Influence of frequency of atrial contraction on coronary blood flow and ventricular performance in the conscious dog with myocardial infarction.

The effects of alterations in the frequency of contraction on coronary blood flow and ventricular performance were studied in 12 conscious, unsedated dogs with established myocardial infarction. Total and regional coronary blood flow was measured using radioactive microspheres. The peak increase in flow to the right ventricle was 71% to the infarcted area of the left ventricle was 72% to the non-infarcted area of the left ventricle was 90% and to the ventricular septum was 104%. Despite the generalized increases in regional myocardial blood flow, flow tended to decrease to the subendocardial portion of the infarcted area of the left ventricle. The peak increases in coronary flow and the reduction in flow to the subendocardial portion of the infarcted area occurred at a heart rate of approximately 200/min provided by atrial pacing. Myocardial contractility, as evidenced by peak increases of 16% in maximum LV dP/dt and 12% in dP/dtP, was only enhanced with abrupt incremental changes in heart rate and not with continuous atrial pacing over 15-min periods. Despite the generalized increases in coronary perfusion coronary sinus oxygen content decreased with a widening of the coronary arteriovenous oxygen difference indicating increased myocardial oxygen usage. Thus increasing frequency of contraction in myocardial infarction results in a slight initial but not sustained inotropic effect, a moderate and generalized increase in regional myocardial blood flow, increased myocardial oxygen consumption, and the potential for subendocardial extension of the area of myocardial damage within the infarcted area.     

Haemostatic disturbances in patients bitten by Russell''s viper (Vipera russelli siamensis) in Burma

Patients who are severely envenomed by Russell's viper develop DIC which is frequently associated with spontaneous bleeding and incoagulable blood. These haemostatic disturbances may be responsible for death or organ/tissue damage both through haemorrhage and microvascular occlusion by fibrin thrombi. The most striking laboratory features of the coagulopathy developing after Russell's viper bite in the 42 patients studied were depletion of fibrinogen (mean 0.09 g/l, range 0-0.6), factor V (6.5 u/dl, range 0-17), factor X (35 u/dl, range 1-85), factor XIIIa (57 u/dl, range 15-82), plasminogen (61 u/dl, range 10-92), antiplasmin (36 u/dl, range 14-62). Protein C (49 u/dl, range 15-100) and platelets (104 x 10(9)/l, range 25-197). Intense fibrinolytic activity was detected in all cases with marked elevation of FDPs (1614 micrograms/ml, range 350-3000), a large proportion of which were cross-linked (1058 micrograms/ml, range 38-3000). The monospecific Burmese antivenom appeared to be very effective in neutralizing the venom procoagulants and in restoring blood coagulability. Moreover, the unexpectedly normal level of AT III provides a theoretical basis for the use of heparin to enhance the inactivation of those serine proteases present before antivenom administration.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Nosocomial transmission of tuberculosis associated with a draining abscess

Nine secondary cases of tuberculosis and 59 tuberculin skin test conversions occurred after exposure to a hospitalized patient with a large tuberculous abscess of the hip and thigh. Among 442 tuberculin-negative hospital employees, the relative risk of skin test conversion associated with recalled exposure to the patient was 14.0 (95% confidence limits, 6.8, 28.7). Four of 5 surgical suite employees who assisted with incision and debridement of the abscess had skin test conversions, as did 85% of 33 employees on a general medical floor who recalled exposure to the patient and 30% of 20 intensive care unit employees who recalled exposure. The prevalence of tuberculin reactivity in visitors and other patients on two floors also showed a strong association with exposure to the patient. A high concentration of Mycobacterium tuberculosis in the abscessed tissue, disturbance of the surface of liquid drainage from the abscess by irrigations and by the agitated behavior of the patient, and positive air pressure in the patient's room are factors that appear to have contributed to the high risk of tuberculosis transmission.     

Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma)

Serial venom antigen levels were measured by enzyme-linked immunosorbent assay (ELISA) in 46 patients with systemic envenoming by the Malayan pit viper (Calloselasma rhodostoma), a major cause of snake bite in Southeast Asia. The principal effects of the venom are defibrination, hemorrhage and local tissue necrosis. Admission venom levels, which varied between 0 and 595 ng/ml, correlated with the incidence of spontaneous systemic bleeding, blood incoagulability and concentrations of plasma fibrinogen and serum fibrin degradation products. The presence or absence of nonclotting blood also correlated with the time elapsed between the bite and hospital admission. The development of nonclotting blood may be delayed by up to 72 hr after the bite even though circulating venom and raised FDP may be detected at presentation. This is probably explained by a temporary equilibrium between synthesis and consumption of fibrinogen. Venom antigenemia recurred in 12 patients (26%) suggesting continuous absorption of venom from the wound or saturation of extravascular binding sites. Admission venom levels also correlated with the extent of local swelling and the occurrence of tissue necrosis at the site of the bite. Venom was detected in 87% of wound aspirates and 88% of urine specimens taken on admission. Tourniquets, of the type used in rural Thailand, did not delay the absorption of venom into the circulation.     

Age‐Matched Dendritic Cell Subpopulations Reference Values in Childhood

Dendritic cells (DCs) are the most potent antigen‐presenting cells and are the key link between the innate and adaptive immune response. Only a few reports with study populations of up to 50 individuals have been published with age‐based reference values for DC subpopulations in healthy children. Therefore, we aimed to establish reference ranges in a larger study population of 100 healthy children, which allowed age‐matched subgroups. Most previous studies were performed using a dual‐platform approach. In this study, a single‐platform approach in a lyse no‐wash procedure was used. DC subpopulations were defined as follows: CD45⁺CD85k⁺HLA‐DR⁺CD14^?CD16^?CD33⁺ cells as myeloid DCs (mDCs) and CD45⁺CD85k⁺HLA‐DR⁺CD14^?CD16^?CD123⁺ cells as plasmacytoid DCs (pDCs). Reference ranges were established using a semi‐parametric regression of age‐matched absolute and relative DC counts. We found a significant decline with increasing age in the medians of mDCs (P = 0.0003) and pDCs per μl peripheral blood (PB) (P = 0.004) and in the 50%, 90% and 95% reference ranges. We also identified significantly lower absolute cell counts of mDCs per μl PB in girls than in boys for all age groups (P = 0.0015). Due to the larger paediatric study population and single‐platform approach, this study may give a more precise overview of the normal age‐matched development of DC subpopulations and may provide a basis for analyzing abnormal DC counts in different illnesses or therapies such as post stem cell transplantation.     

Influence of heart rate and atrial transport on left ventricular volume and function: relation to hemodynamic changes produced by supraventricular arrhythmia

The response of the left ventricle to pacing-induced changes in heart rate and the atrioventricular (A-V) relation was examined with equilibrium gated radionuclide ventriculography in 20 patients who had normal ventricular function after surgery for recurrent supraventricular tachycardia. In 10 patients count-derived left ventricular ejection fraction, end-diastolic volume and stroke volume were measured during sinus rhythm and during atrial pacing at 120, 140 and 160 beats/min. In the other 10 patients similar determinations were made during sequential A-V and simultaneous ventricular and atrial (V/A) pacing, both at rates of 100 and 160 beats/min. Left ventricular ejection fraction did not change significantly with atrial pacing (from 0.65 +/- 0.02 [mean +/- standard error of the mean] at a baseline sinus rate of 91 +/- 3 beats/min to 0.62 +/- 0.03 at 160 beats/min) despite a progressive decrease in end-diastolic volume. The percent reduction in end-diastolic volume (% delta EDV) and stroke volume (+ delta SV) from the baseline values was linear and related to change in heart rate (delta HR) as % delta EDV = -0.60 delta HR + 5.19 (r = 0.71; p less than 0.01) and % delta SV = -0.62 delta HR + 5.03 (r = 0.76; p less than 0.001). Left ventricular ejection fraction with baseline sequential A-V pacing at 100 beats/min was 0.67 +/- 0.03 and not significantly altered by either sequential A-V or simultaneous V/A pacing at 160 beats/min. At 100 beats/min, loss of atrial transport with simultaneous V/A pacing resulted in a small reduction in end-diastolic volume from a baseline value of -9.0 +/- 1.9 percent (p less than 0.01) and a nonsignificant reduction in stroke volume of -3.7 +/- 1.6 percent. During simultaneous V/A pacing at 160 beats/min, the reduction in end-diastolic and stroke volumes from the baseline value was -26.6 +/- 3.8 percent and -28.8 +/- 4.3 percent, respectively (both p less than 0.01), but was significantly smaller (-16.1 +/- 3.6 percent and -19.2 +/- 4.1 percent, respectively [p less than 0.05]) when atrial transport was maintained during sequential A-V pacing at the same heart rate. During simultaneous V/A pacing at 160 beats/min, two thirds of the reduction in end-diastolic and stroke volumes from the baseline value was due to the increment in heart rate as assessed from sequential A-V pacing and the other third was due to loss of atrial transport. The data indicate that the hemodynamic consequences of supraventricular tachyarrhythmias in patients with normal ventricular function are due primarily to decreases in ventricular volume as heart rate is increased and atrial contribution is lost rather than to any changes in left ventricular ejection fraction.     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.