Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib.

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+ leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

Development of multichannel array transducer of displacement mechanical-myogram.

The myoelectric signal (EMG) recorded on the skin surface is a time-related and spatial aggregate of the action potentials of motor units of skeletal muscle, and it indicates the input information for muscle contraction. The mechano-myographic signal (MMG) is a vibration of skin/muscle surface caused by muscle contraction and it directly reflects the activity of muscle contraction. The two-dimensional generation mechanism of MMG is still n ot clarified in detail. In this study, the displacement MMGs were recorded at 25 measuring points using 5 × 5 displacement MMG array transducer within 50× 50 mm, while the motor point of the biceps brachii was electro-stimulated. The spatial propagation map of twitch waveform of displacement MMG was drawn.

QT dispersion measured by automatic computerized 12-lead electrocardiography contributes significantly to detection of left ventricular hypertrophy in Japanese patients.

This study assessed the diagnostic value of QT dispersion for left ventricular hypertrophy (LVH) as determined by echocardiography. The QT and QRS interval parameters were determined automatically using computerized 12-lead electrocardiography in 153 Japanese out-patients. Corrected QT dispersion (QTcD) and maximal QRS duration (MaxQRS) were significantly correlated with left ventricular mass index. The sum of QTcD and MaxQRS showed the highest correlation with left ventricular mass index among QT and QRS interval parameters and their combinations. The cut-off points for LVH discrimination in this study were different to those reported in Western, mainly Caucasian, populations, suggesting the need for ethnicity-specific LVH detection criteria. A scoring system derived from multiple logistic regression analysis, employing a combination of QTcD, QRS time-voltage product and ST-T change, showed a specificity of 86.3%. It was concluded that QTcD, in addition to QRS time-voltage product and ST-T change, improved the detection of LVH.

Mathematical equation of fusion index of tetanic contraction of skeletal muscles.

The fusion index (FI) is an index that can evaluate the tetanic progression of the skeletal muscles. Although the FI-frequency curve (FFC), which is obtained by changing the stimulation frequency, is greatly affected by muscle fiber type and fiber compositions, there are no reports of a mathematical equation that can express the FFC. In this study, the FFC was measured for the gastrocnemius, vastus intermedius, and soleus muscles of rats, and the mathematical equation (FFC-equation) was proposed. The FFC-equation (FI(f)) was proportional to the h-th power of f, and was in inverse proportion to the sum of the h-th power of k and the h-th power of f. f was the stimulation frequency, k was the stimulation frequency at 50% of FI, and h reflected the gradient of FFC. As a result, the approximated curve produced by the FFC-equation corresponded with the measured FFC. k reflected the fiber compositions and h represented the ratio of relaxation time to contraction time of the twitch contraction. The calcium ion fluctuation in muscle plasma may be described by the FFC-equation obtained from the experimental data.

Compromised recovery of natural interferon-alpha/beta-producing cells after allogeneic hematopoietic stem cell transplantation complicated by acute graft-versus-host disease and glucocorticoid administration.

Delayed recovery of the immune system is a major cause of post-transplant infection. Natural interferon (IFN)-alpha/beta-producing cells (IPC) appear to play a critical role in inducing effective immune responses to a variety of microbial pathogens by producing an enormous amount of IFN-alpha/beta and thereafter by differentiating into dendritic cells. Here, we examined the recovery of IPC as well as other immune cells in 28 patients after allogeneic hematopoietic stem cell transplantation (HSCT) in order to investigate the role of IPC in post-transplant immune reconstitution. In uncomplicated cases, IPC frequency recovered to the lower range of normal values within 30 days after transplantation, resembling the prompt recovery of other cell types in innate immunity. In contrast, the recovery of IPC was profoundly suppressed in the cases with acute graft-versus-host disease (GVHD) and glucocorticoid administration. The patients with lower numbers of IPC were significantly more susceptible to viral infection. The prompt recovery of IPC in uncomplicated cases may contribute to establishing a first line of host defense at the early stage after allogeneic HSCT, whereas the marked suppression of IPC recovery accompanying acute GVHD and glucocorticoid administration may increase the risk of opportunistic infections.

Non-Hodgkin's lymphoma involving bilateral breasts.

We describe here two cases of diffuse large cell type non-Hodgkin's lymphoma affecting the bilateral breasts. The contralateral tumor in one case appeared 17 months after the first mastectomy, whereas the bilateral tumors occurred concurrently in the other patient who was pregnant and showed widespread dissemination at initial presentation. Lymphoma cells from both cases showed the mature B-cell immunophenotype and had rearrangements of the BCL6 gene. Both patients developed progressive disease despite chemo-radiotherapy and died of leukemic manifestations. There were no apparent pathological features of lymphomas of mucosa-associated lymphoid tissue origin.

Changes in platelet demand in association with the spread of autologous peripheral blood progenitor cell transplantation.

Changes in platelet demand accompanying widespread application of autologous peripheral blood progenitor cell transplantation (APBPCT) were anticipated. The differences in the transfused volume of platelet concentrate (PC) among 8 patients with malignant lymphoma who were treated with APBPCT and 10 patients with malignant lymphoma who were not treated with APBPCT, although peripheral blood progenitor cell harvests had been performed, were studied. The former was 81 Japanese PC units more than the latter. Considering the supplied volume of PC from Red Cross blood centers and the number of APBPCTs in 1996 in Japan, the Japanese demand for PC increases by 0.16% for enforced APBPCT versus 0.36%, which includes the PC demand necessary in all treatment courses. The total increment in PC demand associated with APBPCT is not large enough to threaten the PC supply of Japan even if the number of APBPCTs increases rapidly.

[Intracranial hemorrhage associated with aplastic anemia].

Intracranial hemorrhage is a fatal complication associated with aplastic anemia. We have encountered four patients who experienced six episodes of intracranial hemorrhage (intracerebral hemorrhage; 3, subarachnoid hemorrhage; 2, and subdural hematoma; 1,). Intracranial hemorrhage occurred without traumatic episodes, and was followed by frequent hemorrhagic episodes in other parts of about one year duration. This disease is considered to recur after a short interval. The site, type and degree of intracranial hemorrhage varied, and therefore intracranial hemorrhage seemed to be caused not only by thrombocytopenia but also by multifactorial hemorrhagic tendency. Transfusion of platelet rich plasma, and administration of Glycerol and steroids produced good results for conservative therapy. Continuous spinal drainage for subarachnoid hemorrhage was a relatively safe and useful means of management. In the patients who showed precipitous deterioration, the CT scan findings indicated that the high-density-area was diffusely spread with an unclear border, just like "contusional hemorrhage". For such severe cases, blood evacuation with craniotomy and emergency splenectomy are considered to be valuable.

Studies on vitamin K-dependent factor deficiency during early childhood with special reference to prothrombin activity and antigen level.

8 young infants aged 14 days to 5 months with vitamin K-dependent factor deficiency were studied with special reference to prothrombin activity and antigen level. Among them, 3 infants had congenital bile duct atresia and 5 were breast-fed babies with severe hemorrhagic tendency of unknown cause. In the patients with both congenital bile duct atresia and breast feeding the ratio of prothrombin activity to prothrombin antigen was lower than 0.1. Furthermore, the arc of prothrombin antigen in these patients demonstrated a faster anodal shift than did normal prothrombin antigen on crossed immunoelectrophoresis. This abnormal prothrombin antigen was not consumed after recalcification of patient plasma, and absorbed poorly on BaSO4. In addition, the abnormal prothrombin antigen disappeared from the patient plasma within a few days after parenteral administration of vitamin K. These results suggest that this abnormal prothrombin is PIVKA-II.

[Therapeutic effect of ticarcillin against severe infection in patients with hematologic malignancy (author's transl)].

Seventy patients with severe infection accompanying hematologic disorders including leukemia and lymphoma were treated with ticarcillin in combination with aminoglycosides and/or cephem derivatives. Of the 58 patients in whom the efficacy could be evaluated, 17 (29%) responded markedly and 22 (38%) moderately, the effective rate being 67%. Side effects attributable to the treatment were noted: rash in 2, fever and rash in 1, vascular pain in 2 (5 and 7 years of age). Renal and hepatic functions were abnormal in 4 each. However, these abnormal findings were not attributed to ticarcillin. These results indicate that ticarcillin is an effective and safe antibiotic for the treatment of severe infection accompanying hematologic malignancy when used in combination with aminoglycosides and/or cephem derivatives.