forest and lasso-cox, two models of immune indices were established and both were identified as independent prognostic factors for cHCC-ICC patients. The selected immune variables in the immune prognostic models derived from both HCC and ICC subregions, indicating that the prognosis of cHCC-ICC patients was a complex interaction of both components. CONCLUSIONS: The immune contexture was heterogeneous among different subregions of cHCC-ICC patients and contributed differently to patient prognosis. Immune score based on the densities of immune cells might serve as a promising prognostic predictor for cHCC-ICC patients.

Antioxidant Activities of Selected Medicinal Mushroom Submerged Cultivated Mycelia.

Medicinal mushrooms fruiting bodies have been used as food or medicine for years but cultured mycelium is faster to grow and costs less. This research studied the antioxidant activities of three species (five strains) of medicinal mushroom mycelia (Cordyceps militaris, Ganoderma tsugae I and II, Trametes versicolor I and II). Two-stage extractions were performed: first the sample was extracted with 70% ethanol, and then the residue was extracted with 95°C hot water. Both ethanolic and hot water extracts showed effective concentration (EC50) values of 0.29-4.22 mg/mL, indicating that these extracts were remarkably effective in antioxidant activities. The ethanolic extracts displayed more effective reducing power, scavenging, and chelating ability (EC50 0.33-2.37 mg/mL) than hot water extracts (EC50 0.58-4.22 mg/g). Besides, ethanolic extracts contained higher total phenol content (75.49-144.99 GAE mg/g) than the hot water extracts (22.77-58.68 GAE mg/g). Furthermore, the ethanolic extracts contained flavonoids but not the hot water extract. Overall, these mycelia were highly effective in the antioxidant activities and might be potent antioxidants.

Effect of Ethanolic Extracts from Taiwanofungus camphoratus and T. salmoneus (Agaricomycetes) Mycelia on Osteoporosis Recovery.

Osteoporosis is common in postmenopausal women and elderly people. In this study, the ovariectomized mice were used as an in vivo test to evaluate the effects of 70% ethanolic extracts of Taiwanofungus camphoratus and T. salmoneus (Polyporales, Agaricomycetes) on postmenopausal osteoporosis. Ovariectomized mice had significantly higher body weight and histopathological alterations of the liver were found to have diffused fatty infiltrated vesicles. The bone parameters of the femur were determined by microcomputed tomography. In addition, the relative weight of the uterus is significantly lower and atrophy of the uterine glands was found in histopathological alterations. The results of trabecular bone parameters showed that feeding high doses of T. camphoratus mycelia ethanolic extract to ovariectomized mice had the ability to delay bone loss. The bone density of trabecular bone and cortical bone were also significantly higher than those of ovariectomized mice, indicating that the ethanolic extract of T. camphoratus has the potential to delay the occurrence of osteoporosis.

Using salvage Boron Neutron Capture Therapy (BNCT) for recurrent malignant brain tumors in Taiwan.

Radiation therapy has an irreplaceable role in modern oncologic therapy, thanks to the advanced radiation techniques developed in recent decades. However, photon-resistant cases are sometimes encountered. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy technique due to the high tumor to tissue ratio of boronophenylalanine (BPA), the unique medication used for the BNCT treatment reaction. In this study, we report on three special patients with malignant brain tumors treated with BNCT.

Synthesis, Characterization and Anti-hepatoma Activity of New Hederagenin Derivatives.

BACKGROUND: Based on the biological significance of hederagenin-type saponins found in our previous investigation, a series of new hederagenin derivatives were designed and synthesized. METHODS: Their in vitro antiproliferative activities were evaluated against the HepG2 liver cancer cell line and normal cell line L929 by MTT assay. RESULTS: The preliminary bioassay results demonstrated that all the tested compounds 1-7 showed potent anti-hepatoma activities, and some compounds exhibited better effects than 5-fluorouracil against human hepatocellular carcinoma HepG2 cell line. Furthermore, compound 5 showed a significant antihepatoma activity against HepG2 cells with an IC50 value of 1.88 µM. Besides, all of the tested compounds showed a low cytotoxic effect against the normal cell line L929. CONCLUSION: All the compounds 1-7 displayed superior selectivity against human hepatocellular carcinoma HepG2 cell line, and the results suggest that the structural modifications of C ring on the hederagenin backbone are vital for modulating anti-hepatoma activities.

Miller Fisher syndrome with early intracranial hypertension and delayed bilateral simultaneous facial nerve palsy: a case report.

Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome, is characterized by ataxia, areflexia and ophthalmoplegia. This case report describes a 40-year old male that presented with a 3-day history of unsteady walking and numbness on both hands, and a 2-day history of seeing double images and unclear articulation. Lumbar puncture revealed an opening pressure of 260 mm H2O. Plasma serology was positive for anti-ganglioside M1-immunoglobulin M (anti-GM1-IgM) antibodies and negative for anti-ganglioside Q1b (anti-GQ1b) antibodies. The patient was diagnosed with MFS based on the clinical course and neurophysiological findings. On the 4th day of treatment with intravenous immunoglobulin (IVIG), his ataxia and unsteady walking improved, but his bilateral eyeballs were fixed, and over the next few days he developed bilateral peripheral facial paralysis. After 5 days of IVIG treatment, methylprednisolone treatment was offered and the patient's symptoms gradually improved. Early intracranial hypertension and delayed facial nerve palsy may be atypical presentations of MFS. Anti-GM1-IgM antibodies may be the causative antibodies for MFS. If the IVIG therapy does not stop the progression of the disease, the addition of corticosteroid therapy may be effective. However, the relationship between IgM type, anti-GM1 antibody and MFS remains unclear and requires further research.

New 4-N-phenylaminoquinoline derivatives as antioxidant, metal chelating and cholinesterase inhibitors for Alzheimer's disease.

A series of new 4-N-phenylaminoquinoline derivatives were designed, synthesized, and their anticholinesterase activities, 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, metal-chelating ability were tested. Among them, compounds 11j, 11k and 11l had comparable inhibition activities to reference drug galantamine both in AChE and in BChE. Especially, compound 11j revealed the most potent inhibition to eeAChE and eqBChE with IC50 values of 1.20 µM and 18.52 µM, respectively. Furthermore, both kinetic analysis of AChE inhibition and molecular docking study indicated that compound 11j was mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE, and propidium iodide displacement assay showed significant displacement of propidium iodide with compound 11k (25.80%) from PAS of eeAChE. More importantly, compound 11l displayed excellent DPPH radical scavenging activity (84% at 1 mg/mL), and its EC50 value was 0.328 µM. In addition, compounds 11a, 11j, 11k and 11l exhibited obvious biometal chelating abilities toward Al3+, Fe2+, Cu2+ and Zn2+ ions. Taken together, 4-N-phenylaminoquinoline derivatives targeting multiple pathogenetic factors deserve further investigation for treatment of AD.