Sources of Variability in the Detection of Cerebral Emboli with Transcranial Doppler During Cardiac Surgery

OBJECTIVE: The application of intensity thresholds for embolus detection with transcranial Doppler (TCD) can exclude from analysis an unrecognized proportion of high-intensity transient signals (HITS))whose intensities are below the threshold. The lack of consistent threshold criteria between clinical trials may explain part of the discrepancy in the reported HITS counts. We investigated the effect of choosing different thresholds on the sensitivity and specificity of detecting HITS during cardiopulmonary bypass (CPB). METHODS: Two observers independently analyzed TCD recordings from 8 patients under CPB. Doppler signals were classified as true HITS, equivocal HITS, artifacts, and Doppler speckles according to preestablished criteria. The relative intensity of Doppler signals was measured by two different methods (TCD software vs manual). Receiver Operating Characteristic curves determined the optimal threshold for each of the two intensity methods. RESULTS: Reviewers achieved agreement in 96% of 2190 Doppler signals (kappa = 0.90). Relative intensities calculated with the TCD-software method were 3 dB (95% CI: 3.0-3.4) higher than the manual method. The optimal threshold was found at 10 dB (sensitivity: 99%; specificity: 90.8%) with the software method and at 7 dB with the manual method (sensitivity: 96%; specificity: 83%). The use of an intensity threshold 2 dB higher than the optimal increased the rejection of true HITS by 8% and 14%, respectively. CONCLUSIONS: Using intensity thresholds higher than the optimal for embolus detection decreases HITS counts. Choosing a threshold depends on the type of method used for measuring the signal intensity. Uniform threshold criteria and comparative studies between different Doppler devices are necessary for making clinical trials more comparable.     

Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 mug/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.     

Human hepatocellular carcinoma tumor xenografts

Castrated or sham-operated male athymic mice were inoculated with cells from the human hepatocellular carcinoma cell line PLC/PRF/5. There were no significant differences between the two groups with respect to the number of animals developing tumors, the time to tumor development, or the subsequent rate of increase in either tumor base area or mouse serum alpha-fetoprotein concentration. Androgen receptors were assayed in nuclei obtained from three separate liver cancer cell lines and from normal adult human liver. Similar concentrations, ranging from 235 to 550 fmol/mg DNA, of nuclear androgen receptors were detected in all tissues. Low percentages of androgen receptors were retained on DNA-cellulose. Although the presence of receptors implies the potential for metabolic effects of androgens in normal and malignant liver, our in vivostudies suggest that castration does not alter significantly the growth of liver cancer xenografts in athymic mice.     

Wortmannin-mediated inhibition of phosphatidylinositol 3-kinase activity triggers apoptosis in normal and neoplastic B lymphocytes which are in cell cycle

The B cell functional response following ligation of surface(s) lgM is dependent upon the differentiation stage of the populationstudied: cross-linking slgM promotes proliferation of restingtonsillar follicular mantle (FM) B lymphocytes but induces apoptosisin the susceptible Epstein- Barr virus genome-negative Burkittlymphoma (BL) cell line Ramos (Ramos-BL). This study investigateswhether phosphatidylinositol-3-kinase (Pl3-kinase), which hasbeen reported to be intimately involved in the regulation ofcellular growth, plays a role in the regulation of these sig-promoted B cell responses, and uses the selective and irreversibleinhibitor of Pl3-kinase activity, wortmannin (Wm). In Ramos-BLB cells, at 8 h post-treatment, Wm triggers a transient increasein apoptosis of 16 ± 6.9% with a concomitant cellularloss of 16 ± 6.1% from the G₁ phase of cell cycle; [³H]thymidineincorporation also decreases by 33 ± 5.0%, from 37,274c.p.m. ± 10% to 25,127 c.p.m. ± 4.0%. Moreover,at 72 h culture, Wm inhibits anti-lgM-induced FM B lymphocytelevels of [³H]thymidine incorporation typically by 47% and triggers80% apoptosis from the G₀G₁ phase of cell cycle. Ramos-BL Bcells exhibit high basal levels of Pl3-kinase activity, as determinedby immunoprecipitation with antibody to the p85 regulatory subunitof Pl3-kinase and ³²P incorporation into phosphatidylinositol,which is not significantly affected by anti-lgM stimulation;by contrast, anti-lgM stimulates significant Pl3-kinase activityover negligible basal levels in FM B lymphocytes. Pre-treatmentwith Wm inhibits Pl3-kinase activity in both cell types. Takentogether these data indicate that in Ramos-BL B cells slgM-triggeredgrowth arrest and apoptosis is Pl3- kinase independent, whereasPl3-kinase activity is critical for slgM-triggered mitogenesisof FM B lymphocytes. Thus Pl3-kinase plays a pivotal role inthe regulation of both normal and neoplastic B lymphocyte progressionthrough the cell cycle, such that if this Pl3-kinase-dependentpathway is inhibited these cells default to apoptosis.     

Measurements of Blood Pressure, Oedema and Proteinuria in a Pregnant Population of New Zealand

Summary: This is the first report of the largest study of blood pressure measurement in pregnancy in a New Zealand population using standardized definitions and methodology. Over 3,800 women who delivered in an 8-month period in the Wellington region were included in the study. Blood pressure measurement and the presence of oedema and proteinuria were recorded from booking until delivery and in the puerperium. Only 2.7% of women were unable to be contacted after delivery for details on outcomes. The results established normal ranges for blood pressure throughout pregnancy. The data show that Mood pressure greater than 140/90 until 35 weeks' gestation is outside 2 standard deviations at all gestations and justifies using these measurements as the definition of hypertension in pregnancy. The fall in blood pressure in the 2nd trimester was less than 1 mm Ffg per week in both the systolic and diastolic pressures. This fall was smaller than previously recorded in other studies. Gestational hypertension was the commonest blood pressure abnormality occurring in 15.2% of the population. This represented 69% of the pregnant women with a hypertensive disorder. The overall incidence of both gestational hypertension and preeclampsia was 18.5% which is higher than reported in other parts of the world. In this study obesity was significantly associated with hypertensive disorders in pregnancy. An arm circumference of >33 cm, one of the measurements of obesity, was found in 6.8% of the study population. Even after the effect of arm circumference was taken into account, hypertensive disorders were also more common in Pacific Island women. Ankle oedema was significantly associated with the development of both gestational hypertension and preeclampsia but the incidence of oedema was noted in only 11.9% of the subjects.