In vitro activity of E-4868, a new trifluoroquinolone,compared to six similar compounds

The compound E-4868 (Laboratorios Dr. Esteve) is a trifluoro, 7-azetidinyl quinolone with properties resembling those of other fluoroquinolones. Its activity in vitro was compared to that of six other similar drugs against more than 700 nosocomial isolates using standard methods. The MIC50s of E-4868 for enteric bacilli ranged from 0.015 to 0.25 µg/ml, being highest forProvidencia spp.Pseudomonas aeruginosa strains were two-fold more susceptible to E-4868 than to ofloxacin. MICs of E-4868 forHaemophilus influenzae, Moraxella catarrhalis and pathogenicNeisseria spp. were all 0.12 µg/ml. E-4868 was equal in activity to or eight-fold more active than ciprofloxacin against gram-positive cocci. The MICs of E-4868 for pneumococci were all 0.5 µg/ml but anaerobes such asBacteroides fragilis were generally less susceptible (MIC90, 4 µg/ml). There was almost complete cross-resistance to several other fluoroquinolones. Resistant mutants were selected by a multiple passage technique but the rate of mutation to resistance was very low (< 10^–8) at an 8 x MIC.     

Comparison of arsenic-induced cell transformation, cytotoxicity, mutation and cytogenetic effects in Syrian hamster embryo cells in culture

Sodium arsenite and sodium arsenate were observed to inducemorphological transformation of Syrian hamster embryo cellsin a dose-dependent manner. A linear dose-dependence with aslope of 1 was observed with both compounds when the data wereplotted on a log-log graph. The trivalent sodium arsenite was> 10-fold more potent than the pentavalent sodium arsenate.The compounds also exhibited toxicity; however, transformationwas observed at non-toxic as well as toxic doses. At low doses,enhanced colony-forming efficiency of the cells was observed.To understand the mechanism of arsenic-induced transformation,the genetic effects of the two arsenicals were examined overthe same doses that induced transformation. No arsenic-inducedgene mutations were detected at two genetic loci. However, celltransformation and cytogenetic effects, including endoreduplication,chromosome aberrations, and sister chromatid exchanges wereinduced by the arsenicals with similar dose-responses. Theseresults support a possible role for chromosomal changes in arsenic-inducedtransformation.     

Changes in stem cell populations of rat tracheal epithelial cell cultures at an early stage in neoplastic progression

The development of transformed colonies and concomitant changes in proliferative and nonproliferative cell compartments were studied in rat tracheal epithelial (RTE) cell cultures following exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Primary RTE cells were plated onto 3T3 feeder layers and treated with MNNG (0.25 micrograms/ml) or solvent. Seven days later, the feeder cells were removed to select for enhanced growth variants, which are the transformants of the RTE cell system, usually scored 5 weeks after carcinogen exposure. Most of the RTE cell colonies, which originally formed during the first 7 days of culture, disappeared within 2 weeks after feeder cell removal in control and MNNG-treated cultures. In control cultures, about 3% of the original colonies persisted, while in MNNG-treated cultures, a larger percentage (approximately 9%) of the colonies persisted. These percentages remained constant from 3 to 7 weeks. Based on colony size, cell density, and cell morphology, the persistent colonies were classified into transformed colonies (large colony size, high cell density, high nuclear:cytoplasmic ratio) and untransformed colonies (small size, low cell density, low nuclear:cytoplasmic ratio). In the MNNG-treated cultures, about 50% of all persistent colonies showed transformed morphology. Their frequency remained unchanged between 3 and 7 weeks of culture. In contrast, only 10 to 15% of the persistent colonies in control cultures showed transformed morphology at 3 weeks, but that proportion increased steadily between 3 and 7 weeks. These data suggest that, in control cultures, transformed colonies developed spontaneously as a function of time within untransformed colonies. Autoradiographic studies with [3H]thymidine showed that labeling indices in the early "normal" RTE cell colonies between Days 4 and 7 of culture were very high, ranging between 75 and 90%. In contrast, the labeling indices of persistent colonies, both those without and those with transformed morphology, were low, i.e., between 18 and 25%, indicating that a major proportion of cells was either noncycling or cycling very slowly. The relative compartment sizes of cells with stem cell characteristics and of cells with characteristics of transformed stem cells were estimated before and after transformed colonies appeared.(ABSTRACT TRUNCATED AT 400 WORDS)     

Why did persons invited to train in cardiopulmonary resuscitation not do so?

All citizens (N = 22066) aged 16 to 65 of a medium-sized Belgiantown were personally invited to CPR training sessions held intheir neighbourhood. 1152 responded by attending a trainingsession. Those who did not so respond were surveyed (randomsample N=600) for reasons of their not coming. The sample fittedwell with census data for gender, age and suburb location butnot for job, because retired persons and women at home wereover represented. 123 persons did not want to answer the questions. 116 personssaid they were already trained in CPR, 276 said they would accepton a future occasion and 82 said they would not. Three personsdid not answer this question. There was no discrimination for job, gender and suburb locationbetween those who did and did not accept a future training opportunity,nor was the existence of a heart patient among relatives. Theolder the person, the less inclined was that person to participatein CPR training (age effect x² = 17.17, d.f. = 9, P<0.05).The 276 who accepted future training, chose their workplace(221) and/or their social meeting place (club etc.) as the placewhere this future training should be held. We suggest that CPR training is well accepted and that the trainingopportunities should be given at places of work and social gatherings.     

Rapid isolation of human kininogens

A rapid, two-step procedure is described for the isolation of both "high molecular weight" (H-) and "low molecular weight" (L-) plasma kininogens from a single sample of plasma. Affinity chromatography on carboxymethyl-papain-Sepharose is used, together with high-resolution anion exchange chromatography.     

Spectrophotometric evaluation of carboxyhemoglobin in blood of mice after exposure to marijuana or tobacco smoke in a modified Walton horizontal smoke exposure machine

Carboxyhemoglobin (COHb) values were determined in mice exposed to varying amounts of marijuana and tobacco cigarette smoke utilizing a spectrophotometric technique. Mice were exposed to smoke inhalation in a modified Walton horizontal smoke exposure machine, whereby rodents can be exposed to multiples of 1-min smoke exposure cycles. Smoke exposure was intermittent; during the first 30 sec of each 1-min cycle, the subjects were exposed to smoke diluted either 1:10 or 1:5 with air. During the second half of the cycle the animals were given fresh air. There was a positive linear relationship between COHb values obtained and the number of puffs of marijuana smoke administered via either 2, 4, 6, or 8 "puffs" of marijuana smoke. COHb levels in plasma did not increase in animals given multiple 8-puff episodes of smoke daily as long as a 60-min period was interposed between smoking episodes. COHb values in mice exposed to tobacco smoke were significantly higher than those in mice receiving equal numbers of exposures to marijuana smoke. Mean COHb values of mice receiving 8 consecutive puffs of marijuana smoke were 18.6 and 22.0% saturation, but CO was rapidly cleared from the blood. This rapid clearance suggests that the binding affinity of CO for mouse hemoglobin may be be weaker than that of human hemoglobin. Mice similarly exposed to 6 or 8 puffs of tobacco smoke had mean COHb values of 24.6 and 28.5% saturation, respectively. No acute lethal effects were observed in mice receiving multiple daily episodes of 8 puffs per episode of marijuana smoke, whereas mice exposed to a single 8-puff episode of tobacco smoke suffered about 50% acute lethal effects.     

A Group Randomized Trial Evaluating High School FLASH,a Comprehensive Sexual Health Curriculum

PurposeTo evaluate the effectiveness of a school-based comprehensive sexual health curriculum (FLASH) on high-school students’ sexual behavior and related outcomes.MethodsA cohort of 1,597 9th and 10th grade students representing 20 schools from two regions in the U.S. (Midwest and South) were enrolled and completed the baseline survey. Following baseline, the 20 schools were randomly assigned to receive FLASH (n = 10 schools, five per region) or a knowledge-based sexual health curriculum (n = 10 schools, five per region). Follow-up surveys were administered at 3 months and 12 months after the instruction period.ResultsThere were no statistically significant differences between conditions for the overall sample on rates of vaginal sex in the past 3 months or the rates of vaginal sex without a condom or other birth control. In supplementary subgroup analyses of students who were not sexually experienced at baseline, FLASH showed a statistically significant protective impact at the 3-month follow-up on vaginal sex without a condom or birth control (p = .04). FLASH also showed statistically significant gains in psychosocial outcomes, such as refusal and condom use self-efficacy, attitudes toward birth control and condoms, and perceived norms.ConclusionsFLASH demonstrated consistent short-term and long-term impacts on key behavioral determinants. It also showed a significant impact on vaginal sex without a condom or other birth control for the subgroup of students who were not sexually experienced at baseline. Behavioral impacts were not evident for the entire study population.     

Derivation and validation of a novel comorbidity‐based delirium risk index to predict postoperative delirium using national administrative healthcare database

ObjectiveTo derive and validate a comorbidity‐based delirium risk index (DRI) to predict postoperative delirium.Data Source/Study SettingData of 506 438 hip fracture repair surgeries from 2006 to 2016 were collected to derive DRI and perform internal validation from the Premier Healthcare Database, which provided billing information on 20‐25 percent of hospitalizations in the USA. Additionally, data of 1 130 569 knee arthroplasty surgeries were retrieved for external validation.Study DesignThirty‐six commonly seen comorbidities were evaluated by logistic regression with the outcome of postoperative delirium. The hip fracture repair surgery cohort was separated into a training dataset (60 percent) and an internal validation (40 percent) dataset. The least absolute shrinkage and selection operator (LASSO) procedure was applied for variable selection, and weights were assigned to selected comorbidities to quantify corresponding risks. The newly developed DRI was then compared to the Charlson‐Deyo Index for goodness‐of‐fit and predictive ability, using the Akaike information criterion (AIC), Bayesian information criterion (BIC), area under the ROC curve (AUC) for goodness‐of‐fit, and odds ratios for predictive performance. Additional internal validation was performed by splitting the data by four regions and in 4 randomly selected hospitals. External validation was conducted in patients with knee arthroplasty surgeries.Data CollectionHip fracture repair surgeries, knee arthroplasty surgeries, and comorbidities were identified by using ICD‐9 codes. Postoperative delirium was defined by using ICD‐9 codes and analyzing billing information for antipsychotics (specifically haloperidol, olanzapine, and quetiapine) typically recommended to treat delirium.Principal FindingsThe derived DRI includes 14 comorbidities and assigns comorbidities weights ranging from 1 to 6. The DRI outperformed the Charlson‐Deyo Comorbidity Index with better goodness‐of‐fit and predictive performance.ConclusionsDelirium risk index is a valid comorbidity index for covariate adjustment and risk prediction in the context of postoperative delirium. Future work is needed to test its performance in different patient populations and varying definitions of delirium.     

Melatonin receptor mRNA expression in Xenopus oocytes: inhibition of G-protein-activated response.

Melatonin is the major endocrine product of the pineal gland in the mammalian brain and plays a variety of roles in photoperiodic functions. In order to investigate melatonin receptors, poly(A)+ RNA was extracted from pars tuberalis of the ovine pituitary and injected into oocytes of Xenopus laevis. After 3-5 days of incubation, functional melatonin receptors were expressed. Receptors were revealed by their inhibitory effect upon oscillatory currents resulting from AlF4-induced activation of G-proteins in the oocyte membrane under voltage clamp conditions. The effect of melatonin was dose-dependent, non-desensitizing and was not observed in uninjected oocytes.