ADR Group Research Articles

#6693 INCREASED INFILTRATION OF LRG1+VCAN+LY6CHIGH MACROPHAGES ARE ESSENTIAL CONTRIBUTORS TO KIDNEY INJURY IN ADR MICE

Abstract Background and Aims The ADR mouse model is a well-established rodent model of FSGS that can manifest with albuminuria. Resident macrophages are present in the tubulointerstitium of the kidney, and circulating macrophages can be recruited to the kidney in disease states. However, the presence of macrophages in glomeruli and the role of macrophages in podocyte injury in ADR mouse models remain unknown. Method Single-cell RNA sequencing comprehensively characterized the expression of macrophages in mice glomeruli. Eight-week-old male BALB/c mice were used to induce ADR model. Immunofluorescence was used to detect the changes of renal macrophages after injected with ADR at different time points. Transwell co-culture system were used to detect the effect of Lrg1+Vcan+Ly6Chigh macrophages on MPCs. HCH6-1,the FPR1 inhibitor were used to restrain ANXA1-FPR1 pathway. Results Totally 506 macrophages were sequenced and Lrg1+Vcan+Ly6Chigh macrophages were significantly increased in ADR induced nephrotic mice glomeruli (P<0.01). The ligand receptor relationship between podocytes and macrophages were changed(P<0.01, means>1). Immunofluorescence demonstrated that macrophages are present in ADR glomeruli(P<0.05). However, the temporal and spatial changes of macrophages in ADR glomeruli still need to be proved by further experiments. After co-culture of Lrg1+Vcan+Ly6Chighmacrophages and MPCs, the expression of nephrin in MPCs decreased(P<0.05), which proved that macrophages can cause podocyte injury. In ADR group, the ANXA1-FPR1 signaling pathway was activated, and renal Lrg1+Vcan+Ly6Chighmacrophage infiltration, albuminuria and renal injury were reduced in ADR+HCH6-1gruop (all P<0.05). Conclusion Lrg1+Vcan+Ly6Chighmacrophages are recruited into mice glomeruli by activation of ANXA1-FPR1 signaling pathway and cause the damage of podocyte.

Metabolic Asymmetry Relates to Clinical Characteristics and Brain Network Abnormalities in Alzheimer's Disease.

Metabolic asymmetry has been observed in Alzheimer's disease (AD), but different studies have inconsistent viewpoints. To analyze the asymmetry of cerebral glucose metabolism in AD and investigate its clinical significance and potential metabolic network abnormalities. Standardized uptake value ratios (SUVRs) were obtained from 18F-FDG positron emission tomography (PET) images of all participants, and the asymmetry indices (AIs) were calculated according to the SUVRs. AD group was divided into left/right-dominant or bilateral symmetric hypometabolism (AD-L/AD-R or AD-BI) when more than half of the AIs of the 20 regions of interest (ROIs) were < -2SD, >2SD, or between±1SD. Differences in clinical features among the three AD groups were compared, and the abnormal network characteristics underlying metabolic asymmetry were explored. In AD group, the proportions of AD-L, AD-R, and AD-BI were 28.4%, 17.9%, and 18.5%, respectively. AD-L/AD-R groups had younger age of onset and faster rate of cognitive decline than AD-BI group (p < 0.05). The absolute values of AIs in half of the 20 ROIs became higher at follow-up than at baseline (p < 0.05). Compared with those in AD-BI group, metabolic connection strength of network, global efficiency, cluster coefficient, degree centrality and local efficiency were lower, but shortest path length was longer in AD-L and AD-R groups (p < 0.05). Asymmetric and symmetric hypometabolism may represent different clinical subtypes of AD, which may provide a clue for future studies on the heterogeneity of AD and help to optimize the design of clinical trials.

Experimental Study on the Mechanism of Cinnamaldehyde Ameliorate Proteinuria Induced by Adriamycin.

Objective Cinnamaldehyde (CA) is the main active component of Guizhi (Cinnamomi ramulus) to ameliorate adriamycin- (ADR-) induced proteinuria in rats. However, the underlying mechanism of CA against proteinuria remains unclear. The aim of this study was to investigate the action mechanisms of CA to treat proteinuria. Methods 13 rats were randomly selected from 78 SD rats as control group, and the other rats were injected with ADR (3 mg/kg/time) twice through tail vein on day 1 and day 8 for modeling. After modeling, the rats were randomly divided into 5 groups as follows: ADR group, ADR+CA low-dose group, ADR+CA middle-dose group, ADR+CA high-dose group and Benazepril group with 13 rats in each group. The urine of SD rats was collected for 24 h, urine protein, creatinine and urea nitrogen were detected, renal index was calculated, and HE staining and western blot were performed. Results The 24 h urine volume and urine protein, renal function, and renal histopathology got worse significantly in the ADR group. To western blot, CA downregulated the protein expression of ACE and Ang-2 and upregulated the protein expression of ACE2 in RAS signaling pathway. Conclusion The underlying action mechanism of CA to treat NS might mainly be achieved by regulating RAS signaling pathway.

The Study of the Transport Mechanism of Isorhynchophylline in Liver.

To investigate the transport mechanism of isorhynchophylline (IRN) by using the specific inhibitors of organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) and attempt illustrate the metabolic mechanism of IRN in the liver. All animals were randomly divided into three groups: control group (only inject IRN), RIF group (inject IRN and rifampicin), and ADR group (inject IRN and adrenalone). The control group was injected with IRN via the caudal vein. The RIF group was injected with rifampicin (RIF) by gavage, and after 1 h, IRN was injected into the caudal vein. Similarly, the ADR group received adrenalone by the caudal vein, and after 0.5 h, IRN was injected into the caudal vein. Thereafter, blood samples were obtained by the heart punctures at 90 min, 180 min, and 300 min following drug administration. Rats were sacrificed at 300 min after drug administration; then, the liver tissue was harvested. The level of IRN was measured by using high-performance liquid chromatography (HPLC), and the Kp values were calculated. After RIF administration (OATPs inhibitors), the Kp value of IRN was slightly decreased when compared with that of the control group. Meanwhile, the Kp value of IRN was dramatically reduced compared to that of the control group following ADR administration (OCTs inhibitors). The results suggested that OCTs have mainly participated in the hepatic uptake process of IRN.

Acute Tumor Inflammation with CD4/8+ and CD11+ Prolong The Survival Effect Induced by Intratumral Injection Optimum Combination of Chemotherapy Drugs with Hydralazine as Hapten in Animal Model

Purpose: To study the survival time of mice with tumor by intratumoral injection with chemotherapy drug Adr plus hapten of DNP or Hydra and find a combination of drugs of Adr with DNP or Hydra can prolong their life, and which one of DNP or Hydra can provide a long life extension of mice with tumor. Method: After inoculation of tumor cells into mice, tumor reach at 4~5mm size as the experiment day 0, the random groups was performed for intratumoral injection with corresponding drugs combination of Adr+DNP or Hydra and Adr or ARA-C control group, follow up to 90 days to find which combination of drugs could provide a longer their life extension of mice with tumor. Result: Comparison the body weight between the groups, there is not significantly different but the control group maintains the stable of weight. it indicated that PYM could not alone induce a expression of immunity at all and DNP as hapten is playing an important role in stimulation of immunity reaction. There is a significant difference between the tumor volume in treatment group and control group from day1 to day 41, it showed that local injection of combination drug can control tumor growth in the difference drugs group. There is a significant difference between survival time in treatment group and the control group. The life extension rate is 31.4% for group of A1 (Adr+Hydra I) is bigger than A2 (Adr+Hydra II) which has same formulation with high dose of Hydra, and A3 (Adr+Ara-C+Hydra) which has one more drug of Ara-CA2; life extension rate for B group, B1 (Adr+DNP) is 24.4%, it is bigger than B2 (Adr+Ara-C+DNP) which has one more drug of Ara-C; Both of A1 and B1 is better than D (Adr+Ara-C) in the life extension rate, it indicated that best Hydra dose in A1 and DNP in B1 played an important role in the life extension, Hydra is a better hapten than DNP. Conclusion: It has further confirmed the abscopal effect induced by chemotherapy drug Adr plus DNP or Hydra is optimum combination with compatibility and could prolong their life of mice, it offer a novel eclectic approach for treating cancer through the Hydra modify with TAA in vivo with intratumoral injection best combination with chemotherapy drug.

An Integration of Network Pharmacology and Experimental Verification to Investigate the Mechanism of Guizhi to Treat Nephrotic Syndrome.

Background: Guizhi has the pharmacological activity of anti-inflammatory. However, the effect mechanism of Guizhi against nephrotic syndrome (NS) remains unclear. A network pharmacological approach with experimental verification in vitro and in vivo was performed to investigate the potential mechanisms of Guizhi to treat NS. Methods: Active compounds and potential targets of Guizhi, as well as the related targets of NS were obtained from the public databases. The intersecting targets of Guizhi and NS were obtained through Venny 2.1.0. The key targets and signaling pathways were determined by protein-protein interaction (PPI), genes ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. And the overall network was constructed with Cytoscape. Molecular docking verification was carried out by AutoDock Vina. Finally, in vitro and in vivo experiments were performed to verify the mechanism of Guizhi to treat NS. Results: 63 intersecting targets were obtained, and the top five key targets mainly involed in NF- Kappa B and MAPK signaling pathway. In the overall network, cinnamaldehyde (CA) was the top one active compound with the highest degree value. The molecular docking showed that the top five key targets were of good binding activity with the active components of Guizhi. To in vitro experiment, CA, the main active component of Guizhi, inhibited the secretion of IL-1β, IL-6, TNF-α in LPS challenged RAW264.7 cells, and down regulated the protein expression of p-NF-κB p65 and p-p38 MAPK in LPS challenged RAW264.7 cells. In vitro experiment showed that, 24 urinary protein and renal function were increased in ADR group. To western blot, CA down regulated the protein expression of p-p38 MAPK in rats of adriamycin-induced nephropathy. Conclusion: CA might be the main active component of Guizhi to treat NS, and the underlying mechanism might mainly be achieved by inhibiting MAPK signaling pathway.

Protective action of ultrasound-guided intraparenchymal transplantation of BMSCs in adriamycin nephropathy rats through the RIPK3/MLKL and NLRP3 pathways

BackgroundBone marrow stromal cells (BMSCs) are an effective new strategy for the treatment of kidney diseases. At present, noninvasive and efficient transplantation approaches to homing BMSCs to the renal parenchyma is still a serious challenge. The aim of this study was to investigate the feasibility and potential mechanism of ultrasound-guided intraparenchymal transplantation of BMSCs for the treatment of adriamycin nephropathy (AN) in rats. Materials and methodsA rat AN model was induced by 2 injections of doxorubicin. The rats were randomly divided into 4 groups (n = 10 animals in each group) : normal group (N group, no treatment), control medium group (CM group, transplant medium 1.0 mL), adriamycin nephropathy group (ADR group, phosphate buffered saline 1.0 mL), or BMSCs group (BMSCs fluid 1.0 mL). Intraparenchymal injection was completed under ultrasound guidance. After 4 weeks of treatment, blood samples were collected for serum biochemical measurements and ELISAs. The kidneys were removed for histopathological examination, electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), and western blot analysis. ResultsNo deaths occurred in any group after BMSCs transplantation through the renal parenchyma under ultrasound guidance. Compared with the N and CM groups, in the ADR group, blood serum creatinine (SCr), blood urea nitrogen (BUN) and urine albumin (ALb) were higher, glomerular and tubular dilatation was observed, the number of apoptotic cells was higher, and the protein levels of receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) and nucleotide leukin-rich polypeptide 3 (NLRP3), key components of pathways in rat kidney, were significantly higher. Compared with those in the ADR group, the levels of SCr, BUN, ALb and serum proinflammatory cytokines in the BMSCs group were lower, the pathological structure of the kidney was improved, the number of apoptotic cells was lower, and the levels of RIPK3/MLKL and NLRP3 were significantly lower. ConclusionUltrasound-guided intraparenchymal transplantation of BMSCs regulated the RIPK3/MLKL and NLRP3 pathways in a minimally invasive and safe manner, thereby inhibiting renal necrosis and inflammation and playing a protective role in rat AN.

1339. Antibiotic Prescribing Varies among Patients with a Documented Penicillin or Cephalosporin Adverse Drug Reaction

BackgroundStudies have shown that over half of hospitalized children receive an antibiotic during their encounter, of which between 30-50% is considered inappropriate. Antibiotic prescribing is further complicated as approximately 10% of children are labeled beta-lactam allergic, resulting in the use of either broad-spectrum or suboptimal therapy. The purpose of this study was to compare antibiotic prescribing between patients with a documented ADR vs. those without using a nationwide sample of hospitalized children.MethodsWe performed a point prevalence study among 32 hospitals between July 2016-December 2017 where data were collected via chart review on pediatric patient and antimicrobial characteristics, including the indication for all antimicrobials. In additional, ADR history data were collected on which antimicrobial(s) were documented (e.g., penicillin, cephalosporins). Patients were mutually assigned into either: 1) no documented ADR; 2) penicillin ADR-only; 3) cephalosporin ADR-only; and 4) ADR for both penicillin and cephalosporin. The distribution of antibiotics were compared between the ADR groups, stratified by the indication for treatment.ResultsA total of 12,250 pediatric patients (17,929 antibiotic orders) who were actively receiving antibiotics were identified. A history of penicillin and cephalosporin ADR was documented in 5.5% and 2.8% of these patients, respectively. When compared to patients with no documented ADR, penicillin ADR patients were more likely to receive a fluoroquinolone for a SSTI infection (odds ratio [OR]: 5.6), surgical prophylaxis (OR: 18.8) or for surgical treatment (OR: 5.2) (see Figure). Conversely, penicillin ADR patients were less likely to receive first-line agents, such as narrow-spectrum penicillin for bacterial LRTI (OR: 0.08) and piperacillin/tazobactam for GI infections (OR: 0.22). Cephalosporin ADR patients exhibited similar patterns with increased use of carbapenems and fluoroquinolones when compared to patients with no ADR.Figure 1: Odds of Receiving Select Antimicrobials Among PCN ADR Patients When Compared to Non-ADR patients, by Indication ConclusionA large, nationwide sample of pediatric patients who were actively prescribed antibiotics helped identify several diagnoses where comprehensive guidelines for appropriate ADR prescribing and increased ADR de-labeling initiatives are needed to ensure optimal treatment.Disclosures Brian R. Lee, MPH, PhD, Merck (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial)

Competitive Environment Analysis in Global Retail Companies Operation Strategy: A Data Envelopment Analysis (DEA) Based Approach

&lt;em&gt;This research aims to find out the most competitive retail company operating in current global market based on the perspective of efficiency. A well-performed company is the company that is efficient in its operations. By using Data Envelopment Analysis (DEA) approach, this research differs from prior research because we used multivariable inputs, namely: asset, operational expense and the number of employees. The output variables used in this research are: total revenue, net profit, return on equity (ROE), return on assets (ROA), return on investment (ROI), dividend yield ratio and asset turnover ratio. The analysis results shows that six retail companies are “efficient” in its operation (efficiency score of 1.00), namely: Carrefour, Costco, Kroger Company, Home Depot Inc, JD.com Inc Adr and Alibaba Group Holdings Ltd ADR. Therefore, these companies are considered the most competitive in its operation strategy in the current global market, whereas there are four retail companies falls into category of “inefficient” (efficiency score &amp;lt; 1.00), namely: Walmart, Amazon.com Inc, Tesco PLC and Walgreens Boots Alliance Inc.&lt;/em&gt;

Competitive Environment Analysis in Global Retail Companies Operation Strategy: A Data Envelopment Analysis (DEA) Based Approach

&lt;em&gt;This research aims to find out the most competitive retail company operating in current global market based on the perspective of efficiency. A well-performed company is the company that is efficient in its operations. By using Data Envelopment Analysis (DEA) approach, this research differs from prior research because we used multivariable inputs, namely: asset, operational expense and the number of employees. The output variables used in this research are: total revenue, net profit, return on equity (ROE), return on assets (ROA), return on investment (ROI), dividend yield ratio and asset turnover ratio. The analysis results shows that six retail companies are “efficient” in its operation (efficiency score of 1.00), namely: Carrefour, Costco, Kroger Company, Home Depot Inc, JD.com Inc Adr and Alibaba Group Holdings Ltd ADR. Therefore, these companies are considered the most competitive in its operation strategy in the current global market, whereas there are four retail companies falls into category of “inefficient” (efficiency score &amp;lt; 1.00), namely: Walmart, Amazon.com Inc, Tesco PLC and Walgreens Boots Alliance Inc.&lt;/em&gt;

Anti-proteinuria effect of antibody against ANGPTL3 coil-coiled domain on adriamycin-induced nephropathy in mice

Proteinuria is an important marker and is closely related to the progressive decline of renal function. Our previous research showed that angiopoietin-like-3 (ANGPTL3) plays a crucial role in proteinuria. In this study, we prepared an antibody against ANGPTL3 coil-coiled domain (ANGPTL3-CCD) and investigated the protective effect of anti-ANGPTL3-CCD antibody in mice with adriamycin-induced nephropathy. Nephropathy was established by adriamycin injection at a dose of 25 mg per kg in 8–12 week-old male mice in the ADR group. Blockade of ANGPTL3 by anti-ANGPTL3-CCD antibody (20 mg per kg) was performed every three days nine times after adriamycin injection in the ADR plus anti-angptl3-antibody group. The anti-ANGPTL3-CCD antibody can specifically recognize ANGPTL3. After anti-ANGPTL3-CCD antibody intervention, the urinary protein level in the ADR plus anti-angptl3-antibody group was significantly lower than that in the ADR group. Serum albumin was higher and triglyceride and total cholesterol were lower in the ADR plus anti-angptl3-antibody group than in the ADR group. The levels of serum creatinine did not significantly differ among the groups. Focal sclerotic glomeruli and podocyte foot processes extensive fusion were found in the renal tissue of the ADR group, whereas no sclerotic glomeruli and only partial fusion were found in the ADR plus anti-angptl3-antibody group. This study demonstrated that the anti-ANGPTL3-CCD antibody ameliorated proteinuria and podocyte dysfunction in adriamycin-induced nephropathy in mice.

Adaptive change in temporomandibular joint tissue and mandibular morphology following surgically induced anterior disc displacement by bFGF injection in a rabbit model

PurposeThe purpose of this study was to examine the effect of injecting basic fibroblast growth factor following surgical induced anterior disc displacement in temporomandibular joints (TMJ). Materials and methodsAdult male Japanese white rabbits (n = 16; 2.0–2.5 kg; 10 weeks old) were assigned to experimental and control groups. In the experimental group, anterior disc displacement was induced in the bilateral TMJ. Recombinant human basic fibroblast growth factor (rh bFGF) 0.1 μg/1 μL aqueous solution was injected into the left retro-discal connective tissue close to the disc (ADL group), and saline alone was injected into the same site on the right (ADR group). In the control group, a sham operation without disc position change was performed in the bilateral TMJ (CR group and CL group). Four animals from the experimental (ADR and ADL) and control (CR and CL) groups were sacrificed at 1 and 12 weeks postoperatively to evaluate the mandibular morphology and computed tomographic (CT) value of the condylar head, using 3 dimensional computed tomography. Furthermore, cartilage layers and disc tissue were examined histologically. ResultsRegarding CT value at the 0° site of the condylar surface, ADR showed the lowest value after 1 week (P = 0.0325). However, there were no significant differences among the 4 groups regarding CT values at the other degree sites after 1 and 12 weeks. Regarding mandibular length, ADR showed the lowest value after 12 weeks (P = 0.0079). In condylar width, ADR showed the lowest value after 1 week (P = 0.0097). ConclusionThis study suggested that surgically induced anterior disc displacement could affect condylar morphology in the early stage, and could decrease mandibular length in the late stage. However, bFGF injection into the TMJ might prevent the degenerative change derived from anterior disc displacement and inhibition of sequential mandibular growth.

Effect of pyruvate kinase M2-regulating aerobic glycolysis on chemotherapy resistance of estrogen receptor-positive breast cancer.

This study aims to explore the effect and mechanism of pyruvate kinase M2 (PKM2) on chemotherapy resistance of estrogen receptor-positive breast cancer (ER BC) by regulating aerobic glycolysis. The expression of PKM2 in ER BC MCF-7 cells, T47D cells and MCF-7/ADR cells (which are subject to adriamycin/ADR induction) were determined by quantitative real-time PCR and western blot. MCF-7/ADR (M/A) cells were grouped into blank group (M/A), negative group (M/A+NC), low expression of PKM2 group (M/A+si-PKM2 group), overexpression of PKM2 group (M/A+PKM2 group) and glycolysis inhibition group (M/A+PKM2+2-DG group). Quantitative real-time PCR and western blot were applied to measure the expressions of PKM2, multidrug resistance, and glutathione-S-transferase π. Glucose and lactic acid kit was used to detect the amount of glucose uptake and lactic production. Cell variability, clone formation ability, and cell apoptosis were respectively measured by MTT, clone formation assay, and flow cytometry. Transwell assay and scratch assay were applied for cell invasion and migration ability. By overexpressing PKM2 in MCF-7 and T47D cells and using 2-DG, the effect on sensitivity of adriamycin amycin was explored. MCF-7/ADR cells have both elevated mRNA and protein expressions of PKM2 when compared with MCF-7 cells (both P<0.05). The cell activity of the M/A+si-PKM2+ADR group was notably lower than that in the M/A+ADR group and M/A+NC+ADR group (both P<0.05). In the M/A+si-PKM2 group, expressions of PKM2, multidrug resistance, and glutathione-S-transferase π, along with the amount of glucose uptake and lactic production, as well as cell variability, clone formation ability, and cell invasion and migration ability were inhibited, whereas cell apoptosis was increased in comparison with the M/A group and M/A+NC group (all P<0.05). On comparing with both the M/A group and the M/A+NC group, the M/A+si-PKM2 group displayed contrary tendency with the M/A+PKM2 group. The M/A+PKM2+2-DG group had elevated PKM2 expression compared with the M/A group and the M/A+NC group (all P<0.05). In MCF-7 and T47D cells with overexpression of PKM2, the sensitivity to adriamycin amycin, and cell apoptosis were suppressed, whereas the clone formation, invasion, and migration ability were enhanced. After 2-DG, the sensitivity on MCF-7 and T47D cells was enhanced while clone formation, invasion, migration and cell apoptosis rate were decreased (all P<0.05). PKM2 enhances chemotherapy resistance on ER BC by promoting aerobic glycolysis.

An intensive monitoring of adverse drug reaction in indoor patients of medicine department at tertiary care teaching hospital

Background: Use of drugs itself may result into illness and death due to their adverse effects. In India 10-20% of inpatients developed adverse drug reactions. Most of these problems can be overcome by undertaking hospital based intensive monitoring. Objective of this study was to estimate the incidence and document the spectrum of ADRs in studied patients in terms of causality, severity, frequency, type and preventability. A prospective, observational, single centre study conducted among the indoor patients of the department of general medicine, Guru Gobind singh government hospital, Jamnagar over a period of 12 months. Methods: Admitted patients who either had developed a clinically suspected ADR after admission (group A) or were admitted primarily because of an ADR (group B) were included. In all ADR related patients the necessary data was recorded on a pre-designed case record form, NCC-PvPI form and analysis was done. Results: Total 3566 patients were screened. 87 patients had 101 ADRs, among them 62 from group A and 25 from group B with 2.44% incidence. In causality, by WHO-UMC and by naranjo scale most common ‘probable’ category in group A (54.7%) and group B (50%) and 89.9% group A and 84.6% in group B respectively.95.05% ADRs were ‘Not preventable’. Hartwig seigle’s scale maximum ADRs 65.4% ADRs in group A and 73.1% in group B were ‘moderate’ in severity. Conclusions: Intercurrent illness, longer hospital stay and poly pharmacy was playing a major role in occurrence of multiple ADRs with 2.44% incidence in our setup.

Characteristics, determinants and cost implications of severe adverse drug reactions in the intensive coronary care unit of a hospital

Background: The objective of the study was to determine the predictors, frequency, characteristics and incremental costs of severe Adverse Drug Reactions in the Intensive Coronary Care Unit (ICCU) of a hospital. Methods: Two trained physicians prospectively reviewed case records of all in-patients admitted to ICCU over one year (July 2015 to June 2016) and identified ADRs. Each ADR was assessed for causality, severity, predictability and preventability. Determinants of severe ADRs were identified using multiple binary logistic regression analysis. Cost of severe ADR was estimated based on the corrected duration of excess hospital stay after adjusting for age, gender, co-morbid conditions and number of drugs. Results: Of 573 cases admitted during one year, 47 (8%) patients had 56 severe ADRs. Streptokinase (16.1%) was the commonest drug associated with severe ADRs. Arrhythmias (30.4%) were the commonest severe ADR. Presence of arrhythmias (OR 4.54, 95% CI 2.25–9.14), renal dysfunction (OR 2.27, 95% CI 1.01–5.11) and poly-pharmacy (&gt;10 drugs) (OR 1.13, 95% CI 1.007- 1.254) were found to be the predictors for occurrence of severe ADRs. Majority of severe ADRs were found to be probable 30 (53.6%). 46 (82%) were predictable and 25 (44.6%) probably preventable severe ADRs. Patients with severe ADRs had a longer duration of ICCU (0.8 extra day) and hospital stay (1.5 extra days) (adjusted analysis). The mean incremental cost incurred by patients in the severe ADR group was $ 32 (INR 2170/-) per patient based on the corrected duration of hospital stay. Conclusions: Severe ADRs in ICCU add considerably to treatment costs. Cardiac arrhythmias, renal dysfunction, and polypharmacy are important predictors of severe ADRs.

Epidural anesthesia: Simulated intravascular test dose with S(+) ketamine, lidocaine and adrenaline. A prospective, randomized, double blind and placebo controlled study

ObjectiveThe use of a test dose in epidural anesthesia is a safety recommendation. However, specificity and sensitivity of the drugs used with this indication have not been conclusive. The main objective of this study was to compare the effectiveness and the adverse effects of a simulated intravascular test dose of adrenaline, lidocaine and S(+)-ketamine. Material and methodsA prospective, randomized, double blinded, placebo controlled study was designed. ASA I patients scheduled for elective surgery were included. These were randomized to the following study groups: S(+)-ketamine 0.5mgkg−1 (S+K group), 5% lidocaine 1.5mgkg−1 (L5% group), adrenaline 15μg (ADR group), and physiological saline 3ml (SF group; control group).An evaluation was made during the first 15min after the study drug was administered. Variables including heart rate (HR) systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP), and SpO2 were recorded at 0min (baseline) and at 2, 5, 8, 10 and 15min after drug injection. An increase of at least 20 beats per minute (bpm) in relation to the baseline measurement was considered a positive result, as was an increase sBP >15mmHg. The clinical effects described as related to IV injection of the study drugs recorded were sedation-hypnosis, dizziness, nystagmus, metallic taste perception, perioral or facial paresthesias, tinnitus, as well as any other effect the patients mentioned. Sensitivity and specificity were calculated as was the percent increase in the parameters in order to see if these were clinically useful. ResultsA total of 80 patients, 20 per group, were included. The sBP, dBP, and MAP were significantly raised at the 2, 5, 8 and 10min measurements in the S(+)K group compared to the rest of the groups (p<.05), as well as HR in the 2, 5, 8, 10 and 15-min measurements in the S(+)K compared to the rest of the groups (p<.05).Sensitivity and specificity were high, and significant in the S(+)K group from minute 2 to minute 8 compared with the placebo group, as well as percentage points differences in the same interval.There were significant differences in the incidence of sedation-hypnosis, nystagmus and dizziness, which were more frequent in the S(+)K group. There were no differences in the incidence of metallic taste, perioral and facial paresthesias or tinnitus. The effects in the S(+)K group always occurred before minute 5 after drug injection. ConclusionBoth lidocaine and adrenaline at the scheduled doses showed low sensitivity and specificity as a simulated IV epidural test dose. S(+)-ketamine could be a feasible marker after accidental IV injection during epidural anesthesia or analgesia.

Molecular mechanisms by which white tea prevents oxidative stress.

The flavonoid content of tea (Camellia sinensis) has beneficial properties in the prevention of diseases. However, the mechanisms by which white tea can protect against oxidative stress remain unclear. To shed light on this issue, rats were given distilled water (controls), 0.15 mg/day (dose 1) or 0.45 mg/day (dose 2) of solid tea extract/kg body weight for 12 months. All the animals received an injection of adriamycin (ADR; 10 mg/kg body weight), except half of the control group, which were given an injection of saline solution. The expression of the nuclear factor, E2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (Nqo1), glutathione S-transferase (Gst), haem oxygenase-1 (Ho1), catalase (Cat), superoxide dismutase (Sod) and glutathione reductase (Gr) in liver was analysed by real-time PCR, and the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) was measured spectrophotometrically. ADR significantly increased the expression of Nrf2, Gst, Nqo1, Ho1, Cat, Sod and Gr with respect to the control levels and also increased the activity of CAT, SOD and GR. The intake of white tea increased in a higher degree the expression of Nrf2, Gst, Nqo1 and Ho1 in the tea + ADR group compared with the control group and C + ADR group. In addition, tea + ADR groups decreased the expression and activity of CAT, SOD and GR in a dose-dependent manner.

Anestesia epidural: dosis test intravascular simulada con S(+)-ketamina, lidocaína y adrenalina. Estudio prospectivo, aleatorizado, doble ciego, controlado con placebo

ObjectiveThe use of a test dose in epidural anaesthesia is a safety recommendation. However specificity and sensitivity of the drugs used with this indication have been not conclusive. The main objective of this study was to compare the effectiveness and the adverse effects of a simulated intravascular test dose of adrenaline, lidocaine and S(+)-ketamine. Material and methodsA prospective, randomized, double blinded, placebo controlled study was designed. ASA I patients scheduled for elective surgery were included. These were randomized to the following study groups: S(+)-ketamine 0.5 mg.kg-1 (S+K group), 5% lidocaine 1.5 mg.kg-1 (L5% group), adrenaline 15μg (ADR group), and physiological saline 3 ml (SF group; control group).An evaluation was made during the first 15 minutes after the study drug was administered. Variables including heart rate (HR) systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP), and SpO2 were recorded at 0 min (baseline) and at 2, 5, 8, 10 and 15 minutes after drug injection. An increase of at least 20 beats per minute (bpm) in relation to the baseline measurement was considered a positive result, as was an increase sBP >15 mmHg. The clinical effects described as related to iv injection of the study drugs recorded were: sedation-hypnosis, dizziness, nystagmus, metallic taste perception, perioral or facial paresthesias, tinnitus, as well as any other effect the patients mentioned. Sensitivity and specificity were calculated as was the percent increase in the parameters in order to see if these were clinically useful. ResultsA total of 80 patients, 20 per group, were included. The sBP, dBP, and MAP were significantly raised at the 2, 5, 8 and 10 minutes measurements in the S(+)K group compared to the rest of the groups (P<.05), as well as HR in the 2, 5, 8, 10 and 15 minute measurements in the S(+)K compared to the rest of the groups (P<.05).Sensitivity and specificity were high, and significant in the S(+)K group from minute 2 to minute 8 compared with the placebo group, as well as percentage points differences in the same interval.There were significant differences in the incidence of sedation-hypnosis, nystagmus and dizziness, which were more frequent in the S(+)K group. There were no differences in the incidence of metallic taste, perioral and facial paresthesias or tinnitus. The effects in the S(+)K group always occurred before minute 5 after drug injection. ConclusionBoth lidocaine an adrenaline at the scheduled doses showed low sensitivity and specificity as a simulated iv epidural test dose. S(+)-ketamine could be a feasible marker after accidental iv injection during epidural anaesthesia or analgesia.

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

GW24-e2244 Ginsenosides-Rbl improves adriamycin-induced heart failure by adjusting connexin 43

ObjectivesOn the basis of adriamycin (Adr)-induced heart failure (HF), the present study elucidated whether the effect of Ginsenosides-Rbl (Gs-Rb1), improving cardiac function, was performed by connexin 43 (CX43) and other...