Early detection of doxorubicin and daunorubicin cardiotoxicity by echocardiography: Diastolic versus systolic parameters

Doxorubicin and daunorubicin are effective anticancer agents in children, however, their therapeutic value is limited by myocardial cardiotoxicity. In 14 children (median age 5,0 years, range 3–12) prospective studies were performed using pulsed Doppler echocardiography to assess the changes in left ventricular systolic and diastolic filling dynamics. None of these children developed cardiomyopathy. M-mode echocardiographic systolic parameters and Doppler transmitral flow velocities were analysed at baseline, after a cumulative anthracycline dose of 138±26 mg/m² (second examination) and after 240±15 mg/m² (third examination). At the second examination the acceleration time/ejection time ratio was significantly reduced (P<0.01), but this was no longer evident at the third examination. There was no significant change of peak velocity over aortic valve, preejection period and change of velocity over time. In contrast, three diastolic parameters changed significantly; the late over early inflow velocity (P<0.05), mitral valve late time velocity integral (P<0.01 at the second andP<0.05 at the third examination) and the ratio A-TVI/TVI (P<0.025 andP<0.01). At the third examination the velocity of the A wave was also significantly increased.Conclusion In anthracyline treated children left ventricular diastolic function deteriorates before systolic function. Diastolic function parameters should be used rather than systolic parameters to monitor these patients.     

Disease activity and pretreatment,rather than hypogammaglobulinaemia,are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia

To identify patients at high risk of life-threatening infections, we retrospectively analysed the prevalence of infectious complications in 187 chronic lymphocytic leukaemia patients treated in our institution since 1999 and correlated them with clinical features. A questionnaire with detailed questions regarding infectious complications was mailed to patients and their general practitioners. Major infections (requiring intravenous antibiotics or inpatient treatment) were reported in 37 patients (19.8%) and minor infections (requiring oral antibiotics and outpatient treatment) in 113 patients (60.4%). Univariate analysis identified advanced disease (P = 0.02), gender (P = 0.01), duration of disease (P = 0.007), number of previous chemotherapy regimens (P < 0.001), previous therapy with purine analogues and monoclonal antibodies (P < 0.001; P = 0.019), massive splenomegaly (P = 0.03), low granulocyte count (P < 0.001), low serum immunoglobulin concentration (P = 0.005), low haemoglobin concentration (P < 0.001) and high serum lactate dehydrogenase (LDH) concentration (P < 0.001) as risk factors for major infections. In multivariable logistic regression analysis, only the number of previous chemotherapy regimens (risk ratio [RR] = 1.8; 95% confidence interval [CI] 1.2-8.0) and haemoglobin concentration (RR = 0.6; CI 0.5-0.8) remained significant for major infections. The number of previous chemotherapy regimens was the only independent risk factor for minor (RR = 7.6; CI 2.2-25.7) and varicella-zoster virus infections (RR = 2.1; CI 1.3-3.4). In untreated patients, the only risk factor for major infections was LDH concentration. Patients treated with purine analogues or autologous stem cell transplantation had a higher risk of developing viral infections. In conclusion, disease activity and pretreatment extent have a stronger impact on the risk of severe infectious complications than hypogammaglobulinaemia. Preferably, prophylactic strategies should be evaluated in patients defined by these parameters.     

Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection

BACKGROUND: Cutaneous manifestations of B-cell chronic lymphocytic leukemia (B-CLL) comprise a wide spectrum of clinicopathologic presentations. In some cases, onset of skin lesions is triggered by antigenic stimulation, and specific skin infiltrates at sites of previous herpes simplex or herpes zoster infection have been well documented. Specific skin manifestations of B-CLL can also be observed at sites typical for lymphadenosis benigna cutis (nipple, scrotum, earlobe), a Borrelia burgdorferi-associated cutaneous B-cell pseudolymphoma. METHODS: We studied specific skin manifestations of B-CLL arising at sites typical for B. burgdorferi-induced lymphadenosis benigna cutis, analyzing tissues for presence of B. burgdorferi DNA using the polymerase chain reaction (PCR) technique. Six patients with B-CLL (M : F = 4 : 2; mean age: 67.8) presented with specific skin lesions located on the nipple (four cases) and scrotum (two cases). RESULTS: Clinically there were solitary erythematous plaques or nodules. Histology revealed in all cases a dense, monomorphous infiltrate of small lymphocytes showing an aberrant CD20+/CD43+ phenotype. In all cases monoclonality was demonstrated by PCR analysis of the JH gene rearrangement. PCR analysis showed in four of the six cases the presence of DNA sequences specific for B.burgdorferi. CONCLUSIONS: Our study demonstrates that infection with B. burgdorferi can trigger the development of specific cutaneous infiltrates in patients with B-CLL.     

A NEW APPROACH TO THE USE OF MANUAL ACTIVITY IN PSYCHIATRIC TREATMENT GROUPS

The following treatment mode was developed as a team effort in the psychiatric unit of Royal North Shore Hospital. We have found this approach so useful that it seems of value to pass it on. Basically it could be described as the use of manual activity and Gestalt techniques in a group setting.     

CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study

OBJECTIVE: Treatment with antidepressants is frequently associated with adverse effects or insufficient clinical response. Several antidepressants are metabolized by cytochrome P450 (CYP) 2D6. The activity of this enzyme markedly varies among individuals from poor to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. This association study investigated whether the CYP2D6 genotype distribution differs from that of the German white population either in patients with marked adverse effects or in nonresponders during treatment with antidepressants metabolized by CYP2D6. METHODS: By use of a retrospective, naturalistic approach, outpatient practices and hospitals in southern Germany were asked to report on patients who either had had adverse drug effects or were nonresponsive during treatment with CYP2D6-dependent antidepressants. CYP2D6 genotyping was performed by a panel of polymerase chain reaction techniques. Poor and intermediate metabolizer alleles, as well as allelic duplications of CYP2D6, were detected. RESULTS: Of 28 patients with adverse effects during treatment with a CYP2D6-dependent antidepressant, 8 (29%) had 2 inactive alleles and thus were poor metabolizers. This is a 4-fold increase as compared with the German population (P <.0001). Amplification of fully functional alleles (associated with ultrarapid metabolism) was found in 3 (19%) of the 16 nonresponders (approximately 5.0-fold higher in nonresponders than in the population) (P =.0012). CONCLUSION: The results suggest that the CYP2D6 genotype is associated with the occurrence of adverse effects and clinical nonresponse in psychiatric patients treated with CYP2D6-dependent antidepressants.     

Association between plasmin activation system and intravascular ultrasound signs of plaque instability in patients with unstable angina and non-st-segment elevation myocardial infarction

Background

The association between intravascular ultrasound (IVUS) signs of plaque instability and plasma levels of biomarkers was determined in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI).

Methods

Fifty-two patients underwent coronary angiography and IVUS 8 ± 5 hours after the onset of chest pain. IVUS analysis included plaque morphology, disruption, thrombi and eccentricity, lumen, external elastic membrane, and plaque plus media areas of culprit lesion and reference segments and arterial remodeling. Plasma levels of the thrombin activation system (thrombin-antithrombin complex [TAT], tissue factor pathway inhibitor [TFPI], and prothrombin fragments 1+2 [F1+2]) and plasmin activation system (tissue and urokinase-type plasminogen activator [t-PA and u-PA], plasminogen activator inhibitor-1 [PAI-1], and D-dimer) were measured with enzyme-linked immunosorbent assay kits before angiography.

Results

Elevated levels of TAT (7.2 ± 6.0 μg/L), F1+2 (1.8 ± 1.0 nmol/L), TFPI (179.1 ± 131.0 ng/mL), PAI-1 (95.4 ± 54.6 ng/mL), t-PA (10.6 ± 8.8 ng/mL), and u-PA (2.6 ± 0.9 ng/mL) were found in patients with UA/NSTEMI. The serum levels of D-dimer (40.0 ± 39.5 ng/mL) remained in reference range. Expansive and constrictive remodeling were found in 18 (35%) and 12 (23%) patients, respectively. Expansive remodeling of the culprit lesion was associated with significantly higher plasma levels of PAI-1 (121.6 ± 55.0 vs 87.7 ± 61.5 and 77.4 ± 42.8 ng/ml, P = .039), and u-PA (3.0 ± 1.2 vs 2.2 ± 0.5 and 2.5 ± 0.7 ng/mL, P = .026) as compared with constrictive and neutral remodeling. Increased plasma levels of u-PA were associated with plaque rupture (3.0 ± 0.7 vs 2.5 ± 0.9 ng/mL, P = .062). Plasma levels of PAI-1 and u-PA correlated positively with plaque plus media (P = .0297 and P = .0093) and external elastic membrane areas (P = .010 and P = .0002).

Conclusions

Elevated levels of biomarkers of plasmin activation system are associated with signs of plaque instability of culprit lesion in UA/NSTEMI and might therefore serve as non-invasive determinants of the population that is at high risk for subsequent adverse events.     

Effects of verteporfin therapy on central visual field function

PURPOSE: To evaluate the effect of photodynamic therapy with verteporfin on the maintenance of central visual field function. DESIGN: Randomized controlled clinical trial. PARTICIPANTS: Forty-six consecutive patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration including a classic component were randomly assigned. Thirty-three participants received standard verteporfin therapy, and 13 received placebo and laser treatment. METHODS: The trial was performed as a single-center, double-masked study. Patients were examined before therapy and continuously in 3-month intervals during 2 years of follow-up. A scanning laser ophthalmoscope (SLO) was used to perform macular microperimetry. Absolute and relative scotomas were documented at each visit, and size was measured in square millimeters. MAIN OUTCOME MEASURES: The change in size of central scotoma in the verteporfin group compared with the placebo group. RESULTS: An absolute scotoma was seen in 88%, and a relative scotoma was seen in 100% of eyes before therapy. Absolute defects were associated with the classic CNV component localized angiographically. In the verteporfin group, the absolute scotoma grew from 2.5 mm(2) at baseline to a final size of 7.3 mm(2) at month 24. In the placebo group, the mean lesion size of the absolute scotoma enlarged from an initial size of 2.7 mm(2) to 31.5 mm(2) after 24 months. The relative scotoma increased from 7.9 mm(2) at baseline to 20.8 mm(2) at month 24 in the verteporfin group, whereas a progression from 8.5 mm(2) initially to 48.3 mm(2) at the final presentation was measured in the placebo group. Statistical analysis showed that both the mean absolute and relative scotoma sizes were significantly smaller in the verteporfin group than the placebo group for all intervals from 6 to 24 months (P<0.001). CONCLUSIONS: Documentation of macular function with SLO perimetry demonstrated a significant benefit of verteporfin therapy for the preservation of the central visual field. Absolute and relative scotoma sizes remained smaller after therapy. This may influence reading ability and visual rehabilitation.     

Mortality due to gastroenteritis of unknown etiology in the United States

Gastroenteritis of unknown etiology (GUE) is a significant cause of mortality in the United States. In the present study, the demographic and medical characteristics of people who died of GUE were examined, using the 1995-1997 Multiple Cause of Death files to calculate GUE death rates and proportionate mortality ratios. There were 13,153 GUE deaths during the period, or approximately 4400 deaths per year. Death rates were highest among infants and elderly persons, especially nursing home residents, and increased during the winter months. Compared with all decedents, GUE decedents were more likely to have certain other medical conditions, including bacteremia, volume depletion, renal failure, and human immunodeficiency virus/acquired immunodeficiency syndrome. Fatal GUE often appeared to be infectious in origin, but death certificates provide insufficient information to determine whether the causative agents were unknown or foodborne. The accuracy of GUE reporting on death certificates and the etiology of fatal GUE merit further investigation.     

Clonal T cell-mediated cyclic thrombocytopenia

Cyclic thrombocytopenia is a rare disorder characterized by periodic platelet count fluctuations of unknown aetiology. We report on a female patient with cyclic changes of platelet counts ranging from 6 x 10(9)/l to 753 x 10(9)/l in 4-week intervals. Platelet counts were inversely correlated to thrombopoietin levels suggesting production failure. Reticulocyte counts and neutrophil counts showed similar, but less prominent, fluctuations. Clonal T-cell receptor rearrangement was detected in bone marrow samples as well as in peripheral blood. Cell typing of blood lymphocytes revealed a relative increase in CD3+ T cells. Treatment with cyclosporine A resulted in a substantial improvement of platelet counts. Taken together, we provide evidence for clonal T-cell mediated bone marrow failure with cyclic impairment of thrombopoiesis responsive to cyclosporine therapy.