Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry

We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo.     

Review of echocardiographically diagnosed right heart entrapment of pulmonary emboli-in-transit with emphasis on management

2DE permits detection of thromboemboli transiently entrapped in the right heart chambers while en route to the pulmonary arteries. Review of the 49 cases recorded to date reveals that the supple elongated clot produces a 2DE picture--a mass of changing configuration and striking mobility--that is highly characteristic. Since emboli that become entrapped are large, when managed by medical measures alone they have an attendant mortality rate of 50%, usually soon after 2DE diagnosis, upon completion of pulmonary embolization. Death occurred in 8 of 16 patients treated with anticoagulants, thrombolytic agents, or antiaggregants and in 6 of 13 who received supportive measures only. Of 20 patients referred for surgery (cardiotomy and, in 17, pulmonary embolectomy), only three died, two of them failures of preceding anticoagulant treatment. These data indicate that thromboemboli entrapped in the right heart chambers are best handled as a surgical emergency.     

Multiple sclerosis: serial study of gadolinium-enhanced MR imaging

Thirteen patients with definite multiple sclerosis (MS), studied 16-24 months previously with magnetic resonance (MR) imaging with and without enhancement by intravenously administered gadolinium diethylenetriaminepentaacetic acid (DTPA) dimeglumine, were reexamined with a similar protocol. Assessment of enhancement and clinical activity in both studies revealed that enhancement was observed in 13 of 14 cases in which clinical activity had changed within 4 weeks of the study and thus appeared more sensitive than clinical examination in determining active disease. The 3-minute postinjection, short repetition time image (TR) was the most efficient for depicting enhancement. Enhancing lesions (active plaques) arose from previously hyper- or isointense regions on long TR images. Previously active lesions reverted to areas of iso- or hyperintensity on long TR images. Serial comparison of long TR images in this population reveals a decrease in high-intensity lesions on long TR images in some cases and an increase in others. The findings of high-intensity regions on long TR images and previously enhancing lesions both becoming isointense suggests that transient inflammatory changes with concomitant edema without demyelination and/or with significant remyelination may occur in some MS lesions. MS lesions are dynamic; both active and inactive lesions may show dramatic change on longitudinal MR imaging studies.     

Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503)

Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal (and one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized.     

A cross-cultural consumer-based decision aid for screening mammography

BACKGROUND: "Women should have mammograms" is the usual perspective of educational interventions about screening. The perspective that "women should be informed" about potential risks and benefits so they can make value- and evidence-integrated personal decisions has recently been advocated. However, this perspective has not previously been operationalized. We developed an evidence-based cross-cultural mammography decision aid (MDA), for European American and Mexican American women who are 50-70 years old, at average risk of breast cancer, of varying educational levels, and English- or Spanish-speaking. METHODS: MDA development included: (1) content development by a multidisciplinary team and lay women and (2) testing for validity and reliability. Four parts include: (1) introduction; (2) information about logistics (cost, time, discomfort) and risks (sequelae of false-positive or negative results; (3) probability of developing breast cancer; and (4) benefit of mammography regarding breast cancer outcomes (e.g., death and recurrence). We assessed reliability (stability of decisions with the same information) after 1-2 weeks. We assessed validity (comprehension of information) quantitatively (probabilities were changed to see whether preferences changed predictably) and qualitatively (focus groups, standardized probes for comprehension). Subjects were a convenience sample of 49 European American (50-81 years old) and 54 Mexican American (49-89 years old) women from administrative staff at a medical school, the waiting room of an indigent primary care clinic, and a community center. RESULTS: Reliability was 100%. In quantitative validity testing, 22 of 28 women (89%) changed preference as predicted with changed probabilities. Comprehension was confirmed qualitatively in all phases of testing with both Spanish and English versions. CONCLUSION: The decision aid is valid and reliable in English and Spanish for southwestern Mexican American and European American women at average risk of breast cancer, including those of low educational levels.     

Shared treatment decision making in a collectively funded health care system: possible conflicts and some potential solutions

In recent years there has been a growth in the advocacy of shared decision making (SDM) between clinicians and patients as a way of practicing medicine. Although there is a range of perspectives on what SDM means, in essence it refers to greater involvement of the individual patient in deliberations about appropriate forms of clinical management. The patient's perception of the role of the doctor in SDM is crucial: for it to work successfully, the patient needs to be able to be confident that the doctor is focused on which treatment will generate the greatest benefit for them. However, the doctor also has responsibilities to others, in particular to other patients and potential patients within the collectively funded health care system. This dual responsibility can create a range of dilemmas for the clinician in the context of SDM: Should they inform patients about all effective treatments or just those that the health care system considers cost-effective? Do they risk losing patients from their books if they inform patients about their responsibilities to the health care system? SDM also raises questions about the wider principles of the health care system: Are its equity principles consistent with SDM? Should patients with a strong preference for an effective but non-cost-effective treatment be permitted to pay for it privately? This paper describes the nature of the conflicts that are likely to emerge if SDM diffuses within collectively funded health care systems, and considers a range of policy responses. It argues that the risk of conflict may be reduced by making a clear distinction between clinical guidelines (focusing on effectiveness) and system guidelines (focusing on cost-effectiveness).     

The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells

The present study demonstrates a novel stimulatory effect of a cannabinoid agonist on calcium channels. DALN (1 nM) potentiated 45Ca(2+)-uptake by N18TG2 neuroblastoma cells, an effect that was abolished by the specific CB1 receptor antagonist SR141716A. The stimulation of 45Ca(2+)-uptake by DALN was resistant to pertussis toxin (PTX), suggesting that Gi/Go GTP-binding proteins did not mediate this effect. Furthermore, PTX unmasked a stimulatory effect of a high concentration of DALN (1 microM), which by itself failed to stimulate calcium uptake in naive cells. The stimulatory effect of DALN on calcium entry to the cells was blocked by nicardipine but not by omega-conotoxin GVIA, indicating the entry of calcium through L-type voltage-dependent calcium channels. Blocking cAMP-dependent protein kinase (PKA) by H-89 completely eliminated the elevation in calcium uptake, while blocking protein kinase C (PKC) by chelerythrine and calphostine-C only partially attenuated the stimulation. Blocking calmodulin by W-7 revealed a similar partial inhibition of the stimulatory effect of DALN. Hence, we suggest a cannabinoid-specific, PTX-insensitive, stimulatory effect on L-type voltage-dependent calcium channels, which is mediated by PKA and modulated by PKC and calmodulin.     

Outcomes at 3 months after planned cesarean vs planned vaginal delivery for breech presentation at term: the international randomized Term Breech Trial

Context  The Term Breech Trial found a significant reduction in adverse perinatal outcomes without an increased risk of immediate maternal morbidity with planned cesarean delivery compared with planned vaginal birth. No randomized controlled trial of planned cesarean delivery has measured benefits and risks of postpartum outcomes months after the birth. Objective  To compare maternal outcomes of planned cesarean delivery and planned vaginal birth at 3 months post partum. Design  Follow-up study to the Term Breech Trial, a randomized controlled trial conducted between January 9, 1997, and April 21, 2000. Setting and Participants  A total of 1596 of 1940 women from 110 centers worldwide who had a singleton fetus in breech presentation at term responded to a follow-up questionnaire at 3 months post partum. Main Outcome Measures  Breastfeeding; infant health; ease of caring for infant and adjusting to being a new mother; sexual relations and relationship with husband/partner; pain; urinary, flatal, and fecal incontinence; depression; and views regarding childbirth experience and study participation. Results  Baseline information was similar for both the cesarean and vaginal delivery groups. Women in the planned cesarean delivery group were less likely to report urinary incontinence than those in the planned vaginal birth group (36/798 [4.5%] vs 58/797 [7.3%]; relative risk, 0.62; 95% confidence interval, 0.41-0.93). Incontinence of flatus was not different between groups but was less of a problem in the planned cesarean delivery group when it occurred (P = .006). There were no differences between groups in other outcomes. Conclusions  Planned cesarean delivery for pregnancies with breech presentation at term may result in a lower risk of incontinence and is not associated with an increased risk of other problems for women at 3 months post partum, although the effect on longer-term outcomes is uncertain.      

Malnutrition as a prognostic factor in lymphoblastic leukaemia: a multivariate analysis

One hundred and twenty eight Brazilian children with lymphoblastic leukaemia were intensively treated with a Berlin-Frankfurt-Munich based protocol. More children had a white cell count above 50 x 10(9)/l (31%) then observed in developed countries. After a median follow up of 31 months (11-58 months), the estimated probability of relapse free survival was 41% (7%) for the whole group. After adjustment in the Cox's multivariate model, malnutrition was the most significant adverse factor affecting duration of complete remission. Age above 8 years and high peripheral white cell count were also significant adverse factors. Among the nutritional indices, the height for age and weight for age z scores were both significant, whether the cut off points of z-2 or z = -1.28 were chosen to define malnutrition. A strong statistical association between the two indices was found; the contribution of height for age z score to the prediction of relapse free survival was more significant. Children with height for age z score < -2 had a relapse risk of 8.2 (95% confidence interval 3.1 to 21.9) relative to children with z score > -2. The results of this study suggest that socioeconomic and nutritional factors should be considered in the prognostic evaluation of children with leukaemia in developing countries.