Early assessment of renal resistance index after kidney transplant can help predict long-term renal function.

BACKGROUND: Color Doppler ultrasonography of intrarenal arterial resistance index (RI), performed early after kidney transplant, has proven to reliably predict short-term allograft function. The aim of this study was to assess whether it could also predict long-term renal function. METHODS: We retrospectively analysed 76 kidney transplant patients who underwent RI assessment within 1 month after the transplant, subdivided into two groups according to RI values, lower (group A) or higher (group B) than its median value (0.635). RESULTS: Compared with group A subjects, the patients of group B were older at the time of transplant (42 +/- 9 vs 35 +/- 8 years; P = 0.001), the donor age was also older (41 +/- 16 vs 33 +/- 13 years; P = 0.02) and had a slightly higher proteinuria (0.54 +/- 0.5 vs 0.32 +/- 0.2 g/24 h; P = 0.02). Serum creatinine, ciclosporin or tacrolimus trough level, arterial blood pressure, number of human leukocyte antigen (HLA) mismatches, anti-hypertensive medications and incidence of delayed graft function were not significantly different between the two groups. By univariate analysis, RI turned out to directly correlate with the recipient age, donor age and daily proteinuria (P = 0.007, P = 0.0007 and P = 0.02, respectively). Multivariate analysis showed that only donor and recipient age maintained their independent predictive value on RI. Kaplan-Meier analysis, considering a serum creatinine increase >50% as the endpoint of the study, showed a statistically significant different graft survival in the two groups (log-rank test = 5.489; P = 0.01). The univariate relative risk of deterioration of graft function among patients with higher RI was 3.77. Proteinuria and recipient age increased the risk as well. CONCLUSIONS: Our data seem to suggest that early determination of RI can help predict long-term graft function in kidney transplant recipients.     

Alteration of acylphosphatase levels in familial Alzheimer''s disease fibroblasts with presenilin gene mutations

Acylphosphatase (ATPase), an enzyme that modulates the activity of Ca²⁺-ATPase by hydrolysing its phosphorylated moiety, has been found to be significantly higher in cultured skin fibroblasts from donors affected by early onset familial Alzheimer's disease (EOFAD) with PS-1 and PS-2 gene mutations. Of the two known isoenzymes of acylphosphatase, only the erythrocyte one accounts for the total increase in activity. No relevant alteration was observed in phosphotyrosine phosphatase activity (PTPase), in Ca²⁺-ATPase and Na⁺,K⁺-ATPase activities of the same cells as compared to age-matched controls. This finding could suggest a possible explanation for the calcium-dependent biochemical alterations previously described in Alzheimer's disease fibroblasts.     

Effect of phosphatidylserine on free radical susceptibility in human diploid fibroblasts

Summary We studied the effect of phosphatidylserine (PdtSER) on oxygen metabolite toxicity in skin fibroblast cell lines from apparently normal subjects. Fibroblast damage was produced by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by xanthineoxidase (Xo). In order to quantify cell damage, we measured lactate dehydrogenase (LDH) activity in culture medium and cell viability in fibroblast cultures, with and without preincubation for 4 days with PdtSER 13 M, after Xo incubation. We found a significant increase of LDH activity in culture medium of cells without preincubation with PdtSER. No significant increase of LDH activity was observed in the same cell lines after preincubation with PdtSER.     

New evidence for,and challenges in,linking small CGG repeat expansion FMR1 alleles with Parkinson's disease

We recently reported a significant increase in the frequency of carriers of grey zone (GZ) alleles of FMR1 gene in Australian males with Parkinson's disease (PD) from Victoria and Tasmania. Here, we report data comparing an independent sample of 817 PD patients from Queensland to 1078 consecutive Australian male newborns from Victoria. We confirmed the earlier finding by observing a significant excess of GZ alleles in PD (4.8%) compared to controls (1.5%). Although both studies provided evidence in support of an association between GZ‐carrier status and increased risk for parkinsonism, the existing evidence in the literature from screening studies remains equivocal and we discuss the need for alternative approaches to resolve the issue.     

Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells

Urokinase-type plasminogen activator receptor (UPA-R-CD87) is a GPI-anchored membrane protein which promotes the generation of plasmin on the surface of many cell types, probably facilitating cellular extravasation and tissue invasion. A flow cytometric quantitative analysis of expression levels for UPA-R was performed on fresh blast cells from patients with acute myeloid leukaemia (AML, n = 74), acute lymphoblastic leukaemia (ALL, n = 24), and biphenotypic leukaemia (BAL, n = 3) using two CD87 monoclonal antibodies (McAbs) (3B10 and VIM5). Peripheral blood and bone marrow (BM) cells from 15 healthy adults served as controls. Using 3B10 McAb, UPA-R was expressed (>99%) by blood monocytes, neutrophils, and BM myelomonocytic precursors in controls, whereas resting T and B lymphocytes, and CD34⁺ cells were UPA-R negative. We also attempted to clarify whether UPA-R has a role in mediating neutrophil functions. Oriented locomotion induced by different chemotaxins and lysozyme release by granules stimulated with fMLP or PMA were significantly decreased when UPA-R was neutralized by CD87 McAb. In contrast, the anti-UPA-R McAb had no effect on superoxide anion generation of normal neutrophils. Blasts from AML showed a heterogenous pattern of expression for the UPA-R McAbs, with reactivity strictly dependent on FAB subtype. The highest UPA-R expression was seen in the M5 group: all patients tested (n = 20) showed strong positivity for the UPA-R McAb whereas only 12% (3/24) of ALL patients were CD87 positive, and 2/3 of BAL patients showed a dim expression for CD87. The number of receptors expressed by blast cells in 6/74 (8.1%) AML patients was higher than those of normal samples; in addition, since co-expression of UPA-R and CD34 was not found in normal haemopoietic cells, it may be postulated that CD87 can be used alone (when overexpressed) or in combination with CD34 for the detection of minimal residual disease. Results also indicated that patients with UPA-receptors >12 × 10³ ABC/cell, irrespective of FAB subtype, had a greater tendency for cutaneous and tissue infiltration and a higher frequency of chromosome abnormalities, thus suggesting the concept that cellular UPA-R content positively correlates with the invasive potential of AML cells. The combination of higher UPA-R positivity, abnormalities of chromosome 11, and M5 FAB morphology may identify a peculiar subset of AML, characterized by a more aggressive clinical course.     

Adolescent nutrition in a rural community in Bangladesh

The objective of this study was to assess the nutritional status of adolescent boys and girls in a rural community in Bangladesh. Between December 1996 and January 1997, a cross-sectional survey was carried out in 803 households, each containing at least one adolescent, sampled consecutively from four purposely-selected villages in Rupganj Thana, Narayanganj district. Initially, the guardians of 1483 healthy and unmarried 10–17 year old adolescents (51% boys and 49% giris) were interviewed about family structure and socio-economic status. Out of these children, 906 (47% boys and 53% girls) from 597 households were weighed, had their height and MUAC measured and were clinically examined. Blood was then collected from 861 adolescents for haemoglobin estimation. The median monthly income per person in these 597 families was approximately Taka 554 (US $12). Twenty seven per cent of the household heads were labourers, 21% were solvent farmers, 14% ran small scale businesses and 6% were unemployed. Sixty seven per cent of adolescents were thin (defined as BMI < 5th centile of WHO recommended reference) with 75% boys and 59% girls being affected. The percentage of thin adolescents fell from 95% at age 10 years to 12 % at age 17 years. The prevalence of stunting (height for age < 3rd centile NCHS/WHO) was 48% for both boys and girls and rose from 34% at age 10 to 65% at age 17. On clinical examination angular stomatitis was present in 46%, 27% nad glossitis, 38% had pallor, 11% ha’d dental caries, 3.2% had an conspicuously enlarged thyroid and 2.1% had eye changes of vitamin A deficiency. According to INACG (International Nutritional Anaemia Consultative Group, 1985) cut-off values, 94% of the boys and 98% of the girls were anaemic. We conclude that rural Bangladesh adolescents suffer from high rates of malnutrition and almost universal anaemia. Nutritional interventions to target this population are urgently required.     

Reduced expression of macrophage-associated antigens on alveolar mononuclear phagocytes from acquired immunodeficiency syndrome

Summary In this study we evaluated the phenotype of alveolar mononuclear phagocytes recovered from the bronchoalveolar lavage fluid of 24 patients with human immunodeficiency virus infection (AIDS-related complex 8 patients, AIDS 16 patients) and 8 healthy individuals by using a panel of monoclonal antibodies known to react with tissue macrophages, in combination with a flow cytometer. The results showed that 90% of patients with AIDS present a marked reduction in the expression of several antigenic determinants (in descreasing order: CD68, CD36, CR1, CD11c, HLA-DR). The levels of antigen expression by flow cytometry seem to decline with disease progression, showing the most dramatic perturbations in patients with full-blown AIDS associated with pulmonary infections (especiallyPneumocystis carinii pneumonia) and lower peripheral CD4 lymphocyte counts. In contrast, patients with AIDS-related complex or AIDS without histological or cultural evidence of pulmonary involvement showed, respectively, only minimal or medium antigenic decreases. However, only a minor proportion (16%, 20%, 20%, 25%, and 25% respectively) of human immunodeficiency virus infected patients (mostly with AIDS) had a significant reduction of the levels of CD4, CD14, CD45R, CD11b, and CD16 antigens in the alveolar macrophages. Since macrophages play a central role in the pathogenesis of AIDS, it may be postulated that the loss of various phenotypic markers on alveolar mononuclear phagocytes (some of them known for their important immunoregulatory actions) could have an important part in the pathogenesis of human immunodeficiency virus induced immunosuppression, and thereby condition the abnormal susceptibility to pulmonary diseases typical of human immunodeficiency virus-infected patients.     

Bepridil up-regulates cardiac Na+ channels as a long-term effect by blunting proteasome signals through inhibition of calmodulin activity

Background and purpose:

Bepridil is an anti-arrhythmic agent with anti-electrical remodelling effects that target many cardiac ion channels, including the voltage-gated Na⁺ channel. However, long-term effects of bepridil on the Na⁺ channel remain unclear. We explored the long-term effect of bepridil on the Na⁺ channel in isolated neonatal rat cardiomyocytes and in a heterologous expression system of human Na_v1.5 channel.

Experimental approach:

Na⁺ currents were recorded by whole-cell voltage-clamp technique. Na⁺ channel message and protein were evaluated by real-time RT-PCR and Western blot analysis.

Key results:

Treatment of cardiomyocytes with 10 µmol·L⁻¹ bepridil for 24 h augmented Na⁺ channel current (I_Na) in a dose- and time-dependent manner. This long-term effect of bepridil was mimicked or masked by application of W-7, a calmodulin inhibitor, but not KN93 [2-[N-(2-hydroxyethyl)-N-(4-methoxy benzenesulphonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine], a Ca²⁺/calmodulin-dependent kinase inhibitor. During inhibition of protein synthesis by cycloheximide, the I_Na increase due to bepridil was larger than the increase without cycloheximide. Bepridil and W-7 significantly slowed the time course of Na_v1.5 protein degradation in neonatal cardiomyocytes, although the mRNA levels of Na_v1.5 were not modified. Bepridil and W-7 did not increase I_Na any further in the presence of the proteasome inhibitor MG132 [N-[(phenylmethoxy)carbonyl]-L-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide]. Bepridil, W-7 and MG132 but not KN93 significantly decreased 20S proteasome activity in a concentration-dependent manner.

Conclusions and implications:

We conclude that long-term exposure of cardiomyocytes to bepridil at therapeutic concentrations inhibits calmodulin action, which decreased degradation of the Na_v1.5 α-subunit, which in turn increased Na⁺ current.     

前列痛栓治疗前列腺痛的药效学研究

目的：探讨和验证前列痛栓治疗前列腺痛的药效。方法：采用小鼠肛门给药，以空白，消炎痛栓为对照组。测定前列痛栓对小鼠扭体次数，网状内皮系统吞噬指数，耳廓肿胀，肉芽增生及大鼠小肠肌电的影响。结果：前列痛栓能明显减少小鼠扭体次数，优于消炎痛栓；对网状内皮系统吞噬功能，二甲苯所致小鼠耳廓肿胀和滤纸片埋入形成的肉芽增生及大鼠小肠肌电的影响。与消炎痛栓相近。结论：前列痛栓治疗前列腺痛有显著的镇痛作用。