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Background This study aimed to describe the burden of community-acquired acute kidney injury (AKI) in China based on a nationwide survey about AKI. Study Design Cross-sectional and retrospective study. Setting & Participants A national sample of 2,223,230 hospitalized adult patients from 44 academic/local hospitals in Mainland China was used. AKI was defined according to the 2012 KDIGO AKI creatinine criteria or an increase or decrease in serum creatinine level of 50% during the hospital stay. Community-acquired AKI was identified when a patient had AKI that could be defined at hospital admission. Predictors The rate, cause, recognition, and treatment of community-acquired AKI were stratified according to hospital type, latitude, and economic development of the regions in which the patients were admitted. Outcomes All-cause in-hospital mortality and recovery of kidney function at hospital discharge. Results 4,136 patients with community-acquired AKI were identified during the 2 single-month snapshots (January 2013 and July 2013). Of these, 2,020 (48.8%) had cases related to decreased kidney perfusion; 1,111 (26.9%), to intrinsic kidney disease; and 499 (12.1%), to urinary tract obstruction. In the north versus the south, more patients were exposed to nephrotoxins or had urinary tract obstructions. 536 (13.0%) patients with community-acquired AKI had indications for renal replacement therapy (RRT), but only 347 (64.7%) of them received RRT. Rates of timely diagnosis and appropriate use of RRT were higher in regions with higher per capita gross domestic product. All-cause in-hospital mortality was 7.3% (295 of 4,068). Delayed AKI recognition and being located in northern China were independent risk factors for in-hospital mortality, and referral to nephrology providers was an independent protective factor. Limitations Possible misclassification of AKI and community-acquired AKI due to nonstandard definitions and missing data for serum creatinine. Conclusions The features of community-acquired AKI varied substantially in different regions of China and were closely linked to the environment, economy, and medical resources.

BackgroundDepression is a major debilitating psychiatric disorder. Current antidepressant drugs are often associated with side effects or treatment resistance. The aim of this meta-analysis was to evaluate therapeutic effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in major depression (MD).MethodsThe medical data bases of PubMed, Medline, Embase and Cochrane Central Register were searched for randomized controlled trials (RCTs) reporting the therapeutic effects of high-frequency rTMS for depression, which were published in English between January 1990 and June 2016. The index terms were “depress*”, “depression” and “transcranial magnetic stimulation”. Depression outcome data of different sessions (5, 10, 15, and 20 sessions of rTMS treatment) were extracted and synthesized by calculating standardized mean difference (SMD) with 95% confidence intervals (CI) by using a random-effect model. Within each session group, the subgroup analyses based on the number of pulses (≤ 1000, 1200–1500, 1600–1800, and 2000–3000) were also conducted.ResultsThirty RCTs with a total of 1754 subjects including 1136 in the rTMS group and 618 in the sham group were included in this meta-analysis. rTMS had a significant overall therapeutic effect on depression severity scores (SMD = −0.73, P < 0.00001). The five, 10, 15, 20 sessions of rTMS treatments yielded the significant mean effect sizes of −0.43, −0.60, −1.13, and −2.74, respectively. In the four groups (5, 10, 15, 20 sessions), the maximal mean effect size was all obtained in the subgroup of 1200–1500 pulses per day (−0.97, −1.14, −1.91, −5.47; P < 0.05).ConclusionsThe increasing of HF-rTMS sessions is associated with the increased efficacy of HF-rTMS in reducing depressed patients’ symptom severity. A total number of pulses of 1200–1500 per day appear to deliver the best antidepressant effects of HF-rTMS.

Objective This study aims to determine whether fetal meconium passage is associated with autism. Study design This retrospective birth cohort analysis of 9 945 896 children born in California 1991 to 2008 linked discharge diagnosis and procedure codes for prenatal stressors, meconium-stained amniotic fluid (MSAF) and meconium aspiration syndrome (MAS) with autism diagnoses for 47 277 children through 2012. We assessed the relative risk of autism by meconium status using logistic regression, adjusting for demographic and clinical features. Results Children exposed to meconium (MSAF and MAS) were more likely to be diagnosed with autism in comparison with unexposed children (0.60% and 0.52%, vs 0.47%, respectively). In adjusted analyses, there was a small increase in autism risk associated with MSAF exposure (adjusted relative risk (aRR) 1.18, 95% confidence interval (CI) 1.12 to 1.25), and a marginal association that failed to achieve significance between MAS and autism (aRR 1.08, 95% CI 0.98 to 1.20). Conclusion Resuscitation of neonates with respiratory compromise from in utero meconium exposure may mitigate long-term neurodevelopmental damage.

Badiranji Buya Keli (BBK) is a traditional Uyghur medicine derived from Dracocephalum Moldavica Herba (DMH, the aerial part of Dracocephalum moldavica L.). BBK has been widely used in treating cardiovascular and cerebrovascular diseases. Here, the quality control of BBK was established by using HPLC analysis of rosmarinic acid and tilianin. After chemical standardization, the biological effects of BBK was tested. First, BBK inhibited platelet aggregation of rabbit plasma. Second, BBK induced vasodilation in rat aortic ring, and this effect was partially mediated by nitric oxide (NO) production in endothelial cells. Third, BBK induced NO production in cultured human umbilical vein endothelial cells (HUVECs). In HUVECs, the phosphorylation of endothelial NO synthase (eNOS) was markedly increased after application of BBK. Pre-treatment with the eNOS blocker N(ω) -nitro-l-arginine methyl ester hydrochloride could abolish BBK-induced NO production and eNOS phosphorylation. Taken together, these results suggest that BBK could exert beneficial effects in cardiovascular system, which may provide parts of molecular explanation to account for its traditional usage in Uyghur medicine.

The study aimed to investigate the bio-distribution and radio-immuno-imaging features of [(131)I]-herceptin in nude mice with BT-474 breast carcinoma. [(131)I]-Herceptin was administrated by tail intravenous injection to the nude mice with BT-474 breast carcinoma. Radiocounting was performed at 4, 12, 24, 48, and 96 h after administration. The activity ratio in the tumor tissue and non-tumor tissue (T/NT) and the radiocounting percentage per gram tissue to the injected dose (%ID/g) were calculated. The nude mice with BT-474 breast carcinoma were also visualized continuously by single photon emission computed tomography at 2, 4, 8, 12, 24, 48, and 96 h after the injection of [(131)I]-herceptin. Nude mice with MDA-MB-231 used as the control group were subjected to the same analyses. Clear tumor images were obtained after the injection of [(131)I]-herceptin in nude mice with BT-474 breast carcinoma. The images were the clearest at 24 h after the injection and remained clear even at 96 h. The T/NT ratio and %ID/g in the tumor tissues of nude mice with BT-474 were both significantly higher than those of the control group (P < 0.01). [(131)I]-Herceptin displays tumors clearly in the nude mice with BT-474 and accumulates well in the tumor tissues.

β-amyloid peptides (Aβs) can exert neurotoxic effects through induction of oxidative damage, whereas lipoic acid (LA), a powerful antioxidant, can alleviate oxidative damage. In this study, we explored the effect and mechanism of action of LA on beta-amyloid-intoxicated C6 glioma cells. Cells were randomly divided into three groups: control (vehicle), Aβ, and LA + Aβ. The LA + Aβ group was treated with LA for 2 h, then both the Aβ-only and the LA + Aβ groups were incubated with 25 μM Aβ for 24 h. Cell viability was measured by the MTT method. Mitochondrial reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were detected by enzyme-linked immunosorbent assay (ELISA), and the GSH to GSSG ratio calculated. Real-time polymerase chain reaction and western blot analyses were used to detect MnSOD mRNA and protein, respectively. Aβ significantly inhibited C6 cell proliferation compared with the control group (P < 0.05). LA markedly increased cell viability compared with the Aβ group (P < 0.05). The increased GSSH and decreased GSH mitochondrial accumulation induced by Aβ was profoundly reversed by treatment with LA (P < 0.05). Aβ significantly reduced MnSOD expression compared to controls (P < 0.05), whereas LA pretreatment increased MnSOD expression compared with the Aβ-only group (P < 0.05); MnSOD protein levels showed similar patterns. These results suggest that LA might protect Aβ-intoxicated C6 glioma cells by alleviating oxidative damage, providing a new treatment strategy for neurodegenerative diseases.

Background:Arthroscopy has become a standard method of treatment for a variety of intra-articular hip disorders. While most arthroscopic hip procedures are performed as outpatient surgeries, patients can still experience significant postoperative pain and opioid-associated side effects.Purpose:The potential benefits of a preoperative femoral nerve block (FNB) in hip arthroscopy were explored in a previous retrospective review. The study objective was to confirm these findings in a prospective randomized study.Study Design:Randomized controlled trial; Level of evidence, 1.Methods:Fifty patients undergoing hip arthroscopy were included in this prospective, single-center, randomized controlled trial that was patient-, operator-, and assessor-blinded. Patients received either a preoperative ultrasound-guided FNB with 20 mL of 0.5% bupivacaine (FNB group) or normal saline (control group). Nerve blockade was confirmed via standardized sensory testing before the induction of general anesthesia. The primary endpoint was cumulative consumption of oral morphine equivalent at 24 hours after discharge. Secondary endpoints included opioid use at various time points, pain scores, Quality of Recovery (QoR-27) score, incidence of nausea and vomiting, time to discharge, block-related complications, falls at 24 hours, and patient satisfaction.Results:Fifty patients completed the study, including 27 in the FNB group and 23 in the control group. Most patient characteristics were statistically similar between groups except for operative time, which was longer in the control group. Cumulative oral morphine consumption was lower in the FNB group at 48 hours; there was no difference at 24 hours or 7 days postoperatively. Pain scores were significantly lower up to 6 hours postoperatively in the FNB group compared with control; however, rebound pain was observed at 24 hours after discharge in patients who received FNB. There was no difference in most secondary outcomes. Importantly, a total of 6 patients in the FNB group reported falls (without injury) within the first 24 hours postoperatively compared with none in the control group. Patient satisfaction with pain control was high in both groups at all time points.Conclusion:Preoperative FNB may improve early pain control after hip arthroscopy. However, given the observed risk of falls, the routine use of FNB for outpatient hip arthroscopy cannot be recommended.

Substantial evidence exists for a cohort effect (earlier onset and increased prevalence) for both unipolar and bipolar affective disorder in every generation born since World War II. This effect could be related to inherited mechanisms (e.g., bi-Hneal pedigrees or genetic anticipation) or to environmental/experiential effects on gene expression (e.g., stressor effects on the induction of transcription and growth factors, enzymes, hormones and their receptors, and signal transduction molecules) as documented in preclinical models of neonatal maternal separation.This laboratory evidence is summarized and new clinical data on the impact of severe stressors on the unfolding course of bipolar illness are noted. The reported occurrence of childhood or adolescent physical or sexual abuse, compared to those who report their absence, is associated with: earlier bipolar illness onset; faster cycling (including ultradian) patterns; increased Axis I and II comorbidities; and increased time ill in a prospective year of follow-up. Selectively, physical abuse was associated with a reported pattern of increasingly severe mania and sexual abuse with increased numbers of serious suicide attempts.In a retrospective survey of parents of children with an approximate average age of 13 who were diagnosed with bipolar illness (compared to those with other diagnoses and those with no diagnosis), a cluster of symptoms related to irritability and dyscontrol differentiated the bipolar children earliest. These symptoms included: temper tantrums, irritability, inattention, hyperactivity, impulsivity, poor frustration tolerance, and increased aggression.Given the growing evidence that episodes of affective dysfunction can not only convey morbidity and mortality, but may also sensitize to further recurrence and thus change the course of illness, opportunities abound for early recognition and intervention in childhood onset bipolar illness. Such a successful endeavor would both allow a more normal psychobiological development and allow the possibility of preventing the unfolding of more full-blown bipolar illness altogether.

During chronic pain states, peripheral nociceptive stimulation can induce long-term potentiation (LTP) in the spinal dorsal horn, but it is not clear how quickly spinal LTP develops after peripheral noxious stimulation. Furthermore, transient receptor potential vanilloid type 1 (TRPV1) receptors are abundant in spinal cord dorsal horn, especially in the superficial layers, and are thought to be involved in synaptic plasticity. In this study, we investigated the time frame of LTP induction after inflammatory insult and electrical stimulation and the involvement of TRPV1 receptors. By using extracellular recordings of C-fiber-evoked field potentials in the superficial spinal dorsal horn and teased fiber recording in vivo, we found that subcutaneous injection of complete Freund's adjuvant (CFA) or 5% formalin induced low-frequency, irregular discharges of C-fibers and LTP of the C-fiber-evoked field potentials in the spinal dorsal horn within 3h. Topical application of the TRPV1 receptor antagonist capsazepine onto the spinal cord inhibited the induction of spinal LTP by CFA or formalin. Furthermore, capsazepine and another TRPV1 antagonist, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide, partially or completely blocked the LTP induced by conditioning stimulation with high- and low-frequency electrical stimulation. These results suggest that acute peripheral inflammatory stimulation by CFA or 5% formalin can induce spinal LTP very early after stimulation onset and that TRPV1 receptors in the spinal dorsal horn might contribute to this LTP induction.

To analyze the effect of Argon-Helium cryosurgery (AHCS) combined with transcatheter renal arterial embolization (TRAE) on the differentiation of regulatory CD4+ CD25+ T cell (Treg) and its implication in patients with renal carcinoma.Seventy seven patients are included in the study, and divided into two groups: TRAE group (n=45, receiving TRAE only) and TRAE+cryoablation group (n=32, receiving cryoablation 2-3 weeks after TRAE). The percentage of Treg cells and T lymphocyte subsets (CD4+T, CD8+T, and CD4+T/CD8+T) in the peripheral blood is measured by flow cytometry previous to the therapy and 3 months after therapy. Meanwhile, the extent of tumor necrosis is measured by MRI or CT 1 month after therapy.The percentages of Treg cells of patients in TRAE + cryoablation group decrease from (6.65±1.22)% to (3.93±1.16)%, (t=42.768, P0.01), and the percentages of CD4+T and CD4+T/CD8+T increase significantly (P0.01). However, the results of patients in TRAE group show that the percentages of Treg, CD4+T, CD8+T and CD4+T/CD8+T increase slightly although the differences had no statistical significance (P0.05). The tumor necrosis rate of TRAE+cryoablation group is 57.5%, significantly higher than those of TRAE group, which shows 31.6% (t=6.784, P0.01). The median survival duration of the TRAE+cryoablation group is 20 months, significantly longer than that of the TRAE group (χ² = 7.368, P0.01). The decreasing extent of Treg cells is correlated with tumor necrosis rates (r=0.90, P0.01) and life time (r=0.67, P0.01).The therapy of TRAE combined with cryoablation contributes to reduce the percentage of Treg cells and improve the immune situation of patients with renal cell carcinoma, which consequently increase tumor necrosis rate and prolong the patients' survival duration.

Dysregulation of cellular signaling pathways can lead to colon cancer. However, research on the key signaling effectors or regulators in colon carcinogenesis is limited. Casein kinase-2 interacting protein-1 (CKIP-1; also known as PLEKHO1) is crucial during adult bone formation and is a promising drug target for osteoporosis therapy. In this study, we observed that CKIP-1 was downregulated in human colon cancer tissues and colon cancer cell lines, and this result was correlated with colon cancer progression. CKIP-1 silencing in colon cancers involved promoter methylation. In colon cancer HCT116 and SW480 cells, CKIP-1 overexpression inhibited cell growth and migration. CKIP-1 also suppressed in-vivo tumor formation. Notably, the growth-suppressive role of CKIP-1 was dependent on the downregulation of the cell cycle-regulated oncogene Smad ubiquitylation regulatory factor-1 (Smurf1). During cell cycle progression, phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling increased Smurf1 production by an mTOR-dependent translational control mechanism. Rapamycin, the mTOR inhibitor, significantly reduced Smurf1 protein levels, and Smurf1 was degraded in mitosis. In colon cancer, CKIP-1 controlled Smurf1 expression by suppressing PI3K/Akt/mTOR signaling and enhancing Smurf1 autodegradation, and CKIP-1 downregulation was correlated with Smurf1 upregulation in colon carcinogenesis. These findings provide novel insight into the mechanisms of the candidate tumor suppressor CKIP-1.

Objectives: : Arthroscopy has become a standard method of treatment for a variety of intra-articular hip pathologies. While most arthroscopic hip procedures are performed as day-surgeries, patients can still experience significant post-operative pain and opioid-associated side-effects. Our group has shown the potential benefits of preoperative femoral nerve block (FNB) in a previous retrospective review. It was our objective to confirm these findings in a prospective study. Methods: Fifty patients undergoing hip arthroscopy were included in this prospective, single centre, double-blinded, randomized controlled trial. All patients received a pre-operative ultrasound-guided femoral nerve block with either 20 mL of 0.5% bupivacaine (treatment group, n=27) or normal saline (control group, n=23). Nerve blockade was confirmed via standardized sensory testing prior to the induction of general anaesthesia. Groups were compared with respect to patient sex, age, body mass index (BMI), physical status classification according to the American Society of Anaesthesiologists (ASA); procedure performed; and opioid requirements. The primary endpoint was total oral morphine equivalent consumption in 24 hours. Secondary endpoints included visual analog pain scores; Quality of Recovery (QoR-27) score at 24 hours; incidence of nausea and vomiting; patient satisfaction; and block-related complications. Results: There were no significant differences between groups with respect to sex, age, weight, height, BMI, ASA classification, or type of procedures performed. Total oral morphine consumption at 24 hours was similar between groups. Patient-reported pain scores were lower at all times points in the femoral nerve block group compared to the placebo group with statistical significance reached at 30 minutes, 1 hour, 2 hour, 4 hour, and 6 hours post-operatively. There was no difference in the rates of nausea and vomiting after surgery, Quality of Recovery score at 24 hours, time to discharge, or symptoms of itching, weakness, and injection site bruising and pain. The placebo group had a significantly higher rate of reported constipation at 48 hours. 6 out of 27 patients in the femoral nerve block reported falls (without injury) at 24 hours compared to 0 out of 23 patients in the placebo group. The satisfaction score, however, was similarly high in both groups at all time-points. Conclusion: Pre-operatively administered femoral nerve blocks lead to decreased pain scores in the early post-operative phase without affecting opioid consumption or opioid-related side effects. Patient satisfaction with pain control was similarly high between groups. Given the rate of falls observed in this study, we cannot recommend the routine use of femoral nerve blocks for outpatient hip arthroscopy.

Rats reared in social isolation exhibit a syndrome of behavioral and biochemical effects indicative of enhanced mesolimbic dopamine (DA) function. The precise nature of the neurodevelopmental changes that produce this state are unknown but result in enhanced DA neurotransmission in the nucleus accumbens (NAC). It was hypothesized that this may be the indirect result of chronic changes in glutamate NMDA receptor function. The same prediction has been made for Fawn hooded (FH) rats that exhibit some of the characteristic effects of isolation-reared rats when compared to Wistar rats. Therefore, mRNA levels of the NMDAR1A receptor subunit were determined by in situ hybridization and were quantified in the striatum, hippocampus and prefrontal cortex of FH and Wistar rats. Isolation rearing alone was not found to have an effect on the expression of NMDAR1A, while FH rats had reduced levels across most brain regions examined. In some areas of the striatum and prefrontal cortex, this effect was greater in FH isolates than in FH socials, while in the hippocampus, the opposite was observed.

The levels and cellular localization of the mRNA encoding the inwardly rectifying potassium ion channel Kir4.1 were investigated in the embryonic rat brain by Northern blots and in situ hybridization. This transcript was absent at embryonic day 13 (E13), whereas it was clearly present in E14-15 preparations, principally in the neuroepithelium of the cerebral cortex, thalamus, and hypothalamus. At later embryonic stages (E17-20), Kir4.1 mRNA levels increased and expanded to the mantle zone, such as the cortical plate, hippocampus, thalamus, and hypothalamus. The early appearance of Kir4.1 mRNA in various brain regions suggests an involvement of the channel in cell proliferation, migration and differentiation in the rat CNS.

Background: Anthracyclines (A) and taxanes (T) are standard neoadjuvant treatments for breast cancer (BC), achieving pathologic complete response (pCR) rates of 20-30% in unselected patient (pt) populations. Ixabepilone (ixa) is approved for treatment of metastatic BC: plus capecitabine (Cap) in pts progressing after A and T or as monotherapy after progression on A, T and Cap. Prior data suggest that overexpression of βIII tubulin is associated with resistance to paclitaxel (P) while activity of ixa was unaffected. We present the first randomized comparison of neoadjuvant ixa and P in early stage BC. Primary objectives were to estimate pathologic complete response rate (pCR) in the overall population and in biomarker-defined populations. Methods Pts with early stage BC were biopsied for immunohistochemical (IHC) and mRNA biomarker analyses prior to chemotherapy. Following 4 cycles of doxorubicin/cyclophosphamide (AC), pts were randomized to either every 3 week ixa (40mg/m2:4 cycles) or weekly P (80mg/m2:12 doses). Post-therapy surgery and pathological reports were used to assess pCR. Baseline βIII expression was assessed via a standardized IHC assay (Dako, CA) and predefined single gene mRNA markers (including TUBB3, CAPG, TACC3) were assessed via Affymetrix gene expression profilling. The pCR rate and cutoff for biomarker positivity were estimated using a cross-validation method. Secondary endpoints in the study included clinical objective response rate and safety. Results Pts (N=384) were enrolled in 15 countries: 313 pts were treated with AC. 295 pts were randomized; 289 were treated with either ixa or P. Of these, 247 (123, ixa; 124, P) had βIII IHC data and 231 (114, ixa; 117, P) had both pathologic and βIII IHC data. Baseline characteristics were balanced between arms, including triple negative pts (TN, 49%). The pCR rate in all randomized pts was 24.3% (90% CI: 18.6-30.8) with ixa and 25.2% (90% CI: 19.4-31.7) with P. pCR rates were similar regardless of sub-group. Table 1. pCR rates No significant interaction was observed between βIII expression and treatment arms (logistic regression analysis). Secondary efficacy measures were consistent with the pCR results. No clinically meaningful differences in efficacy endpoints were noted between ixa and P with mRNA markers (TUBB3, CAPG and TACC3; analyses are ongoing with others). The safety profiles of ixa and P were similar, including incidence of peripheral neuropathy (Grade 3/4: ixa 4.1% vs P 3.5%). An exception was greater neutropenia with ixa (Grade 3/4; 41.3% versus 8.4% with P) although there was no difference in the rate of febrile neutropenia (0.7%). Summary Overall, the results indicated that ixa had similar efficacy to P when measured by pCR in the neoadjuvant BC setting. No clinically meaningful differences were noted in the efficacy profile of ixa compared to P across the subsets analyzed. Ixa or P following AC was well tolerated with similar safety profiles. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-01.

Background: Overexpression of βIII tubulin has been shown to correlate with poor prognosis and reduced response to taxanes. Ixa exhibits activity in βIII overexpressing tumor models and BC patients (pts) with high βIII mRNA levels. We report the prevalence of βIII by a validated IHC assay and the correlation of βIII protein and mRNA expression in BC tissue samples. Methods: In this neoadjuvant BC study CA163-100, 295 patients were randomized 1:1 to ixa (40 mg/m2 IV x 4 cycles) or pac (80 mg/m2 IV wkly x 12) after all pts received 4 cycles of doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2). Pre-chemotherapy formalin-fixed paraffin-embedded pt tissue sections were assessed for intensity and percentage of tumor cell staining of βIII by IHC. RNA was extracted from additional pre-chemotherapy core needle biopsy specimens and profiled for gene expression using Affymetrix HG-U133Av2 gene chips. Tumors were classified as basal-like, Her2-enriched, luminal-like A and B and normal-like using a 50-gene subtype predictor. In addition, Her2 and hormone receptor status was used for tumor subtyping. Results: βIII staining data were obtained for 261 pts, of which 247 were randomized to either ixa or pac arms of study CA163-100. The prevalence of βIII positivity was 39.1% (102/261) using the prespecified cut-off of ≥50% (2+, 3+) positive cells. The distribution of IHC scores was bimodal. 64% of specimens classified as βIII negative had no observable staining, while 77% of βIII positive specimens had a majority of tumor cells staining at the highest intensity (3+). IHC and gene expression profiling data were available for 235 pts and a correlation between βIII tubulin protein and mRNA expression was observed. The relative βIII mRNA expression levels were significantly higher in pts classified as βIII positive vs. βIII negative by IHC (P Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-02.

601 Background: TNBC comprises 15%-20% of all breast cancers (BCs) and is associated with a poor prognosis. In the ixabepilone (Ixa) study CA163-080 (-080) (n = 161), 26% of the patients (pts) had ...

Transplacental cytogenetic effects of triethylenemelamine (TEM), benzene, and vinblastine on maternal mice and their fetuses have been investigated using micronucleus and sister chromatid exchange (SCE) as genetic endpoints. CD-1 mice were treated on day 14 and 15 of gestation with TEM (0.125, 0.25, and 0.5 mg/kg), benzene (439,878, and 1,318 mg/kg), and vinblastine (0.5, 1, and 2 mg/kg) by intraperitoneal injection at 24 hr intervals, and sacrificed 40 hr after the first injection. Erythrocytic precursor cells in maternal bone marrow and fetal livers (2-4) from each pregnant mouse were used for the micronucleus and/or the SCE analyses. Significant dose-related increases in both micronuclei and SCE were found in maternal bone marrow and fetal liver following TEM treatment. Benzene at the highest dose (1,318 mg/kg) also caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells. The embryonic genotoxic effect of TEM was much higher than that of benzene for both genetic endpoints, and the frequency of micronuclei induced by benzene was higher in fetal liver than in maternal bone marrow cells. Vinblastine, a spindle poison, induced micronuclei but not SCE. Micronuclei induction by vinblastine was 7 fold greater in maternal bone marrow than in fetal liver cells. All three chemicals were cytotoxic in maternal bone marrow cells, but not in fetal liver cells except for TEM, which showed a weak cytotoxicity in fetal liver cells in the micronucleus assay. These results indicate that TEM, benzene, and vinblastine are transplacental genotoxicants in mice.

Diesel-exhaust particles from two sources were dispersed in aqueous mixtures of dipalmitoyl phosphatidyl choline, a major component of pulmonary surfactant, and were tested for genotoxicity. Diesel samples from the same sources were extracted with dichloromethane and transferred into dimethyl sulfoxide and subjected to the same assays. Both types of extractions yielded similar results in both the Salmonella mutagenicity assay and the sister-chromatid exchange assay using V79 cells. After separation of the samples into supernatant and sediment fractions, the activity of both diesel samples was shown to reside exclusively in the supernatant fraction for the solvent-extracted samples, and exclusively in the sedimented fraction for surfactant dispersed samples. These findings indicate that genotoxic activity associated with diesel particles inhaled into the lung may be made bioavailable by virtue of the solubilization/dispersion properties of pulmonary surfactant components.

Organics extractable from respirable diesel exhaust soot particles by organic solvents have been known for some time to be direct acting frameshift mutagens in the Ames Salmonella typhimurium histidine reversion assay (Huisingh, et al). Upon deposition in a pulmonary alveolus or respiratory bronchiole, respirable diesel soot particles will contact first the hypophase which is coated by and laden with surfactants. To model interactions of soot and pulmomary surfactant, we dispersed soots in vitro in the primary phospholipid pulmonary surfactant dipalmitoyl glycerophosphorylcholine (lecithin) (DPL) in physiological saline. We have shown that diesel soots dispersed in lecithin surfactant can express mutagenic activity, in the Ames assay system using S. typhimurium TA98, comparable to that expressed by equal amounts of soot extracted by dichloromethane/ dimethylsulfoxide (DCM/DMSO)(Wallace, et al, 1987). Here we report additional data on the same system using additional exhaust soots and also using two other phospholipids, dipalmitoyl glycerophosphoryl ethanolamine (DPPE), and dipalmitoyl phosphatidic acid (DPPA), with different ionic character hydrophilic moieties. A preliminary study of the surfactant dispersed soot in an eucaryotic cell test system also is reported.

In mammals, somatosensory input activates feedback and feed-forward inhibitory circuits within the spinal cord dorsal horn to modulate sensory processing and thereby affecting sensory perception by the brain. Conventionally, feedback and feed-forward inhibitory activity evoked by somatosensory input to the dorsal horn is believed to be driven by glutamate, the principle excitatory neurotransmitter in primary afferent fibers. Substance P (SP), the prototypic neuropeptide released from primary afferent fibers to the dorsal horn, is regarded as a pain substance in the mammalian somatosensory system due to its action on nociceptive projection neurons. Here we report that endogenous SP drives a novel form of feed-forward inhibitory activity in the dorsal horn. The SP-driven feed-forward inhibitory activity is long-lasting and has a temporal phase distinct from glutamate-driven feed-forward inhibitory activity. Compromising SP-driven feed-forward inhibitory activity results in behavioral sensitization. Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets.