Nonlinear Regulation of Capillary Perfusion in Relation to Ambient pO2 Changes in Skeletal Muscle

To study the process of O₂ transport to tissue, we investigated how capillary perfusion is controlled in response to changes in tissue O₂ levels in skeletal muscle. Capillary red blood cell (RBC) velocity and perfused capillary recruitment were measured in rabbit tenuissimus muscle at various ambient oxygen tensions (pO₂) by intravital microscopy. Both RBC velocity and capillary recruitment significantly decreased as the pO₂ level of the suffusate was increased, and the relationship between capillary perfusion, calculated from the velocity and recruitment data, and the pO₂ level of the suffusate clearly yielded a nonlinear correlation that fitted a sigmoidal curve. Capillary perfusion dramatically decreases or increases above or below a suffusate pO₂ level of around 40 Torr, where the O₂ dissociation curve of hemoglobin changes slope. These findings support the hypothesis that microvasculature possesses an intrinsic, effective flow-control mechanism by sensing the metabolic demands of tissue, intimately related to the O₂ saturation of hemoglobin.     

Post-transplant therapy with high-dose intravenous gammaglobulin: Applications to treatment of antibody-mediated rejection

B-cells and their products (antibodies) are now recognized as important mediators of allograft rejection. This represents a significant departure from previous doctrine where the T-cells were felt to be of paramount importance. Antibody-mediated rejection (AMR) has emerged as a significant and common complication of transplantation. The development of donor-specific (anti-HLA class I and class II) antibodies is known to correlate strongly with the development of AMR. Recognition of the unique features of AMR that were often confused with non-specific acute tubular injury is aided considerably by improvements in monitoring of anti-HLA antibodies and the immunopathologic demonstration of C4d staining in affected capillary beds. Although imperfect, the demonstration of C4d (a complement breakdown product) staining in an allograft, especially accompanied by the presence of anti-HLA antibodies in the recipient sera, strongly suggests a diagnosis of AMR. Thus, AMR is a complement-dependent, antibody-mediated disorder. AMR can occur as a de novo complication of transplantation in individuals not previously recognized to be sensitized to HLA antigens, but more often occurs as a complication of desensitization therapies in highly-HLA sensitized patients. AMR may also constitute a significant portion of what is now referred to as chronic allograft nephropathy (CAN). The prognosis of C4d (+) AMR is poor as current therapies for treatment of AR are directed primarily at the T-cell. Until recently, no therapeutic options existed to address this problem from a primary etiological standpoint. Here we discuss the use of high dose IVIG as an option for treatment of AMR. We have significant experience with this approach which is outlined here. IVIG has many ideal advantages as a therapy for AMR. First, it can down regulate B-cell activation and antibody production, second, it can induce anti-inflammatory cytokines and contains blocking antiidiotyic antibodies to anti-HLA antibodies and third, IVIG has the unique ability to block complement-mediated injury through inhibition of C3 activation. Further clinical trials are necessary to prove efficacy for treatment of AMR.     

Current approaches to treatment of antibody-mediated rejection

Antibody-mediated rejection (AMR) has recently been recognized as a significant and unique form of rejection that is not amenable to treatment with standard immunosuppressive medications aimed at modification of T-cell function. Recent interest in AMR and the role of B cells in rejection has been aided by the concomitant discovery that C4d staining of renal biopsy tissue is strongly associated with AMR and a poor prognosis, and the emergence of desensitization protocols for treatment of highly human leukocyte antigen (HLA)-sensitized patients. Treatment options include: (i) the use of high-dose intravenous immunoglobulin (IVIG) which works by blocking anti-HLA antibody activity and through complement inhibition, (ii) the use of Rituxan (anti-CD20 chimeric antibody) to deplete B cells and interfere with antigen-presenting cell (APC) activity of B cells subsequently decreasing T-cell activation, and (iii) the use of plasmapheresis (PE) + anti-cytomegalovirus (CMV) immunoglobulin G (IgG) or IVIG in lower doses. This protocol removes deleterious anti-HLA antibodies and may also allow complexing of anti-HLA with anti-idiotypes in the anti-CMV IgG. Although early, data support the efficacy of all three approaches. Many centers are now designing protocols that utilize a combination of all three agents. In summary, recent advances in the diagnosis and treatment of AMR has allowed for significant improvements in outcomes of a condition usually associated with rapid graft failure. However, much work needs to be done to better understand the immunologic processes leading to AMR and how current therapies can be best used to effectively prevent and treat it.     

Predicting the overall management outcome in patients with a subarachnoid hemorrhage accompanied by a massive intracerebral or full-packed intraventricular hemorrhage: a 15-year retrospective study

BACKGROUND: Patients with a subarachnoid hemorrhage (SAH) accompanied by a massive intracerebral hemorrhage (ICH) or a full-packed intraventricular hemorrhage (IVH) have poor outcomes. We evaluated the clinical factors to predict the overall outcome in such patients. METHODS: Data on nontraumatic SAH patients were collected and classified into 3 groups: the pure SAH group (SAH accompanied with neither ICH nor IVH), the ICH group (SAH accompanied with a massive ICH; hematoma 30 mL), and the IVH group (SAH and all ventricles were full-packed with hematoma). One hundred seventy-nine patients were in the ICH group and 109 in the IVH group. We evaluated clinical factors, such as the Hunt & Hess (H&H) score on admission, age, sex, history, rebleeding ratio, and the computerized tomography findings (SAH score). RESULTS: The result of multivariate logistic regression analysis of clinical variables in the ICH group, good and intermediate H&H grades, younger age (<70), no rebleeding, and lower SAH score were associated with a favorable outcome. In the result of the multivariate logistic regression analysis of clinical variables in the IVH group, only a higher SAH score was associated with an unfavorable outcome. CONCLUSIONS: In the ICH group, factors that could be used to predict a favorable outcome included good and intermediate H&H scores (1, 2, and 3) on admission, younger age (<70), and a lower SAH score. In the IVH group, the main factor that could be used to predict a favorable outcome was a lower SAH score.     

A case of juvenile myelomonocytic leukemia with concomitant cytomegalovirus infection

Infantile cytomegalovirus (CMV)-associated disease and juvenile myelomonocytic leukemia (JMML) frequently present with similar clinical features, and thus the differential diagnosis is often difficult. An early and definite diagnosis of these disorders is required because their therapeutic approaches are very different. The authors describe a 2-month-old Japanese girl with JMML and CMV infection. The CMV antigen was detected by immunologic staining of leukocytes using the peroxidase-labeled monoclonal antibody HRP-C7. To assess clonality, the X-chromosome inactivation pattern was evaluated using polymerase chain reaction analysis of the human androgen receptor gene with or without predigestion of chromosomal DNA with HhaI or HpaII. The patient showed evidence of monoclonal origin of mononuclear cells at diagnosis. Although CMV infection mimicking JMML has previously been reported in two patients, to the authors' knowledge this is the first report describing a firm and definitive diagnosis of JMML based on the study of X-chromosome inactivation patterns.     

Construction of a stress reaction scale based on an item response model and examination of the developmental process of psychological stress reactions by using test characteristic curves

In this study, a stress reaction scale was constructed based on an Item Response Model, and the developmental process of psychological stress reactions was investigated by using test characteristic curves. Subjects consisted of 286 private college students and 234 national college students. The Job Stress Scale (JSS) was revised for college students, and used to assess psychological stress reaction. Graded response model of Item Response Theory (IRT) was used to estimate parameters. After estimating item and subject parameters, we assessed the precision of measurement and the fit of the model, and found both precision and fit to be satisfactory. Then we examined the test characteristic curves of each subscale to investigate the developmental process of psychological stress reactions of college students in comparison with company employees.