Design, synthesis, and antitumor mechanism investigation of iridium(III) complexes conjugated with ibuprofen.

The design and synthesis of a series of metal complexes formed by non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (IBP) and iridium(III), with the molecular formula [Ir(C^N)2bpy(4-CH2OIBP-4'-CH2OIBP)](PF6) (Ir-IBP-1, Ir-IBP-2) (C^N = 2-phenylpyridine (ppy, Ir-IBP-1), 2-(2-thienyl)pyridine (thpy, Ir-IBP-2)) was introduced in this article. Firstly, it was found that the anti-proliferative activity of these complexes was more effective than that of cisplatin. Further research showed that Ir-IBP-1 and Ir-IBP-2 can accumulate in intracellular mitochondria, thereby disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), blocking the G2/M phase of the cell cycle, and inducing cell apoptosis. In terms of protein expression, the expression of COX-2, MMP-9, NLRP3 and Caspase-1 proteins can be downregulated, indicating their ability to anti-inflammatory and overcome immune evasion. Furthermore, Ir-IBP-1 and Ir-IBP-2 can induce immunogenic cell death (ICD) by triggering the release of cell surface calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Overall, iridium(III)-IBP conjugates exhibit various anti-tumor mechanisms, including mitochondrial damage, cell cycle arrest, inflammatory suppression, and induction of ICD.

Iridium(III) complexes conjugated with naproxen exhibit potent anti-tumor activities by inducing mitochondrial damage, modulating inflammation, and enhancing immunity.

A series of Ir(III)-naproxen (NPX) conjugates with the molecular formula [Ir(C^N)2bpy(4-CH2ONPX-4'-CH2ONPX)](PF6) (Ir-NPX-1-3) were designed and synthesized, including C^N = 2-phenylpyridine (ppy, Ir-NPX-1), 2-(2-thienyl)pyridine (thpy, Ir-NPX-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, Ir-NPX-3). Cytotoxicity tests showed that Ir-NPX-1-3 exhibited excellent antitumor activity, especially in A549R cells. The cellular uptake experiment showed that the complexes were mainly localized in mitochondria, and induced apoptosis in A549R cells by damaging the structure and function of mitochondria. The main manifestations are a decrease in the mitochondrial membrane potential (MMP), an increase in reactive oxygen species (ROS) levels, and cell cycle arrest. Furthermore, Ir-NPX-1-3 could inhibit the migration and colony formation of cancer cells, demonstrating potential anti-metastatic ability. Finally, the anti-inflammatory and immunological applications of Ir-NPX-1-3 were verified. The downregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PD-L1) expression levels and the release of immunogenic cell death (ICD) related signaling molecules such as damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP)) indicate that these Ir(III) -NPX conjugates are novel ICD inducers with synergistic effects in multiple anti-tumor pathways.

F-actin/DRP1 axis-mediated mitochondrial fission promotes mitophagy in diabetic submandibular glands.

BACKGROUND: Diabetes is accompanied by a high prevalence of hyposalivation, causing severe damage to oral and systemic health. Mitochondrial dynamics play important roles in the pathogenesis of various diabetic complications; however, little is known about their roles in diabetic hyposalivation. MATERIALS AND METHODS: A diabetic mouse model and a high glucose (HG)-induced diabetic submandibular gland (SMG) cell model were employed. RESULTS: More mitochondria surrounded by autophagosomes and higher expression of mitophagy-related proteins were detected in the SMGs of diabetic mice and HG-treated SMG cells. In diabetic SMGs, dynamin-related protein 1 (DRP1) was upregulated, whereas mitofusin-2 was downregulated both in vivo and in vitro. Shortened mitochondria and impaired mitochondrial functions were observed in the HG group. A DRP1-specific inhibitor, mdivi-1, suppressed mitochondrial fission and mitophagy, as well as restored mitochondrial functions in the HG condition. Moreover, the interaction of F-actin and DRP1 was enhanced in the diabetic group. Inhibiting F-actin with cytochalasin D repaired the injured effects of HG on mitochondrial dynamics and functions. Conversely, the F-actin-polymerization-inducer jasplakinolide aggravated mitochondrial fission and dysfunction. CONCLUSIONS: F-actin contributes to HG-evoked mitochondrial fission by interacting with DRP1, which induces mitophagy and impairs mitochondrial function in SMG cells, ultimately damaging the SMG.

Cyclometalated iridium(III) complexes combined with fluconazole: antifungal activity against resistant C. albicans.

Candida albicans (C. albicans) is a ubiquitous clinical fungal pathogen. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. In this study, we synthesized a series of cyclometalated iridium(III) complexes with the formula [Ir(C-N)2(tpphz)](PF6) (C-N = 2-phenylpyridine (ppy, in Ir1), 2-(2-thienyl)pyridine (thpy, in Ir2), 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir3), tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) and polypyridyl ruthenium(II) complexes with the formula [Ru(N-N)2(tpphz)](PF6)2 (N-N = 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3)), and investigated their antifungal activities against drug-resistant C. albicans and their combination with fluconazole (FLC). Of which, the combination of the lead iridium(III) complex Ir2 and FLC showed strong antifungal activity against drug-resistant C. albicans. Mechanism studies have shown that they can inhibit the formation of hyphae and biofilm, damage mitochondrial function and accumulate intracellular ROS. Therefore, iridium(III) complexes combined with FLC can be used as a promising treatment to exert anti-drug-resistant C. albicans activity, in order to improve the treatment efficiency of fungal infection.

Multicenter epidemiological characteristics of Mycoplasma pneumoniae infection in children in Hainan Province, 2012-2020 / 中国热带医学

@#Abstract: Objective　To analyze the epidemiological characteristics (season, age, gender, mixed infection and clinical manifestations, etc.) of Mycoplasma pneumoniae (MP) infection in children in Hainan Province, so as to provide epidemiological evidence-based medical basis for the prevention and control of MP infection in children in Hainan Province. Methods　The serum IgM antibodies of MP, Legionella pneumophila, Chlamydia pneumoniae, adenovirus, respiratory syncytial virus (RSV), Q fever Rickettsia, parainfluenza virus, influenza A virus and influenza B virus in children with respiratory tract infections (RTIs) who were hospitalized in pediatrics of many hospitals in Hainan Province from March 2012 to February 2020 were detected by indirect immunofluorescence method. The positive serum MP-IgM antibody was defined as MP infection. The epidemiological and clinical data of MP infected cases were analyzed retrospectively. Results　From March, 2012 to February, 2020, a total of 35 731 qualified pediatric inpatients with RTIs in many hospitals in Hainan Province were tested for serum MP-IgM with the total positive rate of 39.12% (13 978/35 731). The yearly positive rates of MP-IgM from 2012 to 2020 were 48.39%, 56.23%, 56.62%, 47.04%, 29.71%, 24.14%, 47.55%, 36.84% and 24.46% respectively. The positive rates of MP-IgM in 2013 and 2014 were significantly higher than those in other years (P<0.05). The positive rate of MP-IgM in summer in Hainan Province was the highest (41.34%) and the lowest in winter (35.77%) (P<0.05). MP infection occurred in all age groups, the positive rate of MP-IgM in children of preschool (51.80%) was significantly higher than that in other age groups (P<0.01), and the positive rate of MP IgM in children of infancy (15.36%) was lower than that in other age groups (P<0.01). The positive rate of MP-IgM in female was 44.77%, which was significantly higher than that in male (35.83%) (P<0.05). MP infection combined with positive IgM of another pathogen accounted for 32.63% (4 561 cases), positive IgM of another two pathogens accounted for 1.26% (176 cases). MP infection was mostly found in pneumonia (68.73%), and the main clinical symptoms were cough (84.72%), fever (51.01%) and wheezing (3.16%). Conclusions　MP is an important pathogen of respiratory tract infection in children in Hainan Province, and infection is more common in children in early school age and early childhood. Mp-specific tests should be performed to identify the pathogen in children suspected of MP infection. In the high incidence season, health education should be strengthened in kindergartens, schools and other places to prevent respiratory tract infection.

Advances in N-methyl-D-aspartate Receptor Signaling Pathway and Mechanism of the Pathway-mediated Apoptosis / 中国医学科学院学报

N-methyl-D-aspartate receptor (NMDAR),an important ionic glutamate receptor and a ligand and voltage-gated ion channel characterized by complex composition and functions and wide distribution,plays a key role in the pathological and physiological process of diseases or stress states.NMDAR can mediate apoptosis through different pathways such as mitochondrial and endoplasmic reticulum damage,production of reactive oxygen species and peroxynitrite,and activation of mitogen-activated protein kinase and calpain.This paper reviews the structure,distribution,and biological characteristics of NMDAR and the mechanisms of NMDAR-mediated apoptosis.

Prevalence of Vertebral artery anomaly in upper cervical and its surgical implications: a systematic review.

BACKGROUND: The presence vertebral artery (VA) abnormalities in the upper cervical may be a potential cause of catastrophic complication in the posterior approach of the upper cervical spine surgery. The aim of this study was to demonstrate the real incidence of the V3 segment anomaly in patients who need upper cervical surgery, and tried to find out the risk factors of V3 segment anomaly to evaluate the necessary of computed tomographic angiography (CTA) for upper cervical surgery. METHOD: This systematic review was conducted following the preferred reporting items for systematic reviews and meta-Analyses (PRISMA). Retrospective studies and reports of case series involving human subjects with data on anomalies of vertebral artery in upper cervical spine were included. Data on the prevalence of persistent first intersegmental artery (PIA), fenestration of the VA (FA), posterior inferior cerebellar artery (PICA) were extracted. RESULTS: A total of 16 articles involving 5927 subjects met the inclusion criteria. The total incidence of V3 segment anomaly in the patients with bony abnormalities was 25.9% (74/286): PIA was 17.5%, FA was 6.6% and PICA was 1.8%. The total incidence of V3 segment anomaly in the patients without bony abnormalities was 2.7% (152/5671): PIA was 1.76%, FA was 0.4% and PICA was 0.5%. The total incidence of V3 segment anomaly in Asian population without bony abnormalities was 5.8%, while in European and American population was 0.8 and 0.6%, respectively. CONCLUSION: Patients with bone abnormalities are high risk factor for VA abnormalities, CTA is of paramount importance to evaluate the variant VA anatomy. However, regarding to the low incidence of V3 variation in normal population, we do not recommend preoperative CT angiography as mandatory part of preoperative.

Shexiang Tongxin Dropping Pill () Reduces Coronary Microembolization in Rats via Regulation of Mitochondrial Permeability Transition Pore Opening and AKT-GSK3ß Phosphorylation.

OBJECTIVE: To investigate the protective effects of Shexiang Tongxin Dropping Pill (, STDP) following sodium laurate-induced coronary microembolization (CME) in rats. METHODS: Forty rats were divided into 4 groups: the control (sham) group, CME group, low-dose STDP pretreatment group (20 mg·kg-1·d-1), and high-dose STDP pretreatment group (40 mg·kg-1·d-1). The rats were intragastric administrated with STDP 2 weeks before operation. Moreover, the histopathological alterations were observed using optical microscopy and transmission electron microscopy. Antioxidant biomarkers were analyzed by enzyme-linked immunosorbent assay. Mitochondrial functions including the mitochondrial permeability transition pore (mPTP) mtDNA copy number were determined and proteins of AKT/GSK3ß were analyzed by Western blot. RESULTS: The rats in the CME group showed a significant increase in the fibrinogen-like protein 2 expression level and mitochondrial dysfunction and a decrease in the expression level of antioxidant biomarkers (superoxide dismutase and catalase, P<0.01 for all). In contrast, the rats in the low- and high-dose STDP pretreatment groups showed a significant decrease in coronary microthrombi (P<0.05); moreover, STDP restored the antioxidant-related protein activities and mitochondrial function, inhibited mPTP opening, decreased AKT-Ser473 phosphorylation, and increased GSK3ß-Ser9 phosphorylation (P<0.05 or P<0.01). CONCLUSION: STDP may be useful for treatment of CME, possibly via regulation of mPTP opening and AKT/GSK3ß phosphorylation.

[Study on quality standard of Bufonis Venenum and its processed slice, toad venom powder].

Bufonis Venenum(toad venom) is prepared from the dried secretion of Bufo bufo gargarizans or B. melanostictus. Toad venom powder is one of the processed slices of crude material toad venom. In the present study, the global quality control method and standard of toad venom and its processed slice, toad venom powder were established, including TLC identification, characteristic chromatogram and QAMS by HPLC. The relative correction factor(RCF) was re-calculated and validated. The average RCFs of cinobufagin to gamabufotalin, bufotalin, bufalin and resibufogenin were considered for the determination of five bufadienolides in the samples. The total amount in the different batches of the dried samples varied from 4.06% to 17.0%. Referring to the revised methods for crude materials, the quality standard of toad venom powder was drafted including appearance description, TLC examination, characteristic chromatogram, water content and the total amount of five bufadienolides. The present investigation provided scientific evidences for the quality standard improvement of toad venom to be described in the next edition of Chinese pharmacopoeia(2020 edition).

[Determination of five steroidal saponins in Paridis Rhizoma and its adulterants as well as consideration on its quantitative method described in Chinese Pharmacopoeia (2015 edition)].

Paridis Rhizoma is prepared from the dried rhizoma of Paris polyphylla var. yunnanensis or P. polyphylla var. chinensis. For the improvement of the quality standard of Paridis Rhizoma described in Chinese Pharmacopoeia(2015 edition), it is proposed that the quality marker no longer contains polyphyllin Ⅵ, and instead, polyphyllin H is an alternative for the quantitative analysis. To determine polyphyllin Ⅰ, Ⅱ, H and Ⅶ in the Paridis Rhizoma samples collected from the different growing area in China, HPLC method was established using the same chromatographic conditions as those for simultaneous determination of polyphyllin Ⅰ, Ⅱ, Ⅵ and Ⅶ described in Chinese Pharmacopoeia(2015 edition). The methodology validation indicated that there was a good linearity among the ranges of 0.006 48-0.828, 0.006 52-0.834, 0.006 17-0.790, 0.006 31-0.808 g·L~(-1) for polyphyllin Ⅰ, Ⅱ, H and Ⅶ, respectively. The average recoveries of four components were 100.2%-101.4%, with RSD less than 3.5%. The total amount of polyphyllin Ⅰ, Ⅱ, H and Ⅶ in the analyzed samples of P. polyphylla var. chinensis and P. polyphylla var. yunnanensis ranged from 0.050 9% to 3.99% and from 0.115% to 3.23%, respectively. In the tested samples collected from other Paris plants, there are high content of steroidal saponins in the samples of P. fargesii and P. forrestii, low content in the samples of P. polyphylla var. stenophylla, P. delavayi and P. thibetica, and almost not occurrence in the sample of P. mairei. As a representative adulterant of Paridis Rhizoma processed slices, 7 batches of Trillium samples contained high amount of polyphyllin Ⅵ and did not have polyphyllin H. Based on the present investigation, it is recommended that polyphyllin H together with polyphyllin Ⅰ, Ⅱ and Ⅶ are suitable for the improvement of quality standard of Paridis Rhizoma and the total amount of four components are not less than 0.80%.

[Study on revision of quality standard of Sophorae Flavescentis Radix and its processed slices].

Sophorae Flavescentis Radix is prepared from the root of Sophora flavescens. The comprehensive knowledge of the effective components in S. flavescens makes its quality standard improvement more possible. TLC identification method for main flavonoids and alkaloids in one test was established using GF_(254) thin layer plate and the lower solution of chloroform-methanol-water-formic acid(4∶2∶1∶0.6) as developing solvent. The quantitative method of marker alkaloids was revised including the simplified sample preparation procedure and the chromatographic conditions. The determination of four alkaloids in the samples indicated that 32 batches of tested samples were qualified ones. The total oxymatrine and matrine, total oxysophocarpine and sophocarpine, as well as total amount of four tested components in the different samples were 1.08%-2.55%, 0.369%-0.860%, 1.67%-3.40%, respectively. There was a significantly positive correlation between oxymatrine and oxysophocarpine. Total oxymatrine and matrine had same correlation with total oxysophocarpine and sophocarpine. The moisture content and extractive in 32 batches of samples fulfilled the require of not more than 11.0% and not less than 20.0%, respectively. Thirteen tested pesticides were not detected in 12 batches of samples. The present study provided the evidence for the revision of quality standard of Sophora Flavescentis Radix.

[Analysis and structural identification of relevant substances in Breviscapine for Injection].

To define the composition of relevant substances in Breviscapine for Injection, in order to improve the quality control of impurity, and ensure the clinical safety. The analysis and structural identification of relevant substances in different specifications and batches of Breviscapine for Injection powders were carried out by HPLC and UPLC-QTOF-MS. Three primary relevant substances, namely 5,6,7,3',4'-pentahydroxyflavone-7-O-glucuronide(3), 3,5,6,7,4'-pentahydroxyflavone-3-O-glucuronide(4) and scutellarein(10), as well as three minor impurities, namely 6-hydroxyapigenin-6-O-glucosyl-7-O-glucuronide(1), methoxylscutellarin(6) and apigenin-7-O-glucuronide(7) were structurally identified by matching retention time, UV spectra, and mass spectra with authentic compounds and MS fragmentation rules. The main relevant substances(3) and(4) were separated and purified by semi-preparative HPLC, and their structures were further confirmed by NMR data. The study defined relevant substances of Breviscapine for Injection, and provided reference for improving the quality control level of single impurity in breviscapine preparation.

Meta-analysis of Influencing Factors ofF-Fluorodeoxyglucose Uptake of Brown Adipose Tissue in PET/CT Imaging / 中国医学科学院学报

Objective To explore the influencing factors ofF-Fluorodeoxyglucose(F-FDG) uptake of brown adipose tissue(BAT) in PET/CT imaging by performing meta-analysis.Methods Relevant articles published between 1980 and 2016 were searched in PubMed,EMBASE,Web of Science,CBM,WanFang Data,CNKI,and VIP.The factors of gender,season and age were extracted according to the inclusive criteria.Meta-analysis was performed to analyze the factors.Results The merger OR value and 95% CI ofF-FDG uptake of BAT with gender,age,season were 2.67 (2.30-3.11),2.17 (1.38-3.39),and 15.35 (4.72-49.95) respectively.TheF-FDG uptake rate of BAT was 2.16 times in females as that in males,8.67 times in the minors as that in the adults,and 1.94 times in winter as that in summer.Conclusion Gender,season,and age are risk factors forF-FDG uptake of BAT.

Infralimbic Endothelin1 Is Critical for the Modulation of Anxiety-Like Behaviors.

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.

Scientific Evaluation of TCM Clinical Outcomes Rating Scale for Heart Failure Based on Patients Report / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To evaluate the reliability, validity, and responsiveness of traditional Chinese medicine (TCM) clinical outcomes rating scale for heart failure (HF) based on patients' report.</p><p><b>METHODS</b>TCM clinical outcomes rating scale for HF (TCM-HF-PRO) were evaluated based on 340 HF patients' report from multiple centers. The completion of the investigation was recorded. Cronbach's α coefficient and split-half reliability were used for reliability analysis, and factor analysis was used to assess the construct validity of the rating scale. Pearson correlation analysis was then used for criterion validity analysis. Discriminant analysis was used to assess the responsiveness of the scale. All 340 HF patients having complete TCM-HF-PRO data were assigned to the treatment group and the control group by central randomization. The total TCM-HF-PRO scores of the two groups were compared using paired t-test to reflect the longitude responsiveness of the scale before treatment and at week 2 after treatment.</p><p><b>RESULTS</b>(1) The recycling rate of the scale was 100.0%. One of them was not filled completely, which was rejected thereby. So the completion rate was 99.7%. The completion time for TCM-HF-PRO scale ranged 15 to 25 min. (2) The Cronbach's α coefficient of rating scale was 0.903, split-half reliability was 0.844 and 0.849. (3) Confirmatory factor analysis showed that 7 factors and items formed according to maximum load factor basically coincided with the construct of the rating scale, 7 factors accumulated contribution rate was 43.8%. TCM clinical outcomes rating scale for HF based on patients' report was relatively better correlated with the Minnesota living with HF questionnaire (r = 0.726, P < 0.01). (4) Discriminant analysis showed that the rating scale correctly classified more than 78.8% of case studies having confirmed initial differential diagnosis by experts. The total scale of the rating scale decreased more in the two group after treatment, with significant difference as compared with before treatment (P < 0.01.</p><p><b>CONCLUSION</b>TCM clinical outcomes rating scale for HF based on patients' report had good reliability, validity and responsiveness, hence it could be used to assess clinical efficacy for HF patients.</p>

Analysis of Medication Laws for Chinese Medicine Treating Hypertension Patients with Yin Defi- ciency Yang Hyperactivity Syndrome Based on Literatures / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To analyze medication laws of Chinese medicine (CM) treatment in hypertension patients with yin deficiency yang hyperactivity syndrome.</p><p><b>METHODS</b>China National Knowledge Infrastructure (CNKI, Jan. 1979-Dec 2014), Chinese Scientific Journals Database (VIP, Jan 1989-Dec2014), Chinese Biomedical Literature Database (CBM, Jan.1978-Dec.2014), Wanfang Database (Jan 1990-Dec 2014) were retrieved by using "hypertension", "CM", "Chinese herbs", "syndrome" as keywords. Totally 149 literatures concerning CM treatment for hypertension patients with yin deficiency yanghyperactivity syndrome were included in this study. The herbs database was established by SPSS20.0,and correlation laws were analyzed by SAS9.3. With the Pajek3.1, results were presented visually withcomplex networks.</p><p><b>RESULTS</b>There were 149 literatures including 131 kinds of herbs with 1,598 frequencies. The conventional compatibility program of herbs for asthenic yin and predominant yang syndrome of hypertension were two toothed achyranthes root, tall gastrodia rhizome, Cassia obtusifolia L., eucommiabark, baikal skullcap root, and so on, about 29 kinds. Of them, core herbs were two toothed achyranthes root, tall gastrodia rhizome, Cassia obtusifolia L., poria, prepared rhizome of rehmannia, oriental water-plantain tuber, asiatic cornelian cherry fruit, Uncariae Rhynchophylla, common yam rhizome, the rootbark of the peony tree, and so on.</p><p><b>CONCLUSION</b>Medication laws of CM treatment in hypertension patientswith yin deficiency yang hyperactivity syndrome obtained by analysis of complex networks reflected thetherapeutics of nourishing yin to suppress yang, which could further provide reference for clinical studies.</p>

Immunogenicity of intradermal trivalent influenza vaccine with topical imiquimod: a double blind randomized controlled trial.

BACKGROUND: Imiquimod, a synthetic Toll-like receptor 7 agonist enhanced immunogenicity of influenza vaccine in a mouse model. We hypothesized that topical imiquimod before intradermal influenza vaccination (TIV) would produce similar effect in human. METHODS: We performed a prospective 1-year follow-up, double-blind, randomized, controlled trial with adults with comorbidities. Participants were randomized to 1 of the following 3 vaccinations: topical 5% 250 mg imiquimod ointment followed by intradermal TIV, topical aqueous-cream followed by intradermal TIV, or topical aqueous-cream followed by intramuscular TIV. Patients and investigators were blinded to the type of topical treatment applied. Hemagglutination inhibition (HI) and microneutralization antibody titers were measured. The primary outcome was the day 7 seroconversion rate. RESULTS: Ninety-one recruited participants completed the study. The median age was 73 years. On day 7, 27/30 (90%) patients who received imiquimod and intradermal TIV achieved seroconversion against the H1N1 strain by HI, compared with 4/30 (13.3%) who received aqueous-cream and intramuscular TIV (P < .001), and 12/31 (38.7%) who received aqueous-cream and intradermal TIV (P < .001). The seroconversion, seroprotection, and geometric mean titer-fold increase were met in all 3 strains in the imiquimod and intradermal TIV group 2 weeks earlier, and the better seroconversion rate was sustained from day 7 to year 1 (P ≤ .001). The better immunogenicity was associated with fewer hospitalizations for influenza or pneumonia (P < .05). All adverse reactions were self-limited. CONCLUSIONS: Pretreatment with topical imiquimod significantly expedited, augmented, and prolonged the immunogenicity of influenza vaccination. This strategy for influenza immunization should be considered for the elderly population.

Toll-like receptor 7 agonist imiquimod in combination with influenza vaccine expedites and augments humoral immune responses against influenza A(H1N1)pdm09 virus infection in BALB/c mice.

Toll-like receptors (TLRs) of the innate immune system are known targets for enhancing vaccine efficacy. We investigated whether imiquimod, a synthetic TLR7 agonist, can expedite the immune response against influenza virus infection when combined with influenza vaccine. BALB/c mice were immunized intraperitoneally with monovalent A(H1N1)pdm09 vaccine combined with imiquimod (VCI) prior to intranasal inoculation with a lethal dose of mouse-adapted A(H1N1)pdm09 virus. For mice immunized 3 days before infection, the survival rates were significantly higher in the VCI group (60%, mean survival time[MST], 11 days) than in the vaccine-alone (30%; MST, 8.8 days), imiquimod-alone (5%; MST, 8.4 days), and phosphate-buffered saline (PBS) (0%; MST, 6.2 days) groups (P < 0.01). In the VCI group, 45 and 35% of the mice survived even when they were infected 2 days or 1 day after immunization. Virus-specific serum IgM, IgG, and neutralizing antibodies appeared earlier with higher geometric mean titers in the VCI group than in the control groups. The pulmonary viral load was significantly lower at all time points postinfection in the VCI, vaccine-alone, and imiquimod-alone groups than in the PBS control group (P < 0.05). The protection induced by VCI was specific for A(H1N1)pdm09 virus but not for A(H5N1) virus. Since imiquimod combined with RNase-treated vaccine is as protective as imiquimod combined with untreated vaccine, mechanisms other than TLR7 may operate in expediting and augmenting immune protection. Moreover, increased gamma interferon mRNA expression and IgG isotype switching, which are markers of the Th1 response induced by imiquimod, were not apparent in our mouse model. The mechanisms of imiquimod-induced immune protection deserve further study.

Anatomic investigation of the pedicle fat grafts with the third lumbar segmental artery and its application in reoperation for lumbar disc herniation / 中国骨伤

<p><b>OBJECTIVE</b>To investigate the blood supply of the pedicle fat grafts with the third lumbar segmental artery and its clinical effects on reoperation for lumbar disc herniation.</p><p><b>METHODS</b>Twelve sides of 6 adult cadaver examples were contributed to investigate the courser of lumbar segmental vessels and the distribution of hypodermic capillary net of the dorsal branch of the third lumbar segmental artery. From January 2000 to January 2007,49 patients needed reoperation to treat lumbar disc herniation,including 26 males and 23 females with an average age of 55.6 years (ranged from 39 to 70 years). Duration between two operations ranged from 8 months to 15 years with an average of 6.9 years. Reoperative reasons included recurrent lumbar disc protrusion(30 cases)postoperative epidural scar formation (17 cases), postoperative epidural cyst formation (2 cases). Of them,9 patients underwent posterior lumbar interbody fusion at the second operation. The pedicle fat grafts with the third lumbar segmental artery were covered on the sites of the laminectomy in these patients. After negative pressure drainage tube were pulled out, 2 ml Chitsan were injected to the sites of the laminectomy and around epidural nerve root through epidural catheter. VAS score and the Oswestry Disability Index (ODI) were used to assess clinical outcomes before and after operation.</p><p><b>RESULTS</b>The courser of third lumbar segmental vessels were invariant at the lateral face of the lumbar vertebral body. The dorsal branch of the third lumbar segmental artery penetrated thoracolumbar fascia and formed rich hypodermic capillary net in the region. All patients were followed up from 5 to 8 years with an average of 5.6 years. VAS score of low back pain and leg pain decreased respectively from preoperative 7.6 +/- 1.2, 8.9 +/- 0.9 to 3.6 +/- 0.5, 3.0 +/- 0.4 at final follow-up (P < 0.01); and ODI score decreased from preoperative 44.1 +/- 6.2 to 13.9 +/- 3.6 at final follow-up (P < 0.01). According to ODI score to evaluate the clinical outcomes, 29 cases got excellent results, 11 good, 7 fair, 2 poor.</p><p><b>CONCLUSION</b>The pedicle fat grafts with the third lumbar segmental artery and Chitsan can reduce epidural scar formation and prevent peridural fibrosis and adhesion and improve clinical effects of reoperation for lumbar disc herniation.</p>

Prognostic value of PSA kinetics in locally advanced prostate cancer treated by maximal androgen blockade combined with brachytherapy / 中华男科学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of post-treatment PSA kinetics on the prognosis of prostate cancer (PCa).</p><p><b>METHODS</b>We retrospectively reviewed the clinical data of 114 cases of locally advanced PCa treated by maximal androgen blockade (MAB) combined with brachytherapy, and analyzed the association of the changes in PSA kinetics with the prognosis of the patients.</p><p><b>RESULTS</b>The median survival time of the patients was 81 (15 - 144) months, with 1-, 3- and 5-year survival rates of 91. 23%, 78.07% and 68.42% , respectively. Univariate analysis indicated that the baseline PSA level, PSA nadir, the time of PSA decreasing to nadir, PSA doubling time, and the extent of PSA declining were all predictive factors for the survival time of the PCa patients. Multivariate analysis demonstrated that PSA nadir, the time of PSA decreasing to nadir, and the extent of PSA declining were three independent prognostic factors, which prolonged the long-term survival of the patients by 1.7, 3.2 and 6.8 times, respectively.</p><p><b>CONCLUSION</b>For locally advanced PCa treated by MAB combined with brachytherapy, PSA nadir <1 micro g/L, the time to nadir <3 months, and the extent of PSA declining >96% are independent prognostic factors.</p>