Exercise Capacity and Quality of Life in Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease with a high mortality rate that can be divided into different groups according to etiology and prognosis. Few studies have investigated differences in the exercise capacity and quality of life (QOL) among the different groups of PAH patients. Therefore, we aimed to (1) compare the hemodynamic exercise responses between patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with other diseases (APAH), and (2) determine the factors associated with exercise capacity in patients with PAH. METHODS: Six patients diagnosed with IPAH and eight with APAH [congenital heart disease (CHD)-dominant PAH] were included in this study. The main outcome measures included body composition, exercise capacity, hemodynamic measurements, physical activity levels, fatigue severity, and QOL. RESULTS: The CHD-dominant PAH group had a significantly lower predicted peak oxygen consumption (VO2pred %), pressure of end-tidal carbon dioxide at the peak and at anaerobic threshold (PETCO2peak and PETCO2@AT), and significantly elevated ventilatory equivalent (VE/VCO2slope and VE/VCO2@AT) compared with the IPAH group. Multiple regression analysis indicated that PETCO2@AT was significantly associated with either VO2peak (ß = 0.805, adjusted R2 = 0.619, p = 0.001) or 6-minute walk distance (ß = 0.816, adjusted R2 = 0.638, p < 0.001). CONCLUSIONS: Patients with CHD-dominant PAH had poor exercise capacity and exercise responses compared to those with IPAH. Evaluating exercise capacity and the patient response to exercise using cardiopulmonary exercise testing is increasingly important in view of the etiology of PAH.

Involvement of bone marrow in lymphoma: pathological investigation in a single-center from northern China.

OBJECTIVES: This study aimed to evaluate key features of bone marrow trephine biopsy (BMT) involvement of lymphoma in Northern China. METHODS: 950 cases were assessed for the occurrence of bone marrow involvement and architectural features including volume percentage, involvement pattern (diffuse, nodular, focal, para trabecular, or interstitial), and presence/absence of background changes (granuloma, stromal fibrosis or necrosis). Correlations with bone marrow aspirate (BMA) and flow cytometry (FCM) findings were made in a subset of paired cases (359 BMA and 364 FCM). RESULTS: 153 (16.1%) cases involved BMT. The most frequent type was mantle cell lymphoma (28/153, 18.3%). Architectural features were similar to previous studies except that diffuse large B-cell lymphoma (DLBCL) preferred focal pattern (16/22 cases, 72.7%) most of all. BMA and BMT agreed in 84.1% of cases (302 of 359: 277 both negative, 25 both positive), while FCM and BMT agreed in 80.8% of cases (294 of 364: 242 both negative, 52 both positive). Both varied widely among different subgroups. CONCLUSIONS: Occurrence of BMT involvement by lymphoma in Northern China is relatively low. The volume percentage, distribution patterns and background changes may be useful pointers towards a particular lymphoma type in Chinese. FCM is more sensitive and reliable than BMA in China.

[Expression of interleukin-6 and its clinicopathological significance in Castleman's disease].

OBJECTIVE: To evaluate the expression of interleukin-6 (IL-6) and its clinicopathological significance in Castleman's disease (CD). METHODS: Clinical data and paraffin blocks of 92 CD patients and 20 cases of lymph node reactive hyperplasia (LRH) as a control group were collected from department of pathology of Peking University Health Science Center. The expression of IL-6 was detected by using immunohistochemical method. RESULTS: The 92 patients were composed of 42 multicentric variant (MCDs) and 50 unicentric variant (UCDs) clinically, and 30 hyaline-vascular variant (HV-CDs) and 62 plasma cell variant (PC-CDs) morphologically. None of them was positive for HIV tests. There were 56 males and 36 females, and their ages ranged from 4 years to 90 years with the median 41 years. IL-6 was expressed in 77 (83.7%) of 92 CD cases and 1 (5.0%) of 20 LRH cases. The expression rate of IL-6 was 90.5% in MCDs, 78.0% in UCDs, 93.6% in PC-CDs and 63.4% in HV-CDs, respectively. PC-CD cases showed a significantly higher expression rate of IL-6 than HV-CD cases (P = 0.001). All cases with positive IL-6 expression in plasmacytes were PC-CDs, showing obviously higher expression in MCDs than that in UCDs (P = 0.003). Compared with HV-CD cases, much more PC-CD cases showed IL-6 positivity in endothelial cells (P = 0.008). However, IL-6 was rarely expressed by both FDCs and macrophages, with only 3.3% and 10.9% positive cases, respectively. There are 53.2% (41/77) of the IL-6 positive cases and 20.0% (3/15) of IL-6 negative cases suffered from systemic symptoms, showing a significant difference between the two groups (P = 0.018). Cases with IL-6 expression in plasmacytes and macrophages were more likely to suffer from systemic symptoms, especially B type symptoms (P < 0.05). CONCLUSION: There is a high expression rate of IL-6 in CD, which is different from LRH. The expression of IL-6 has close relationship with CD subtypes and the presence of systemic symptoms. In all, the evaluation of interleukin-6 is of great value to guide the diagnosis and therapy of CD.

[Clinicopathologic analysis of nodal marginal zone B cell lymphoma].

OBJECTIVE: To investigate the clinicopathologic features of primary nodal marginal zone B-cell lymphoma (NMZL). METHODS: Hematoxylin-Eosin staining and immunohistochemistry were used to evaluate the histological and immunophenotypic characteristics of lymph node (LN) tissue in 22 NMZL cases. Additionally, interphase fluorescence in-situ hybridization (FISH) was carried out to detect the presence of t(11;18) (q21;q21)/API2-MALT1 and/or t(14;18)(q32;q21)/IGH-MALT1 in 9 cases. RESULTS: The median age of the 22 patients was 62 (16 - 77) ys. The male-to-female ratio was 1.2:1. All patients exhibited asymptomatic lymphadenopathy with the cervical region as the most often site to be involved (n = 11), followed by axillary (n = 9), inguinal (n = 7), submandibular (n = 6), mediastinal (n = 4), supraclavicular (n = 2) and retroperitoneal lymph nodes (n = 1). The Ann Arbor stages were I/II in 13 (59%) cases and III/IV in 9 (41%). Immunohistochemical study showed a consistently strong expression of CD20 and an absence in the expression of CD3ε, CD10, CD21, CD23, CyclinD1 and BCL6 by the tumor cells in all the cases. Frequency of expression of CD5 and BCL2 were 39% (7/18) and 30% (3/14) respectively. Among the 9 cases performed with FISH, 2 cases harbored t(14;18)and another 1 case positive for t(11;18) and t(14;18). Complete follow-up data were available for 13 cases. The follow-up time was 6 to 44 months. 3 of them died. 3-year cumulative survival rate was 67%. CONCLUSIONS: NMZL patients are often elderly, which mainly present with multiple lymphadenopathy, rare involvement of extranodal organ and early stage. The diagnosis must be based on a combination of clinicopathologic features, especially those patients detected t(11;18) and/or t(14;18).

Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors.

The molecular interactions between human melanocortin receptor-1 and -4 (hMC1R and hMC4R) and their endogenous antagonists, agouti signaling protein (ASIP) and agouti-related protein (AGRP), were assessed by studying the effects of site-directed mutations on the binding affinity of (125)I-ASIP[90-132(L89Y)] and (125)I-AGRP(86-132). Mutations of homologous residues from transmembrane helices (TMHs) 3 and 6 and extracellular loop (EL) 3 (D121A, T124A, F257A, and F277M in hMC1R and D126A, I129A F261A, and M281F in hMC4R) impaired binding of both antagonists to hMC4R and binding of the ASIP fragment to hMC1R. However, the mutations in TMH2 (E94A in hMC1R and E100A in hMC4R), TMH7 (F280A in hMC1R and F284A in hMC4R), and EL2 (Y183S, H184S, and D184H in hMC1R) only significantly affected binding of the ASIP fragment. The dependence of agonist binding on the dithiothreitol concentration followed a monophasic curve for wild-type hMC4R and its C40A, C271A, and C279A mutants and a biphasic curve for hMC1R, suggesting the presence of at least one structurally and functionally essential disulfide bond in both wild-type receptors and the hMC4R mutants. Models of complexes of both receptors with the ASIP fragment and hMC4R with the AGRP fragment were calculated using constraints from the experimental structures of rhodopsin and AGRP fragments, a set of deduced hydrogen bonds, supplemented by two proposed disulfide bridges and receptor-ligand contacts, derived from our mutagenesis data. In the models of the ASIP fragment complexed with both receptors, the core ligand tripeptide, Arg-Phe-Phe, positioned between TMHs 3 and 6, is shifted toward TMHs 2 and 7 relative to its position in the AGRP-hMC4R model, while the N-terminal loop and two central disulfides of the antagonists interact with EL2 of the receptors.

Inverse agonist activity of agouti and agouti-related protein.

Agouti and agouti-related protein (AgRP) are endogenous antagonists of the melanocortin receptors (MCxR). Previous data showed that recombinant full-length agouti and a synthetic fragment of AgRP, AgRP (83-132), are inverse agonists at the MC1R and MC4R, respectively. This study demonstrates the smaller analogs AgRP (87-120) and ASIP [90-132 (L89Y)], and short peptides Yc[CRFFNAFC]Y and Qc[CRFFRSAC]S are also MC4R inverse agonists. Furthermore, the relative affinity of the series of MC4R ligands for displacement of radiolabeled antagonist 125I-AgRP (86-132) versus radiolabeled agonist 125I-NDP-MSH did not correlate with ligand efficacy, which is more consistent with an induced-fit model than a simple two-state model of MC4R activation. These data shed new light on the determinants and mechanism of inverse agonism at the MC4R.

Food deprivation-induced expression of minoxidil sulfotransferase in the hypothalamus uncovered by microarray analysis.

We used oligonucleotide microarrays to analyze comprehensively hypothalamic gene expression changes that correlate with energy homeostasis. We compared the hypothalamic gene expression profiles of freely fed and 48-h fasted rats using 26,379 oligonucleotide probe sets. Expression of 96 genes was up-regulated and expression of 73 genes was down-regulated in a statistically significant manner with fasting. The gene encoding the enzyme minoxidil sulfotransferase, an enzyme that catalyzes the transfer of sulfonate groups to biogenic amines and other substrates, was foremost among a set of genes whose mRNAs were uniformly detectable and displaying the greatest transcriptional changes with fasting. Northern blot analysis indicated that minoxidil sulfotransferase mRNA is up-regulated in the fasted rat and mouse, ob/ob mouse, and fa/fa rat. Results of reverse transcription quantitative PCR indicated that minoxidil sulfotransferase mRNA is also up-regulated in the microdissected arcuate and paraventricular nuclei of the fasted rat. Several index genes known to be either up-regulated (neuropeptide Y) or down-regulated (amphetamine-regulated transcript and proopiomelanocortin) with fasting were also found to be present among our set of "differentially expressed" genes. This study identifies a novel gene induced by fasting and demonstrates the feasibility of using oligonucleotide microarrays for the study of complex neuronal processes.