Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities

The incidence of transient hypogammaglobulinaemia of infancy (THI) detected in a major paediatric centre over a 10 year period was examined. A total of 2468 subjects less than 2 years of age had an IgG measurement taken between July 1979 and March 1990. Subjects with known immunodeficiencies were excluded. Fifteen patients were classified as having THI with an initial IgG level less than the fifth centile followed by a second measurement within the normal range. A further 24 patients were identified as having possible THI with a single low IgG concentration. There were 60,174 live births each year in Victoria in the years 1979-88. This gives an incidence of proved THI of 23 per 10(6) births, and including proved and probable THI an incidence of 61 per 10(6) live births. Of those patients with proved THI 12/15 had symptoms of either atopic disease or food allergy/intolerance and three had gastrointestinal symptoms without any evidence of atopic disease. At presentation 12/15 (80%) were IgA deficient and 9/15 had IgM concentrations less than the 20th centile for age. It is suggested that in view of the preponderance of atopic and food intolerant patients that subclinical protein loss from the bowel due to allergic inflammation may be a contributing factor to the development of THI in some patients.     

Novel actions of the antitumor drugs vinflunine and vinorelbine on microtubules

Vinflunine is a novel Vinca alkaloid presently in Phase I clinical trials. In preclinical studies, it exhibited superior antitumor activity to that of other Vinca alkaloids, including vinorelbine from which it was synthetically derived. Vinca alkaloids appear to inhibit cell proliferation by affecting the dynamics of spindle microtubules. Here we have analyzed the effects of vinflunine and vinorelbine on microtubule dynamic instability and treadmilling and found that these newer drugs exert effects on microtubule dynamics that differ significantly from those of the classic Vinca alkaloid, vinblastine. The major effects of vinflunine and vinorelbine on dynamic instability were a slowing of the microtubule growth rate, an increase in growth duration, and a reduction in shortening duration. In marked contrast to the action of vinblastine, they neither reduced the rate of shortening nor increased the percentage of time the microtubules spent in an attenuated state, neither growing nor shortening detectably. In addition, vinflunine and vinorelbine suppressed treadmilling, but less strongly than vinblastine. The diverse actions of these drugs on microtubules are likely to produce different effects on mitotic spindle function, leading to different effects on cell cycle progression and cell killing. Nontumor cells with normal checkpoint proteins may tolerate the relatively less powerful inhibitory effects of vinflunine and vinorelbine on microtubule dynamics better than the more powerful effects of vinblastine. Thus the unique constellation of effects of vinflunine and vinorelbine on dynamic instability and treadmilling may contribute to their superior antitumor efficacies.     

Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery

AIMS: Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775, 606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries. METHODS: Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 microm ). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. RESULTS: Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1+/-4.22 and 41.5+/-2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 microm and 0.2 microm, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 microm. CONCLUSIONS: The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors.     

What Do Executive Factors Contribute to the Failure on False Belief Tasks by Children with Autism?

As children with autism have pervasive executive difficulties it is necessary to determine whether these contribute to their often-reported failure on the false belief task. Failure on this task is frequently taken to diagnose the lack of a "theory of mind". We report two studies using two tasks that make similar executive demands to the false belief task. The first experiment showed that children with autism are significantly challenged by a "conflicting desire" task, which suggests that their difficulty with the false belief task is not rooted in difficulty with grasping the representational nature of belief. In the second study children with autism were also found to be impaired on a novel version of the "false photograph task". A parsimonious reading of these data is that their difficulty with all three tasks is due to commonalities in the tasks' executive structure.     

Preventing adolescent health-risk behaviors by strengthening protection during childhood

OBJECTIVE: To examine the long-term effects of an intervention combining teacher training, parent education, and social competence training for children during the elementary grades on adolescent health-risk behaviors at age 18 years. DESIGN: Nonrandomized controlled trial with follow-up 6 years after intervention. SETTING: Public elementary schools serving high-crime areas in Seattle, Wash. PARTICIPANTS: Of the fifth-grade students enrolled in participating schools, 643 (76%) were given written parental consent for the longitudinal study and 598 (93%) were followed up and interviewed at age 18 years. INTERVENTIONS: A full intervention provided in grades 1 through 6 of 5 days of in-service training for teachers each intervention year, developmentally appropriate parenting classes offered to parents when children were in grades 1 through 3 and 5 through 6, and developmentally adjusted social competence training for children in grades 1 and 6. A late intervention, provided in grades 5 and 6 only, paralleled the full intervention at these grades. MAIN OUTCOME MEASURES: Self-reported violent and nonviolent crime, substance use, sexual activity, pregnancy, bonding to school, school achievement, grade repetition and school dropout, suspension and/or expulsion, and school misbehavior; delinquency charges from court records; grade point average; California Achievement Test scores: and disciplinary action reports from school records. RESULTS: Fewer students receiving full intervention than control students reported violent delinquent acts (48.3% vs 59.7%; P=.04), heavy drinking (15.4% vs 25.6%; P=.04), sexual intercourse (72.1% vs 83.0%; P=.02), having multiple sex partners (49.7% vs 61.5%; P=.04), and pregnancy or causing pregnancy (17.1% vs 26.4%; P=.06) by age 18 years. The full intervention student group reported more commitment (P=.03) and attachment (P=.006) to school, better academic achievement (P=.01), and less school misbehavior (P=.02) than control students. Late intervention in grades 5 and 6 only did not significantly affect health-risk behaviors in adolescence. CONCLUSIONS: A package of interventions with teachers, parents, and children provided throughout the elementary grades can have enduring effects in reducing violent behavior, heavy drinking, and sexual intercourse by age 18 years among multiethnic urban children. Results are consistent with the theoretical model guiding the intervention and support efforts to reduce health-risk behaviors through universal interventions in selected communities or schools serving high-crime neighborhoods.     

Pelvic inflammation induced by diagnostic laparoscopy in baboons

Objective: To test the hypothesis that diagnostic laparoscopy can cause pelviperitoneal inflammation.

Design: Retrospective analysis of data collected during a prospective controlled study in baboons.

Setting: An academic research environment.

Animal(s): Samples were collected during laparoscopies in female baboons at the Institute of Primate Research, Kenya.

Intervention(s): In the first part of the study, 44 laparoscopies were performed in 16 baboons (5 with a normal pelvis, 11 with endometriosis) during the luteal phase, with a time interval of 1 month. In the second part of the study, 53 laparoscopies were performed in 15 baboons (6 with a normal pelvis, 9 with endometriosis) during the late follicular and luteal phases of one cycle, with a median time of 3–4 days between each laparoscopy.

Main Outcome Measure(s): Peritoneal fluid (PF) was measured and analyzed for white blood cell (WBC) concentrations and, in the second part of the study, for the distribution of lymphocyte subsets (CD3, CD4, CD8, and CD20) and for the presence of cytokines transforming growth factor-β1, interleukin (IL)-6, and IL-10.

Result(s): In the first part of the study, PF volumes and WBC concentrations were comparable at the baseline and follow-up laparoscopies. In the second part of the study, PF obtained at the second laparoscopy showed a 10-fold increase in volume, a 3-fold increase in WBC concentration, a 10-fold increase in IL-6 concentration, and a 2-fold increase in transforming growth factor-β1 concentration when compared with PF obtained at the first laparoscopy. The PF subset of granulocytes and CD3-positive cells was higher and the PF subset of macrophages was lower at follow-up laparoscopies than at the baseline laparoscopy.

Conclusion(s): Diagnostic laparoscopy can cause peritoneal inflammation in baboons.     

Is Intracytoplasmic Sperm Injection Necessary for Couples Undergoing In Vitro Fertilization–Embryo Transfer with Normal Semen Analyses but Failing Hamster Egg Penetration Assays?

Purpose: Our purpose was to assess whether in vitro fertilization (IVF)–embryo transfer (ET) candidate couples with basically normal semen analyses but failing zona-free hamster egg penetration assay (HEPA) scares benefit from intracytoplasmic sperm injection (ICSI). Methods: Twenty consecutive IVF candidate couples with normal–borderline semen analyses and failing HEPA scores were recruited. Mature oocytes obtained from each woman were randomly divided between ICSI (group I; n = 126 oocytes) and standard insemination techniques (group II; 138 oocytes). Fertilization (two pronuclei) and cleavage (2–4 cells) rates were assessed for both groups. Results: There were no statistically significant differences between the two groups with respect to (mean ± standard error of the mean) fertilization (group I, 63.1 ± 7.75; group II, 77.8 ± 4.7%) or cleavage (group I, 87.3 ± 2.4%; group II, 91.2 ± 3.5%) rates. Conclusions: ICSI is not beneficial for IVF-ET when sperm samples demonstrate a failing HEPA score but have normal or minimally compromised semen analysis parameters.     

In-field and out-of-field effects in partial volume lung irradiation in rodents: possible correlation between early dna damage and functional endpoints

Purpose: Recent observations have shown that there are regional variations in radiation response in mouse lung as measured by functional assays. Furthermore, there are both in-field and out-of-field effects in radiation-induced lung damage as observed by DNA assay in rats. The purpose of this work is: (a) to examine mice lethality data following partial volume lung irradiation to assess the possibility of directional or regional effects, (b) to evaluate the correlation between mice lethality data and DNA damage assayed by micronuclei production in rat lung, and (c) to re-interpret mice lethality considering the existence of directional effects in lung cellular response to partial volume irradiation.

Methods and Materials: The lethality data for mice, generated at the M. D. Anderson Cancer Center, Houston, and micronuclei yield data for rats obtained at Princess Margaret Hospital, Toronto, were used. A radiobiological model that allows for out-of-field and in-field effects for lung cell damage and lung response was developed. This model is based on the observation of DNA damage in shielded parts of rat lung that was assumed relevant to cell lethality and consequently overall lung response.

Results: While the experimental data indicated directional or regional volume effects, the applicability of dose and volume as sole predictors of lung response to radiation was found to be unreliable for lower lung (base) irradiation in mice. This conforms well to rat lung response where micronuclei were observed in shielded apical parts of lung following base irradiation. The radiobiological model, which was specifically developed to account for the lung response outside of primary irradiated volume, provides a good fit to mice lethality data, using parameters inferred from rat micronuclei data.

Conclusion: Response to lung irradiation in rodents, in particular, elevated sensitivity to base irradiation, can be interpreted with a hypothesis of in-field and out-of-field effects for cellular response. If the existence of these effects for lung is subsequently proven in humans, it will require the incorporation of geometrical and directional information in normal tissue complication probability calculations for lung. These considerations are ignored in present approaches based only on conventional dose-volume histograms.