Left heart pressures can be the key to know the limitation of left ventricular assist device support against progression of aortic insufficiency

Aortic insufficiency (AI) is a worrisome complication under left ventricular assist device (LVAD) support. AI progression causes LVAD-left ventricular (LV) recirculation and can require surgical intervention to the aortic valve. However, the limitations of LVAD support are not well known. Using an animal model of LVAD with AI, the effect of AI progression on hemodynamics and myocardial oxygen metabolism were investigated. Five goats (Saanen 48?±?2 kg) underwent centrifugal type LVAD, EVAHEART, implantation. The AI model was established by placing a vena cava filter in the aortic valve. Cardiac dysfunction was induced by continuous beta-blockade (esmolol) infusion. Hemodynamic values and myocardial oxygen extraction ratio (O₂ER) were evaluated while changing the degree of AI which was expressed as the flow rate of LVAD-LV recirculation (recirculation rate). Diastolic aortic pressure was decreased with AI progression and correlated negatively with the recirculation rate (p?=?0.00055). Systolic left ventricular pressure (LVP) and mean left atrial pressure (LAP) were increased with AI progression and correlated positively with the recirculation rate (p?=?0.010, 0.023, respectively). LVP and LAP showed marked exponential increases when the recirculation rate surpassed 40%. O₂ER was also increased with AI progression and had a significant positive correlation with the recirculation rate (p?=?0.000043). O₂ER was increased linearly, with no exponential increase. AI progression made it difficult to reduce the cardiac pressure load, worsening myocardial oxygen metabolism. The exponential increase of left heart pressures could be the key to know the limitation of LVAD support against AI progression.     

Outflow graft anastomosis site design could be correlated to aortic valve regurgitation under left ventricular assist device support

Aortic valve regurgitation (AR) is a critical complication during circulatory support with a left ventricular assist device (LVAD). The time-course of AR and related factors, including outflow graft anastomosis site design, were investigated. Twenty-three patients who had continuous-flow LVAD implantation and were supported for more than 6 months were investigated. AR grade (none, 0; trivial, 0.5; mild, 1; mild-moderate, 1.5; moderate, 2; moderate-severe, 2.5; severe, 3) and aortic valve opening were evaluated with echocardiography. Computed tomography was performed to all the patients postoperatively. The angle of the outflow graft to the aorta (O-A angle, parallel 0; tangent 90°, 0–180°), aortic diameter at the anastomosis site, sino-tubular junction (STJ) diameter, distance between the STJ and the anastomosis site, and distance between the anastomosis site and the brachiocephalic artery were measured. The patients’ age was 38?±?11 years. Support duration was 686?±?354 days. Mean AR grade after continuous-flow LVAD implantation was increased to around mild and was maintained thereafter. No patient needed any intervention to the aortic valve. The aortic valves of 82.6% of patients were closed continuously. The O-A angle (83?±?14) was positively correlated with maximum AR grade (p?=?0.0095). The O-A angle was significantly smaller in patients with maximum AR grade of 1 or less (77?±?9°) than in those with 1.5 or greater (94?±?15°, p?=?0.021). The other CT measurements had no correlation with AR grade. In conclusion, the O-A angle was correlated with AR grade progression. The O-A angle appears to be one of the important factors related to AR under continuous-flow LVAD support.     

Urinary macrophages as activity markers of renal injury

The presence of macrophages (Mφ) in the urine of patients with glomerulonephritis (GN) reflects the pathological events in the kidney, and we have discovered the following correlations between the Mφ phenotype and the pattern of renal injury. (1) Urinary macrophage (Mφ) counts increase in patients with proliferative GN, especially in the presence of active glomerular lesions (glomerular tuft necrosis, crescent, and endocapillary proliferation). In patients with hematuria, a combination of urinary Mφ and T-lymphocyte counts can be used to differentiate proliferative GN from non-proliferative renal disease (hereditary nephropathy and idiopathic renal hematuria). (2) The urinary Mφ of patients with active proliferative GN express FcgammaRIII (CD16) regardless of the type of GN. (3) There are two types of urinary CD68(+) cells, CD68(+)25F9(-) cells (infiltrating Mφ) and CD68(+)25F9(+) cells (mature Mφ). The CD68(+)25F9(-) cell counts in the urine correlate well with the activity of proliferative GN, and the CD68(+)25F9(+) cell counts in the urine correlate with the magnitude of non-selective proteinuria and with the subsequent decline of renal function. The CD68(+)25F9(+) cell count increases in the urine of patients with focal segmental glomerular sclerosis, but their numbers are negligible in minimal change nephrotic syndrome. These findings indicate that the analysis of the urinary Mφ phenotype is a useful strategy for evaluating renal injury as a 'risk-free renal biopsy'.     

An idiotypic marker associated with a germ-line encoded kappa light chain variable region that predominates the vaccine-induced human antibody response to the Haemophilus influenzae b polysaccharide.

Human antibodies specific for the Haemophilus influenzae b polysaccharide (Hib PS) frequently express a cross-reactive idiotype (CRI), and commonly utilize a VL region that is the product of the V kappa II gene A2. To examine further anti-Hib PS V region expression and to determine whether CRI expression is correlated with the V kappa IIA2 chain, we isolated a monoclonal antibody (MAb) reactive with an idiotypic determinant of anti-Hib PS antibodies. This MAb inhibited Hib PS binding but did not react with Ig isotypic determinants. The CRI recognized by this MAb, designated HibId-1, was associated with the Hib PS-combining site since the reactivity of the MAb with anti-Hib PS antibodies could be inhibited by Hib PS. HibId-1 was expressed by 17 of 17 clonally purified and sequence-defined anti-Hib PS antibodies having V kappa IIA2 L chains. In contrast, 0 of 10 anti-Hib PS antibodies having either V lambda, V kappa I, or V kappa III chains expressed HibId-1. Western blot analysis showed that the MAb anti-CRI reacted with isolated anti-Hib PS V kappa IIA2 L chains but not with H chains or other L chains, indicating that the HibId-1 determinant is localized to the V kappa IIA2 chain, and does not require pairing with H chain for expression. Anti-Hib PS antibodies bearing HibId-1 were present in at least 85% of subjects immunized with either free Hib PS or Hib PS coupled to diphtheria toxoid (Hib PS-DT), and comprised on the average 60% of the total vaccine-induced serum anti-Hib PS. HibId-1 expression was not related to age at vaccination inasmuch as infants, children, and adults had similar distributions of HibId-1-positive anti-Hib PS after vaccination with Hib PS-DT. HibId-1 was expressed at a lower frequency and comprised a smaller fraction of the total anti-Hib PS antibody in adult preimmunization sera as compared to post-Hib PS immunization sera, suggesting that immunization preferentially stimulates HibId-1-positive B cells. These data demonstrate that antibodies bearing HibId-1/V kappa IIA2 comprise a predominant component of the anti-Hib PS response induced by immunization, and that this pattern of VL expression is established early in ontogeny.     

Biochemical studies on the purine metabolism of four cases with hereditary xanthinuria

The purine metabolism of four cases with marked hypouricemia (serum uric acid concentration of less than 0.018 mmol/l) from three Japanese families was investigated. Erythrocyte adenosine deaminase (EC 3.5.4.4) and purine-nucleoside phosphorylase (EC 2.4.2.1) activities of the patients were within the normal ranges. Urinary hypoxanthine and xanthine concentrations were 0.096-0.397 mmol/l and 0.743-1.717 mmol/l, respectively. Xanthine oxidase (EC 1.2.3.2) activities in the jejunal mucosa of the two normal controls were 0.257 and 0.283 units/g protein, while those of three of the patients were extremely low and could not be determined. The findings of these biochemical features may indicate that the four patients have hereditary xanthinuria. In order to study the purine metabolism in the hypouricemic condition of this disorder, a single oral dose of allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine) was administered in one case. The excretion pattern of allopurinol and oxypurinol (4,6-dihydroxypyrazolo[3,4-d]pyrimidine) in the urine of the patient was similar to that of a normal control male. These data suggest that some residual enzyme activity may be functioning in vivo, although the presence of xanthine oxidase could not be detected.     

Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction

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Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that frequently metastasizes and that overexpresses transforming growth factor-beta s (TGF-beta s). To determine whether TGF-beta s can act to enhance the metastatic potential of PDAC, PANC-1 human pancreatic cancer cells were transfected with an expression construct encoding a soluble type II TGF-beta receptor (sT beta RII) that blocks cellular responsiveness to TGF-beta 1. When injected s.c. in athymic mice, PANC-1 clones expressing sT beta RII exhibited decreased tumor growth in comparison with sham-transfected cells and attenuated expression of plasminogen activator inhibitor 1 (PAI-1), a gene associated with tumor growth. When tested in an orthotopic mouse model, these clones formed small intrapancreatic tumors that exhibited a suppressed metastatic capacity and decreased expression of plasminogen activator inhibitor 1 and the metastasis-associated urokinase plasminogen activator. These results indicate that TGF-beta s act in vivo to enhance the expression of genes that promote the growth and metastasis of pancreatic cancer cells and suggest that sT beta RII may ultimately have a therapeutic benefit in PDAC.