Significant variability in response to inhaled corticosteroids for persistent asthma

BACKGROUND: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. OBJECTIVE: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. METHODS: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day. RESULTS: Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). CONCLUSIONS: Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations.     

Airway epithelial cells release MIP-3alpha/CCL20 in response to cytokines and ambient particulate matter

The initiation and maintenance of airway immune responses in Th2 type allergic diseases such as asthma are dependent on the specific activation of local airway dendritic cells (DCs). The cytokine microenvironment, produced by local cells, influences the recruitment of specific subsets of immature DCs and their subsequent maturation. In the airway, DCs reside in close proximity to airway epithelial cells (AECs). We examined the ability of primary culture human bronchial epithelial cells (HBECs) to synthesize and secrete the recently described CC-chemokine, MIP-3alpha/CCL20. MIP-3alpha/CCL20 is the unique chemokine ligand for CCR6, a receptor with a restricted distribution. MIP-3alpha/CCL20 induces selective migration of DCs because CCR6 is expressed on some immature DCs but not on CD14+ DC precursors or mature DCs. HBECs were stimulated with pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta or, because of their critical role in allergic diseases, IL-4 and IL-13. Cells were also exposed to small size-fractions of ambient particulate matter. Each of these stimuli induced MIP-3alpha/CCL20 gene and protein expression. Moreover, these agents upregulated mitogen-activated protein kinase pathways in HBECs. Inhibition of the ERK1/2 pathway or p38 reduced cytokine-induced MIP-3alpha/CCL20 expression. These data suggest a mechanism by which AEC may facilitate recruitment of DC subsets to the airway.     

Heteroarm Star Polystyrene‐block‐Poly(4‐vinylpyridine): Multiple Morphologies in Dilute Solutions

Synthesis and solution morphologies of four new heteroarm star polystyrene‐block‐poly(4‐vinylpyridine) were studied. As the water content increased, a morphological transformation of heteroarm PS₄‐P4VP₄ from spheres to cylinders, vesicles, and large compound vesicles was observed. The morphology of PS₄‐P4VP₄ in the solvent mixture of DMF/water or 1,4‐dioxane/water was spherical, but changed to large compound micelles in THF/water. As the P4VP molar ratio decreased, the morphology changed from spherical mixed with cylindrical to vesicles, giant vesicles, and then to LCMs. The present study demonstrated the formation of multiple morphologies through manipulating solvent polarity and block ratio in dilute solution.

     

Fine-needle aspiration of histiocytic necrotizing lymphadenitis (Kikuchi's disease)

Fine-needle aspiration (FNA) of the lymph node was done in five patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease). In four patients, the aspirates were found to have many small and large atypical lymphocytes, some reactive, phagocytic histiocytes, and intense extracellular debris. Neutrophils, plasma cells, or multinucleated giant cells were not seen. These cytologic findings were considered diagnostic for Kikuchi's disease. In one patient, the aspirate did not show significant histiocytosis or tissue necrosis and was considered nondiagnostic. In patients with both typical clinical features and characteristic cytologic findings in the lymph node aspirates, FNA of the lymph node alone will suffice for diagnosis. In those patients with typical clinical features but nondiagnostic findings in the FNA aspirates, the diagnosis of Kikuchi's disease may have to be established either on repeated nodal FNA or on lymph node biopsy.     

Social support and striatal dopaminergic activities: Is there a connection?

Objectives

Although patients' social support is a critical factor for the prognosis of mental disorder treatments, biological mechanisms responsible for the impact of social support remain scarcely explored. We speculated that there may be an association between social support and central dopaminergic activities in humans.

Methods

A total of 65 medicated patients with schizophrenia and their primary first-degree caregivers and 54 healthy volunteers were recruited for Studies 1 and 2, respectively. In Study 1, the extrapyramidal side effects (EPS) of medicated patients with schizophrenia and the social support scores of their caregivers were examined. In Study 2, the availability of striatal D₂/D₃ receptors, dopamine transporters (DAT) and social support scores were measured in 54 healthy volunteers.

Result

Study 1: the EPS scores of medicated patients with schizophrenia were negatively correlated with the social support scores of their relatives. Study 2: a positive correlation between the subjective social support scores and striatal DAT availability was noted.

Conclusion

The central dopaminergic activity may be linked to the sense of social support.     

Exploring the burden of the primary family caregivers of schizophrenia patients in Taiwan

Aim: The purpose of the present study was to investigate the burden of the primary family caregivers of schizophrenia patients and the factors that affect caregiver burden. Methods: A total of 126 pairs of patients and their primary family caregivers were recruited from the day care and acute wards of two teaching general hospitals. Demographic information was collected. All patients went through an interview with a senior psychiatrist using the Brief Psychiatric Rating Scale (BPRS). The Caregiver Burden Inventory–Brief Version and the Chinese Health Questionnaire (CHQ) were used to assess the caregiver burden and the caregivers' health condition. One‐way analysis of variance and Pearson correlation were used to analyze the relationship between demographic factors and caregiver burden. Multiple regression was used to analyze predictors of burden of caregivers. Statistical significance in this study was defined as P ≤ 0.05. Results: The caregiver burden scores (25.9 ± 10.7; range, 3–61) indicated a moderate burden level. Among the five dimensions of burden, caregiver anxiety (2.13 ± 0.86) was the highest, followed by dependency of the patient (1.85 ± 1.02), feeling shame and guilt (1.56 ± 1.02), and family interference (1.43 ± 0.83). The burden level of stigmata (1.32 ± 1.24) was the lowest. The first three rankings of burden were ‘I worry about his/her safety when he/she is alone’ (2.26 ± 1.15), ‘I worry that she/he will become sick at any time’ (2.23 ± 1.10), and ‘I feel he/she depends on me very much’ (2.02 ± 1.29). Patient satisfaction with medical staff support (P = 0.00), CHQ scores of the caregivers (P = 0.00), and the BPRS scores of the patients (P = 0.01) were significantly associated with the caregiver burden scores. Conclusions: The physical and mental health condition of the primary family caregiver of schizophrenia patients was the most important factor determining the caregiver burden level. Comprehensive multidisciplinary care of chronic schizophrenia patients is needed, care that supports the needs and improves the psychiatric symptoms of the patients, helps to decrease the caregiver burden level, and facilitates family participation in treatment.     

Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty‐two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47–38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53–0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65–0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality.     

The Eurotransplant Study on Twin Lung Transplants (ESOTWIN): 90 paired single-lung transplants from the same donor

BACKGROUND: Despite its reduced benefit for a single recipient, the transplantation of two single-lung allografts as opposed to one bilateral lung transplant has the indisputable advantage of maximizing the number of patients that benefit from a single donor. METHODS: In the period 1997 to 1999, 90 paired single-lung transplants (SLTx) from 45 donors were performed in 16 lung centers in Eurotransplant, with a complete follow-up of 1 year. RESULTS: No significant differences between left- and right-lung allograft recipients were observed regarding age, sex, primary disease, number of human leukocyte antigen mismatches, cold ischemic time, and donor-to-recipient cytomegalovirus match. Early posttransplant outcome, as assessed by oxygenation index at 12, 24, and 48 hr, also did not differ significantly, and there were no differences in time to extubation and time spent in the intensive care unit. In the first month, six left- and three right-lung allograft recipients died. Bronchiolitis obliterans syndrome developed in 5 of 39 left-lung and 10 of 42 right-lung allograft recipients. If the retrieval team was different from the transplanting team, a significantly worse 1-year posttransplant survival rate was seen in patients who underwent left SLTx compared with those who underwent right SLTx (62% vs. 92%, respectively; P=0.04). CONCLUSIONS: More fatal posttransplant complications occur in patients undergoing left SLTx compared with right SLTx. A less optimistic assessment of the left lung by the not-implanting retrieval team is warranted.