LSD-induced alterations of locomotor patterns and exploration in rats

A free exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20–30 g/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual derement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.     

Permeant lipophilicity and vehicle composition influence accumulation of dyes in hair follicles of human skin

In skin and hair research drug targeting to the hair follicle is of great interest. Therefore the influence of permeant lipophilicity and vehicle composition on local accumulation has been examined using confocal laser scanning microscopy (CLSM). Formulations saturated with either Oregon Green^® 488, Bodipy^® FL C₅ or Bodipy^® 564/570 C₅ were prepared. The dyes were applied in citric acid buffer, 8% (w/v) surfactants in citric acid buffer or 8% (w/v) surfactants/20% (w/v) propylene glycol in citric acid buffer. Flow-through diffusion experiments were performed with fresh human scalp skin, after which the skin was imaged using CLSM. Diffusion studies showed for Oregon Green^® 488 (low lipophilicity) a higher flux when applied in citric acid buffer compared to surfactants. In contrast the fluxes of the more lipophilic dyes (Bodipy^® FL C₅ and Bodipy^® 564/570 C₅) are highest when applied in surfactants/propylene glycol. CLSM studies revealed that follicular accumulation increased with (i) a lipophilic dye and (ii) application of lipophilic dyes in surfactants–propylene glycol. Therefore we conclude that targeting to the hair follicle can be increased by the use of lipophilic drugs in combination with surfactant solutions and propylene glycol.     

Comparison of evoked arousability in breast and formula fed infants.

BACKGROUND: Currently, there is no consistent evidence that breast feeding reduces the risk for sudden infant death syndrome (SIDS). Arousal from sleep is believed to be an important survival mechanism that may be impaired in victims of SIDS. Previously it has been shown that arousability is impaired by the major risk factors for SIDS such as prone sleeping and maternal smoking. AIMS: To establish whether arousability was altered by method of feeding, and whether breast fed infants would have lower arousal thresholds. METHODS: Forty three healthy term infants were studied using daytime polysomnography on three occasions: 2-4 weeks post-term, 2-3 months post-term, and 5-6 months post-term. Multiple measurements of arousal threshold (cm H(2)O) in response to nasal air jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS) while infants slept supine. Arousal thresholds and sleep period lengths were compared between formula fed and breast fed infants at each age. RESULTS: Arousal thresholds were not different between breast fed and formula fed infants in QS. However, in AS breast fed infants were significantly more arousable than formula fed infants at 2-3 months of age. There was no difference between groups of infants when sleep period length was compared at any study. CONCLUSIONS: Breast fed infants are more easily aroused from AS at 2-3 months of age than formula fed infants. This age coincides with the peak incidence of SIDS.     

Polymorphisms of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and IL-18 and the risk of ovarian cancer

OBJECTIVE: Recent studies of ovarian cancer have suggested a role for inflammation in carcinogenesis. Data from a population-based case-control study in Hawaii were examined to assess the relation between polymorphisms in cytokines involved with the inflammatory response, specifically members of the interleukin (IL) family and the incidence of ovarian cancer. PATIENTS AND METHODS: The analysis of 182 epithelial ovarian cancer cases and 219 controls focused on the polymorphisms in the following genes: IL-1alpha, IL-1beta, IL-6, IL-10, and IL-18. Genotype data were obtained from blood samples collected in participants' homes, and reproductive, demographic, and lifestyle histories were collected during interview. RESULTS: There were no significant odds ratios (ORs) for ovarian cancer by allelic variants in any of the IL genes after adjusting for age, ethnicity, education, oral contraceptive pill use, pregnancy, and history of tubal ligation. Although there was a significantly reduced risk of ovarian cancer risk among women with an IL-1alpha (-4845) T allele compared to women with two G alleles (OR: 0.59; 95% confidence interval: 0.37-0.97) after adjustment for age and ethnicity, the trend was not significant (p = 0.10). Further examination of the data suggested that women with at least one IL-18 variant allele (a G to C transition at position -137) were at significantly decreased risk of advanced ovarian cancer (OR: 0.51; 95% confidence interval: 0.28-0.90) compared to women with the IL-18 GG genotype. There was a significant difference in the risk of ovarian cancer associated with the IL-18 C allele by stage at diagnosis (p = 0.04 for homogeneity in the ORs): cases with IL-18 GC or CC genotypes were less likely to be diagnosed at regional/distant stages. Analysis of the data within ethnic subgroups revealed a significant positive association of the heterozygous IL-18 GC genotype with ovarian cancer risk among Native Hawaiian women (OR: 9.96; 95% CI: 1.88-52.90). The OR for ovarian cancer was not significant for Native Hawaiian women homozygous for the IL-18 C allele, but only one case and control had the IL-18 CC genotype. CONCLUSIONS: Overall, this study does not support an association of selected IL-1alpha, IL-1beta, IL-6, IL-10, or IL-18 polymorphisms with the risk for ovarian cancer. However, the IL-18 G137C variant may be a marker for ovarian cancer progression or metastasis.     

Differential uptake and catabolism of prostaglandin (PG)E(2) versus PGF(2alpha) in the sheep choroid plexus during development

The early postnatal decrease in prostaglandin (PG)E(2) levels in cerebrospinal fluid (CSF) likely contributes to the establishment of continuous breathing. To elucidate mechanisms underlying this event, choroid plexuses from lateral (L-CP) and third/fourth (III/IV-CP) ventricles were incubated with [3H]-PGE(2) and label uptake (tissue-to-medium ratio for radioactivity, T/M) and catabolism (%radioactivity associated with metabolites, PGM) were measured. [3H]-PGF(2alpha) was a reference. Uptake of [3H]-PGE(2) was lower than [3H]-PGF(2alpha) in the term fetus (L-CP: 5.9+/-0.5 vs. 9.6+/-0. 9, n=11; III/IV-CP: 2.7+/-0.4 vs. 7.7+/-1.0, n=5) and 17 d lamb (L-CP: 5.3+/-0.8 vs. 11.0+/-1.2, n=7; III/IV-CP: 3.1+/-0.2 vs. 11. 6+/-2.8, n=3 and 4, respectively). This difference was not significant in the pregnant adult. Release of the two compounds was similar and did not change with age. [3H]-PGE(2) uptake was reduced by probenecid (1 mM) and excess PG (60 microM PGE(2) or PGF(2alpha)). Excess PG also reduced catabolism in the fetus, which was extensive for [3H]-PGE(2) and [3H]-PGF(2alpha)60%). In the lamb, catabolism remained high for [3H]-PGE(2) (L-CP: 64+/-4%, n=7; III/IV-CP: 41+/-4%, n=3), but not [3H]-PGF(2alpha) (L-CP: 26+/-4%, n=7; III/IV-CP: 4+/-1%, n=4). In the pregnant adult, catabolism was above background only for [3H]-PGE(2) in the L-CP (26+/-5%, n=11). Unlike the perinatal animal, this catabolism was reduced by probenecid. In conclusion, PGE(2) uptake and catabolism operate independently in the choroid plexus from perinatal sheep. Differences between PGE(2) and PGF(2alpha) are developmentally-regulated for both mechanisms. While neither process explains the postnatal decrease in CSF PGE(2), both may help keep CSF levels low during early postnatal development.     

Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study.

PURPOSE: On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens. PATIENTS AND METHODS: Eligible patients were randomly allocated to receive cisplatin 50 mg/m(2) every 3 weeks (CPT); cisplatin 50 mg/m(2) day 1 plus topotecan 0.75 mg/m(2) days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m(2) days 1, 15, and 22, vinblastine 3 mg/m(2) days 2, 15, and 22, doxorubicin 30 mg/m(2) day 2, and cisplatin 70 mg/m(2) day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately. RESULTS: The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. CONCLUSION: This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.     

The virtuous orthopaedist has fewer malpractice suits

It generally is believed that physicians who have poor relationships with their patients are more likely to be sued. We studied certain physician characteristics and related them to their number of malpractice suits and the amount paid to settle those claims. Physicians with better rapport with their patients, who took more time to explain, and who were available had fewer malpractice suits. The most significant correlation was found in time spent with the patient. As the time spent increased, the number of suits decreased.     

Insights into pediatric rhabdomyosarcoma research: Challenges and goals

Overall survival rates for pediatric patients with high‐risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.