Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model.

In our earlier studies, Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN-I)-unresponsive human U87-luc glioma xenografts, whereas interferon-responsive mouse gliomas proved refractory. Here, we describe in two clones of CT26 murine colon carcinoma, opposed patterns of IFN-I responsiveness and sensitivity to VA7. Both CT26WT and CT26LacZ clones secreted biologically active interferon in vitro upon virus infection but only CT26WT cells were protected. Focal infection of CT26WT cultures was self-limiting but could be rescued using IFN-I pathway inhibitor Ruxolitinib or antibody against IFNß. Whole transcriptome sequencing (RNA-Seq) and protein expression analysis revealed that CT26WT cells constitutively expressed 56 different genes associated with pattern recognition and IFN-I signaling pathways, spanning two reported anti-RNA virus gene signatures and 22 genes with reported anti-alphaviral activity. Whereas CT26WT tumors were strictly virus-resistant in vivo, infection of CT26LacZ tumors resulted in complete tumor eradication in both immunocompetent and severe combined immune deficient mice. In double-flank transplantation experiments, CT26WT tumors grew despite successful eradication of CT26LacZ tumors from the contralateral flank. Tumor growth progressed uninhibited also when CT26LacZ inoculums contained only a small fraction of CT26WT cells, demonstrating dominance of IFN responsiveness when heterogeneous tumors are targeted with interferon-sensitive oncolytic viruses.

Developing community health worker diabetes training.

We designed, implemented and evaluated a 48-hour training program for community health workers (CHWs) deployed to diabetes care teams in community health centers (CHCs). The curriculum included core knowledge/skills with diabetes content to assist CHWs in developing patient self-management goals. Our qualitative evaluation included pre/post-knowledge outcomes and encounter data from the field. CHWs and their supervisors were interviewed providing qualitative outcome data of the training process and program implementation. There were statistically significant increases in the scores of CHWs' self-reported knowledge in 8 of 15 curricular domains. Qualitative analysis revealed that CHWs preferred skill-based and case-based teaching, shorter training days but more contact hours. CHWs reported that pre-deployment training alone is insufficient for successful integration into care teams. CHW supervisors reported that CHC's readiness to accept CHWs as members of the care team was as important to successful deployment as training. With respect to implementation, supervision by social workers was deemed more successful than nursing supervision. Field data showed that patient encounters lasted less than 30 min and self-management goals focused on appointment keeping, diet, exercise and glucose testing. Integration and analysis of qualitative and descriptive field data provide an opportunity to continuously evaluate the effectiveness of implementation.

Maternal serum screening for fetal Down's syndrome, a retrospective study.

A retrospective study of the different biochemical markers used in screening for Down's syndrome was carried out on serum from 18,600 women between their 15th and 18th week of pregnancy. Thirty-two sera were from women with fetal Down's syndrome. The retrospective study of these 32 sera involves: (a) the screening of the maternal serum concentrations of human chorionic gonadotropin (hCG) and of alpha-fetoprotein (AFP); (b) the evaluation of the risk of Down's syndrome when screening maternal serum concentrations of hCG alone, then the combination of the two markers and finally the maternal serum concentrations of unconjugated estriol (uE3). The mean of MOM (multiples of the median) for the pathological sera were calculated for hCG (1.91), for AFP (0.63), for the ratio hCG over AFP (3.02) and for uE3 (0.72). With the use of hCG alone we estimated a 41% detection rate for an amniocentesis rate of 5.3%, whereas when hCG was combined with AFP the detection rate approached 65% for an amniocentesis rate of 5.5% at a risk cut-off of 1:300. The results of the uE3 determination confirm the validity of this marker. The comparison of these results with other retrospective studies shows the incidence of different factors in the detection rate such as the choice of markers, the age group studied, the modes of calculating the risk and the actual cut-off chosen.

Use of solid phase biochemistry for potentiometric enzyme immunoassay of oestradiol-17 beta - preliminary report.

The present report gives preliminary results of a new sensitive method for potentiometric determination of oestradiol-17 beta in solution, as an application of the competitive enzyme-linked immunoassay technique. Anti-oestradiol-17 beta antibodies are immobilized on a pig skin gelatin membrane, which is incubated with peroxidase-labelled steroid and oestradiol. After fixation of the membrane onto the sensor of an iodide sensitive electrode, the enzymatic activity was evaluated in the presence of hydrogen peroxide and iodides, the electrode potential being a function of hapten concentration in the solution. The purpose of this preliminary work was to determine the optimized conditions for specificity and sensitivity of the antibody-coated membrane in the presence of peroxidase-labelled oestradiol and oestradiol, and to eliminate possible interferences due to adsorption or ionic fixation of enzyme-labelled steroid. The first tests carried out with oestradiol standard solutions gave satisfactory results at levels ranging from 57 pmol/l to 9.2 nmol/l, suggesting that this new procedure should find application in the determination of oestradiol-17 beta in biological fluids.

Lipid concentration affects the kinetic stability of dielaidoylphosphatidylethanolamine bilayers.

The bilayer to hexagonal phase transition temperature (Th) of dielaidoylphosphatidylethanolamine is 65.5 degrees C as measured by DSC heating scans at lipid concentrations below 100 mg/ml and at scan rates ranging from 1.7 to 45 degrees C/h. However, at lipid concentrations above 100 mg/ml and at scan rates of 1-3 degrees C/h the measured Th decreases below 65.5 degrees C. At a lipid concentration of 500 mg/ml and a heating scan of 1.2 degrees C/h the transition to the hexagonal phase occurs at 62.7 degrees C. However, this same sample scanned at a rate of 34 degrees C/h has a transition temperature of 64.6 degrees C. Thus a combination of high lipid concentration and slow scan rate is required to significantly lower the hexagonal phase transition temperature below 65 degrees C. These results demonstrate that the rate of conversion of the bilayer to the hexagonal phase is dependent on the concentration of the lipid suspension even under conditions of full hydration. Furthermore, a 100 mg/ml suspension of this lipid which has a Th of 64.3 degrees C at a scan rate of 3.2 degrees C/h has a lower hexagonal phase transition temperature of 62.8 degrees C after pelleting the lipid with low-speed centrifugation but retaining the same amount of solvent in the supernatant above the pellet. Pelleting of the lipid also has a marked effect on the isothermal rate of conversion of the bilayer to hexagonal phase as observed by 31P NMR. The conversion is highly temperature-dependent and is orders of magnitude more rapid for the pelleted sample than for the suspension.(ABSTRACT TRUNCATED AT 250 WORDS)

Fusion of influenza to liposomes is not inhibited by aliphatic primary alcohols.

Reports of the antiviral activity of aliphatic alcohols led us to investigate the effects of aliphatic alcohols, from 10 to 20 carbons in length, on the phase transition behaviour of model phospholipids and on the fusion of influenza to liposomes. Contrary to the effects of many other antiviral agents, we find that alcohols are potent promoters of the inverted hexagonal phase. However, we also find that aliphatic alcohols have little effect on influenza fusion to liposomes. Eicosanol is the only aliphatic alcohol tested which substantially increases in fusion of influenza virus. We also find that long chain alcohols display multi-component bilayer to hexagonal phase transitions at higher mole fractions. This suggests that eicosanol may be facilitating fusion by creating defects between alcohol-rich and alcohol-poor regions of the lipid bilayer.

The role of adjunctive Rodogyl therapy in the treatment of advanced periodontal disease. A longitudinal clinical and microbiologic study.

Several studies have indicated that the combination of metronidazole and spiramycin is synergistic against anaerobic bacteria and may be effective against oral infections. The present study sought to determine the efficacy and safety of a commercial preparation of these two antibiotics (Rodogyl) when used adjunctively in the treatment of advanced periodontal disease. In a double-blind parallel randomized trial, 56 patients (mean age = 44 years) with advanced periodontitis (50 of whom completed the study) were assigned to either the Rodogyl or placebo group. Both groups were thoroughly scaled and root planned for approximately 6 hours, with one group receiving Rodogyl for 2 weeks and the other a placebo. No other therapy was received during the study period. Two sites in each patient with probing depths of at least 7 mm were selected for study. Plaque level (P1I), gingival inflammation (GI), probing depth (PD), and attachment level (AL) were measured at baseline, 14 days, 1 month, and then at monthly intervals up to 6 months. Subgingival bacteria were monitored with dark-field microscopy. The development of resistant bacteria, as well as side effects to the medications, was also monitored. The Rodogyl group exhibited a greater gain in AL (0.67 mm) from the 2-month interval until the end of the study. Although this difference was statistically significant (P less than 0.05), it was not necessarily of biologic significance. There was a significantly greater decline in the proportion of spirochetes in the Rodogyl group at the 14-day interval, and this difference remained significant (P less than 0.05) at all study intervals. No difference in the proportion of motile organisms was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of attachment level measurements using the cementoenamel junction and a plastic stent.

Repeated measurements of attachment level appear to be important assessments in periodontal clinical trials, yet the lack of reliability for this assessment creates measurement error which in turn demands increased sample sizes or reduces the power of the test. A plastic occlusal stent has been developed as a fixed reference point to assess changes in probing depths over time and thus reflect differences in attachment levels. The advantages of this system over traditional methods have not been measured. The purpose of this study was to determine intra- and interexaminer reliability for probing depths from the stent and the CEJ. Paired measurements of attachment level using the stent produced correlation coefficients for inter- and intraexaminer readings of 0.84 and 0.76, respectively. For subgingival cementoenamel (CEJ) measurements, lower coefficients of 0.71 and 0.59 were found for inter- and intraexaminer paired readings, respectively. Thus, measurements using the stent appear to be more reliable than subgingival CEJ readings.

Coexistence of hypothyroidism and myocardial infarction.

OBJECTIVE: To assess the coexistence of overt hypothyroidism and acute myocardial infarction (MI) in respect of clinical and biological manifestations and outcome. DESIGN: Retrospective study of patients with coincident untreated or uncontrolled hypothyroidism presenting to Notre-Dame Hospital with acute MI. Each patient's MI was matched with two controls for date of admission (within three years) of MI, age, sex, diabetes mellitus and number of previous MIs. SETTING: All patients were admitted to Notre-Dame Hospital, which is a secondary and tertiary care institution. PATIENTS: From 1975 to 1990, 5691 patients were seen at the authors' institution with acute MI, of whom 17 had simultaneously an untreated or uncontrolled hypothyroidism. Hypothyroidism was defined as thyroid-stimulating hormone levels greater than 40 mU/L associated with low or normal levels of serum thyroxine. RESULTS: Chest pain was documented in each case. Electrocardiogram location of the MI was inferior in 10 (59%) patients and in 14 (41%) controls, anterior in seven (41%) patients and in 20 (59%) controls. There was a trend towards higher creatine kinase peak levels in patients with hypothyroidism (1409 +/- 1145 U/L versus 943 +/- 788 U/L). The Killip index was similar in the two groups (1.8 +/- 1 versus 1.8 +/- 1), as was the incidence of arrhythmias (seven of 17 versus 11 of 32). There was no significant difference in mortality between the two groups (18% [three of 17] versus 12% [four of 34]). However, the incidence of residual ischemia was greater in patients with hypothyroidism (12 of 17 versus 10 of 34, P < 0.008). CONCLUSIONS: Hypothyroidism is not associated with an unfavourable effect on the clinical course of acute MI. However, patients with hypothyroidism seem to have an increased incidence of residual ischemia.

100% rapid (partial) rescreening for quality assurance.

OBJECTIVE: To compare the efficiency of two methods for routine quality assurance in gynecologic cytology: random rescreening of 10% of negative gynecologic smears and rapid rescreening of all negative gynecologic smears. STUDY DESIGN: All gynecologic smears considered to be negative or benign and diagnosed between November 1, 1996, and December 31, 1997, were rescreened using the rapid, partial rescreening technique. Results were compared to those of the 10% random rescreening method. RESULTS: Comparing the 10% review of negatives to the rapid rescreening in two comparable periods of three months, the former required review by the supervisor of 160 cases in order to find a true false negative. With rapid rescreening, the supervisor had to review fewer than eight cases to find a true false negative. Also, rapid rescreening found about four times more true false negatives than random 10% review. CONCLUSION: Rapid rescreening of all negative gynecologic smears proved more efficient than 10% random rescreening.

[Effect of estroprogestative drugs on the secretion of corticoadrenal hormones]. / Influence des estroprogestatifs sur la sécrétion des hormones corticosurrénaliennes.

Estro-progestative drugs (EPD) have been used for many years and multiple secondary effects have been reported concerning mainly the glucidic and lipidic metabolisms. Effects of EPD on steroid metabolism have also been described and the authors present a review of the literature on this subject. Particularly it appears that EPD affect: the glucocorticoid metabolism, with augmentation of total cortisol although not in its free-form (augmentation of transcortine), the adrenal androgens metabolism, with diminution of their circulating rates, the aldosterone metabolism with augmentation of its secretion. These biological constatations could help explaining some clinical features occurring with administration of EPD: diminution of hirsutism and/or acne, augmentation of body weight, appearance of hypertension.

[Plasma beta chorionic gonadotropin between 14 and 20 weeks of amenorrhea: a sign of pregnancy-related hypertension]. / Gonadotrophines chorioniques beta plasmatiques entre 14 et 20 semaines d'aménorrhée: un marqueur de l'hypertension gravidique.

A defect of placenta maturation has been described in hypertension of pregnancy. Plasma beta chorionic gonadotropins (beta HCG) of placental origin rise at the onset of pregnancy and reach a peak between 9 and 10 weeks of amenorrhoea. As we were making systematic assays between 14 and 20 weeks in a trisomy detection programme, we looked for differences in plasma beta HCG levels between women with pregnancy-induced arterial hypertension and pregnant women with normal blood pressure. We also studied the predictive value of such assays. Pregnancy-induced hypertension was found in 6 women in a population of 89 nulliparas and in 12 women in a population of 163 multiparas. beta HCG levels were significantly higher in women who later developed hypertension among both nulliparas (52,833 +/- 19,538 IU vs 24,499 +/- 16,485 IU) and multiparas (50,558 +/- 23,597 IU vs 20,911 +/- 11,677 IU). In nulliparas, taking 43,000 IU as threshold of pathology we found that the predictive value of beta HCG was higher than that of other tests which had gone through controlled studies (sensitivity 67 percent, specificity 91.6 percent, positive predictive value 36 percent, negative predictive value 97.4 percent, relative risk 5.4). In multiparas, taking 38,000 as threshold and combining this marker with obstetrical history it was possible to predict the occurrence of hypertension more precisely than with other markers which had gone through controlled studies (sensitivity 66.7 percent, specificity 98 percent, positive predictive value 61.4 percent, negative predictive value 97.3 percent, relative risk 8.4).

Responses of the socially anxious to the prospect of interpersonal evaluation.

We predicted that socially anxious people who are faced with the prospect of an interpersonal evaluation will act in an inhibited and withdrawn way. Subjects who scored low or high on a measure of social anxiety told four stories about themselves to an interviewer. In the anticipated-evaluation condition, the subjects learned that after they had told their stories, the interviewer would tell them her impressions of them. In the control condition, no mention was made of an evaluation. Judges rated transcripts of the stories. As predicted, socially anxious subjects who thought they were going to be evaluated (relative to anxious subjects in the control condition and nonanxious subjects in both conditions) told shorter stories, and the events in their stories were commonplace rather than unique. Their stories were also less revealing about them as individuals, and less vivid. Contrary to a second prediction, socially anxious subjects who expected to be evaluated did not act any less inhibited or withdrawn when their interviewers were described as very trusting than when they were described as very wary. Implications are discussed.

Comparison of spiramycin and tetracycline used adjunctively in the treatment of advanced chronic periodontitis.

This study was designed to compare both clinical and microbiological changes during the treatment of advanced periodontal disease with mechanical debridement, with or without the adjunctive use of either spiramycin or tetracycline. The study, which included 96 patients with advanced periodontitis, was performed as a controlled double-blind parallel randomized trial. All patients received thorough scaling and root planing as well as adjunctive placebo or spiramycin or tetracycline. Probing depth measurements, attachment level changes, plaque level, gingival crevicular fluid, bleeding on probing and microbiological evaluation were carried out at baseline, 2-, 8-, 12- and 24-week visits. Seventy-nine patients (24 placebo, 27 tetracycline and 28 spiramycin) completed the study. At 24 weeks there were no intergroup differences in the improvement of any of the clinical parameters. Spiramycin was the only antibiotic which produced a significantly greater decrease in the proportion of spirochaetes than the placebo group at the 24-week visit. It was concluded that mechanical debridement alone was sufficient in decreasing the subgingival bacteria to a level which would result in the return to periodontal health. The study was not long enough to determine whether or not the difference in spirochaete level was an indication that the spiramycin group would have maintained the benefits of treatment for a longer time.