PDIA3 mRNA expression and IL-2, IL-4, IL-6, and CRP levels of acute kidney allograft rejection in rat

Kidney transplantation to treat end-stage renal disease has evolved rapidly from the first successful transplantations to the current widespread use of grafts from both cadaveric and living donors. But acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate possible mechanisms, we describe a comparison between differentially proteins expression and immune markers profile (IL-2, IL-4, IL-6, and CRP) of acute rejection and the controls. Through quantitative real-time RT-PCR confirmation, PDIA3 mRNA and protein expression levels in serum and transplanted kidney in experiment group was significantly (P < 0.05) higher than that in control group. Immunity analysis showed that plasma IL-2, IL-4, IL-6, and CRP levels were higher in experimental rats than those in control rats. Our data thus indicate that PDIA3 might be potentially involve into the occurence and development of acute rejection response in renal transplantation and increased plasma IL-2, IL-4, IL-6, and CRP levels play an important role to prevent acute kidney allograft rejection in rats.     

Association of IL-10-1082 promoter polymorphism with susceptibility to gastric cancer: evidence from 22 case–control studies

Evidence suggested that interleukin-10 (IL-10) may be involved in the etiology of gastric cancer (GC). However, epidemiological studies on the association between IL-10-1082 promoter polymorphism and GC risk are still ambiguous. To quantitatively summarize the evidence for such a relationship, we performed a meta-analysis. Systemic searches of the PubMed and Medline databases were performed, with the last report up to July 2011. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. 22 independent studies including 4,289 cases and 5,965 controls were involved in this meta-analysis. Obvious association was found when all studies were pooled into the meta-analysis (A vs. G: OR = 0.489, 95% CI = 0.335–0.713, P < 0.001). In the subgroup analysis by ethnicity, we observed significant associations in Asians (A vs. G: OR = 0.651, 95% CI = 0.506–0.838, P = 0.001; AA vs. GG: OR = 0.482, 95% CI = 0.328–0.709, P < 0.001; AA/AG vs. GG: OR = 0.711, 95% CI = 0.527–0.959, P = 0.025; AA vs. AG/GG: OR = 0.701, 95% CI = 0.520–0.944, P = 0.019) and Caucasians (A vs. G: OR = 0.365, 95% CI = 0.140–0.949, P = 0.039), but not in Latino population. When stratified analysis by control sources, our results indicated that A allele decreased approximately 48% risk among population-based studies (A vs. G: OR = 0.524, 95% CI = 0.374–0.733, P < 0.001). Taken together, this meta-analysis suggests that IL-10-1082 polymorphism is associated with GC risk.     

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

Although chronic infection with cytomegalovirus (CMV) is known to drive T lymphocytes toward a senescent phenotype, it remains controversial whether and how CMV can cause coronary heart disease (CHD). To explore whether CMV seropositivity or T‐cell populations associated with immunosenescence were informative for adverse cardiovascular outcome in the very old, we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65‐month follow‐up (47.3% survival rate). CMV‐seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%, P = 0.030) compared to CMV‐seronegative participants together with lower CD4/CD8 ratio (1.7 vs. 4.1, P < 0.0001) and higher frequencies of senescence‐like CD4 memory cells (41.1% vs. 4.5%, P < 0.001) and senescence‐like CD8 memory cells (TEMRA, 28.1% vs. 6.7%, P < 0.001). CMV seropositivity was also associated with increased six‐year cardiovascular mortality (HR 1.75 [1.09–2.82], P = 0.021) or death from myocardial infarction and stroke (HR 1.89 [107–3.36], P = 0.029). Gender‐adjusted multivariate Cox regression analysis revealed that low percentages of senescence‐like CD4 T cells (HR 0.48 [0.32–0.72], P < 0.001) and near‐senescent (CD27 negative) CD8 T cells (HR 0.60 [0.41–0.88], P = 0.029) reduced the risk of cardiovascular death. For senescence‐like CD4, but not near‐senescent CD8 T cells, these associations remained robust after additional adjustment for CMV status, comorbidities, and inflammation markers. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T‐cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.     

The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept

Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney‐transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post‐transplant (M3) (22.5% ± 15.4% vs 33.4% ± 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus‐mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.     

Characterization of acute renal allograft rejection by proteomic analysis of renal tissue in rat

Rapid and reliable biomarkers of renal allograft rejection have not been available. This study aimed to investigate biomarkers in renal allograft tissue using proteomic analysis. Orthotopic kidney transplantations were performed using Fisher (F344) or Lewis rats as donors and Lewis rats as recipients. Syngenic control group (Group I) constituted F344-to-F344 orthotopic kidney allo-transplantations (n = 8); and allogenic group (Group II) consisted of F344-to-Lewis orthotopic kidney allo-transplantations (n = 8). Renal tissues were harvested 7 days after transplantation. Samples were analyzed using 2-D electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry. 6 differentially expressed proteins were identified between allogenic group and syngenic control group. A rat model of acute renal allograft rejection was successfully set up. Differentially expressed proteins in renal allograft tissue of rat were detected using proteomic analysis and might serve as novel diagnostic and therapeutic targets in human. Quantitative proteomics, using MALDL-TOF-MS methodology has the potential to provide a profiling and a deeper understanding of acute renal rejection.     

Ethnic diversity and cord blood banking: satisfying the unmet need

Background aimsIn this study, the authors sought to assess whether cord blood units (CBUs) collected from donors of non-European ethnic backgrounds are utilized for umbilical cord blood transplantation (UCBT) at a different rate than those of European ethnic backgrounds. The authors also examined potential methods of enriching these under-represented ethnic backgrounds in cord blood bank (CBB) inventories without increasing financial overheads and without compromising total inventory utilization or post-transplant outcomes.MethodsData from N = 6506 searchable or shipped Anthony Nolan Cell Therapy Centre grafts were used in this study. Banked grafts were graded from A+ to D based on total nucleated cell and CD34+ cell content. Utilizations of each grade group were further stratified by graft ethnic background. The Mantel–Cox log-rank test was performed in conjunction with Kaplan–Meier survival analysis to compare utilization rates and post-transplant outcomes. For shipped grafts, levels of HLA matching at HLA-A, HLA-B and HLA-DR loci were also analyzed by graft ethnic background and grade using data from the Eurocord/EBMT registry.ResultsOverall utilization of non-European grafts did not significantly differ from that of European grafts (2.5% versus 2.2%, P = 0.23). However, significant differences were found when stratifying utilization rates by cell content. The probability of non-European D grade grafts being utilized was 3-fold higher than that of European D grade grafts (1.1% versus 0.4%, P = 0.03) and comparable to that of European C grade grafts (1.1% versus 0.9%, P = 0.90). No significant differences were found between D and C grade grafts in terms of overall survival (OS) (P = 0.12), in part due to a disproportionate utilization of D grade grafts for pediatric UCBT (74% versus 39%, age difference P < 0.001). Furthermore, non-European graft shipments were 4-fold less likely to be a 6/6 HLA match to their recipients relative to European graft shipments (7% versus 29%).ConclusionsThe authors have identified a niche for CBUs of low cell content collected from donors of non-European ethnic backgrounds that has been overlooked by previous studies. Banking of these CBUs for pediatric UCBT instead of CBUs from European donors containing modestly higher cell content is an ethical approach to increasing the ethnic diversity of CBB inventory—and, consequently, the probability of non-European recipients finding a 6/6 HLA-matched graft—without compromising post-transplant OS or overall rate of inventory utilization.     

The impact of cytomegalovirus infection on clinical severity and outcomes in kidney transplant recipients with Pneumocystis jirovecii pneumonia

Cytomegalovirus (CMV) infection is associated with Pneumocystis jirovecii pneumonia (PJP) in kidney transplant recipients (KTRs), but its impact on clinical severity and outcomes in KTRs with PJP is unknown. We reviewed 1994 medical records of KTRs from January 1997 to March 2019. PJP or CMV infection was diagnosed by polymerase chain reaction or culturing using blood or respiratory specimens. We divided patients into PJP and PJP+CMV groups, and evaluated the clinical severity and outcomes. Fifty two patients had PJP (2.6%) in the whole study cohort. Among patients with PJP, 38 (73.1%) had PJP alone and 14 (26.9%) had combined PJP and CMV co-infection. The PJP+CMV group showed worse laboratory findings (serum albumin and C-reactive protein, P = 0.010 for both) and higher requirement of continuous renal replacement therapy than the PJP group (P = 0.050). The pneumonia severity was worse in the PJP+CMV group than in the PJP group (P < 0.05), and CMV infection was a high risk factor of pneumonia severity (odds ratio 16.0; P = 0.002). The graft function was worse in the PJP+CMV group (P < 0.001), and the incidence of graft failure was higher in the PJP+CMV group than in the PJP group (85.7% vs 36.8%; P < 0.001). Mortality was double in the PJP+CMV group than in the PJP group, but not statistically significant (21.4% vs 10.5%; P = 0.370). Our results show that approximately one in four patients with PJP after kidney transplantation develops CMV with increased clinical severity and risk of graft failure. The possibility of increased clinical severity and worse clinical outcomes by CMV co-infection should be considered in KTRs with PJP.     

Unloading the infarcted heart affect MMPs–TIMPs axis in a rat cardiac heterotopic transplantation model

Ventricular assist devices may function as a bridge to recovery or heart transplantation, however, little is known about its mechanisms. This study examined the role of matrix metalloproteinases (MMP)-tissue inhibitors of metalloproteinases (TIMP) axis in the process of recovery after unloading in a rat ischemic-induce heart failure (HF) model. Myocardial infarction model was created with the coronary artery ligation. The infarcted rats hearts were unloaded by heterotopic cardiac transplantation (n = 14). 2 weeks later, the function of normal and infarcted hearts with or without loading was evaluated by Langendorff perfusion model. The hearts were then harvested and prepared for the study of expression of MMPs and TIMPs. Developed pressure in the unloading group was higher than the loading group (P = 0.0074). Unloading increased the ratio of TIMP-1–MMP-1(1.38 ± 0.11 vs. 0.76 ± 0.09, P < 0.05), TIMP-2–MMP-2 (1.06 ± 0.10 vs. 0.33 ± 0.07, P < 0.01), TIMP-3–MMP-9(1.07 ± 0.08 vs. 0.59 ± 0.06, P < 0.05). Although MMP-1, 2, 9 were downregulated (P < 0.01, 0.01, 0.05, respectively), TIMP-2 and TIMP-3 upregulated (P < 0.01, 0.05, respectively), MMP-7 and TIMP-1 was not affected significantly. The infarcted cardiac function could be improved by unloading. It was attributed to downregulation of MMP-1, 2 and 9, and upregulation of TIMP-2 and -3, and furthermore, the ratio of TIMPs to MMPs was increased, which might be more sensitive than sole MMPs or TIMPs for the judgment of myocardial matrix homeostasis.     

Platelet transfusion refractoriness after T-cell-replete haploidentical transplantation is associated with inferior clinical outcomes

Haploidentical stem cell transplantation (haplo-SCT) has been an alternative source of bone marrow for patients without human leukocyte antigen (HLA)-matched donors. The aim of this study was to investigate the relationships between platelet transfusion refractoriness (PTR) and clinical outcomes in the setting of haplo-SCT. Between May 2012 and March 2014, 345 patients who underwent unmanipulated haplo-SCT were retrospectively enrolled. PTR occurred in 20.6% of all patients. Patients in the PTR group experienced higher transplant-related mortality (TRM, 43.7% vs. 13.5%, P<0.001), lower overall survival (OS, 47.9% vs. 76.3%, P<0.001) and lower leukemia-free survival (LFS, 47.9% vs. 72.3%, P<0.001) compared to patients in the non-PTR group. The multivariate analysis showed that PTR was associated with TRM (P=0.002), LFS (P<0.001), and OS (P<0.001). The cumulative incidences of PTR in patients receiving >12 platelet (PLT) transfusions (third quartile of PLT transfusions) were higher than in patients receiving either >6 (second quartile) or >3 (first quartile) PLT transfusions (56.1% vs. 41.6% vs. 28.2%, respectively; P<0.001). The multivariate analysis also showed that PTR was associated with the number of PLT transfusions (P<0.001). PTR could predict poor transplant outcomes in patients who underwent haploidentical SCT.     

Contribution of the IBD5 locus to inflammatory bowel disease: a meta-analysis

To evaluate the association of the IBD5 locus to the predisposition of inflammatory bowel diseases (IBDs), a series of meta-analyses between five IBD5 variants (OCTN1 C1672T, OCTN2 G-207C, OCTN1/2 TC haplotype, IGR2096a_1, IGR2198a_1 and IGR2230a_1) and Crohn’s disease (CD) and ulcerative colitis (UC) were performed, which included a total of 26 studies. Overall, five IBD5 variants in a per-allele model of inheritance were significantly associated with elevated CD risk (for OCTN1: OR = 1.23, 95% CI = 1.16–1.30, P < 0.001; for OCTN2: OR = 1.20, 95% CI = 1.11–1.30, P < 0.001; for IGR2096a_1: OR = 1.36, 95% CI = 1.24–1.46, P < 0.001; for IGR2198a_1: OR = 1.34, 95% CI = 1.24–1.46, P < 0.001; for IGR2230a_1: OR = 1.35, 95% CI = 1.23–1.48, P < 0.001) and OCTN1/2 TC haplotype (OR = 1.32, 95% CI = 1.22–1.43, P < 0.001). In the subgroup analysis, the statistically significant associations were also observed in adult- and pediatric-onset CD and in Caucasians for five IBD5 variants and the OCTN1/2 TC haplotype. A statistically significant increase in the risk of UC was detected in a recessive model of inheritances for OCTN1 (OR = 1.23, 95% CI = 1.08–1.40, P < 0.001), OCTN2 (OR = 1.18, 95% CI = 1.05–1.33, P = 0.006), IGR2096a_1 (OR = 1.37, 95% CI = 1.15–1.62, P < 0.001) and IGR2198a_1 (OR = 1.35, 95% CI = 1.10–1.66, P = 0.004); the increased risks of UC were maintained in the adult and Caucasian subgroups, but not the pediatric subgroup. In summary, our results suggested that the IBD5 locus contributes to the susceptibility of CD in a per-allele manner in adults, children and Caucasians, and the locus contributes to the susceptibility of UC in a recessive manner in adult and Caucasian populations.     

Expression of stromal derived factor-1 (SDF-1) and chemokine receptor (CXCR4) in bone metastasis of renal carcinoma

Renal cancer is a relatively common malignant carcinoma that metastasizes to bone. The chemokine stromal derived factor-1 (SDF-1) and its corresponding receptor CXCR4 have been shown to regulate organ-specific metastasis in other cancer types. Based on this observation, we predicted that the expressions of SDF-1 and CXCR4 play a role in renal carcinoma metastasis to bone. To investigate the expressions of SDF-1 and CXCR4, and to assess the correlation between SDF-1 and CXCR4 immunoreactivity in bone metastasis of renal carcinoma, we collected 10 in situ renal carcinoma samples and 30 bone metastasis samples. We analyzed SDF-1 and CXCR4 expression with immunohistochemical analysis on paraffin-embedded sections. Compared with primary renal carcinomas, the SDF-1 expression in bone metastases was significantly higher [80% (24/30) vs. 30% (3/10), P = 0.006]; the expression of CXCR4 was also higher [83.3% (25/30) vs. 40% (4/10), P = 0.014]. Pearson correlation analysis supports a positive correlation between SDF-1 and CXCR4 in bone metastasis of renal carcinoma. In addition, RT-PCR demonstrated that, as compared with in situ renal carcinoma tissues, SDF-1 expression was predominant in the bone metastasis samples (P = 0.001), while CXCR4 was overexpressed in the bone metastasis tissues (P = 0.028). Western blot analysis confirmed these trends. Our data suggest that the expression of SDF-1/CXCR4 is high in bone metastases and over-expression of SDF-1/CXCR4 may play important roles in the bone metastasis of renal carcinoma.     

Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma

The purpose of this study was to assess the value of cytokeratin 19 (CK19) and matrix metalloproteinase 2 (MMP-2) in predicting lymph node metastasis (LNM) and survival after curative resection in hepatocellular carcinoma (HCC) patients. Expression of CK19 and MMP-2 in tumor tissue was assessed through immunohistochemical staining of tissue microarrays (TMAs), which were constructed using samples from HCC patients with (n = 123) and without (n = 145) LNM. Positive CK19 expression was correlated with LNM (P < 0.001), satellite lesions (P = 0.016), and lymph node location (P = 0.039). High MMP-2 expression correlated with LNM (P < 0.001), UICC T stage (P = 0.023), and Edmondson grade (P = 0.022). Moreover, CK19 expression correlated with MMP-2 expression (P = 0.033). CK19 and MMP-2 expression were predictive of HCC LNM (AUC: 0.640; 95% CI: 0.572–0.707; P < 0.001 and AUC: 0.611; 95% CI: 0.544–0.679; P = 0.002, respectively). CK19 and MMP-2 expression were independent prognostic factors for disease-free survival (P = 0.031 and P = 0.012, respectively) and overall survival (P = 0.013 and P = 0.018, respectively) in HCC patients with LNM. CK19 expression (P < 0.001), MMP-2 expression (P = 0.006), and UICC T stage (P < 0.001) were independent risk factors for developing LNM in HCC. These findings show that CK19 and MMP-2 expression may be beneficial in predicting HCC LNM and survival.     

Current evidence on mesenchymal stem cell therapy for traumatic spinal cord injury: systematic review and meta-analysis

Background aimsThe authors aim to analyze the evidence in the literature regarding the efficacy and safety of mesenchymal stem cell (MSC) therapy in human subjects with traumatic spinal cord injury (SCI) and identify its potential role in the management of SCI.MethodsThe authors conducted independent and duplicate searches of electronic databases, including PubMed, Embase and the Cochrane Library, until May 2020 for studies analyzing the efficacy and safety of stem cell therapy for SCI. American Spine Injury Association (ASIA) impairment scale (AIS) grade improvement, ASIA sensorimotor score, activities of daily living score, residual urine volume, bladder function improvement, somatosensory evoked potential (SSEP) improvement and adverse reactions were the outcomes analyzed. Analysis was performed in R platform using OpenMeta[Analyst] software.ResultsNineteen studies involving 670 patients were included for analysis. On analysis, the intervention group showed statistically significant improvement in AIS grade (P < 0.001), ASIA sensory score (P < 0.017), light touch (P < 0.001), pinprick (P = 0.046), bladder function (P = 0.012), residual urine volume (P = 0.023) and SSEP (P = 0.002). However, no significant difference was noted in motor score (P = 0.193) or activities of daily living score (P = 0.161). Although the intervention group had a significant increase in complications (P < 0.001), no serious or permanent adverse events were reported. On subgroup analysis, low concentration of MSCs (<5 × 10⁷ cells) and initial AIS grade A presentation showed significantly better outcomes than their counterparts.ConclusionsThe authors’ analysis establishes the efficacy and safety of MSC transplantation in terms of improvement in AIS grade, ASIA sensory score, bladder function and electrophysiological parameters like SSEP compared with controls, without major adverse events. However, further research is needed to standardize dose, timing, route and source of MSCs used for transplantation.     

Advantages of peripheral blood stem cells from unrelated donors versus bone marrow transplants in outcomes of adult acute myeloid leukemia patients

Background aimsIn allogeneic stem cell transplantation, unrelated donors are chosen in cases where appropriate related donors are not available. Peripheral blood stem cells (PBSCs) are more often selected as a graft source than bone marrow (BM). However, the prognostic benefits of PBSCs versus BM transplants from unrelated donors have not been carefully examined in patients with acute myeloid leukemia (AML). This study compared outcomes of adult AML patients who underwent unrelated PBSC and BM transplantation, evaluating post-transplant complications, including engraftment, graft-versus-host disease (GVHD) and infections, and determined subgroups of patients who are most likely to benefit from unrelated PBSCs compared with BM transplants.MethodsThe authors analyzed 2962 adult AML patients who underwent unrelated PBSC or BM transplants between 2011 and 2018 (221 PBSC and 2741 BM) using the Japanese nationwide registry database, in which graft source selection is not skewed toward PBSCs.ResultsIn 49.7% of patients, disease status at transplantation was first complete remission (CR1). In 57.1% of cases, HLA-matched donors were selected. Myeloablative conditioning was performed in 75.1% of cases, and anti-thymocyte globulin (ATG) was added to conditioning in 10.5%. Multivariate analyses showed a trend toward favorable non-relapse mortality (NRM) in PBSC recipients compared with BM recipients (hazard ratio [HR], 0.731, P = 0.096), whereas overall survival (OS) (HR, 0.959, P = 0.230) and disease-free survival (DFS) (HR, 0.868, P = 0.221) were comparable between PBSC and BM recipients. Although the rate of chronic GVHD (cGVHD) was significantly higher in PBSC patients (HR, 1.367, P = 0.016), NRM was not increased, mainly as a result of significantly reduced risk of bacterial infections (HR, 0.618, P = 0.010), reflecting more prompt engraftments in PBSC recipients. Subgroup analyses revealed that PBSC transplantation was advantageous in patients transplanted at CR1 and in those without ATG use. PBSC recipients experienced significantly better OS and/or DFS compared with BM recipients in this patient group.ConclusionsThe authors' results confirmed the overall safety of unrelated PBSC transplantation for adult AML patients and suggested an advantage of PBSCs, especially for those in CR1. Further optimization of the prophylactic strategy for cGVHD is required to improve the overall outcome in transplantation from unrelated PBSC donors.     

Staphylococcal cassette chromosome mec (SCCmec) characterization and panton-valentine leukocidin gene occurrence for methicillin-resistant Staphylococcus aureus in Turkey, from 2003 to 2006

Methicillin-resistant Staphylococcus aureus (MRSA) cause serious community-acquired and nosocomial diseases all over the world. We determined the SCCmec types and occurrence of the PVL gene by using TaqMan real-time PCR method, and correlated these with phenotypic antibiotic susceptibility patterns for MRSA strains collected from Gulhane Military Medical Academy Hospital (GMMAH) during 4 years study period. To our knowledge, this is the first report from Turkey of molecular SCCmec typing analysis of MRSA stains. A total of 385 clinical MRSA isolates collected in the clinical and Microbiology Laboratory at GMMAH between 2003 and 2006 were included in the study. Overall, SCCmec types-I, II, III, IV, V, nontypeable and PVL occurrence were detected in 11 (2.8%), 3 (0.8%), 316 (82.1%), 20 (5.1%), 20 (5.1%), 15 (3.9%) and 5 (1.3%) isolates, respectively. A total of 330 (85.5%) were SCCmec-I/II/III and 40 (10.3%) were SCCmec IV/V. SCCmec-I/II/III isolates were recovered more from patients with serious infections in surgical departments especially those with intensive care units than the SCCmec-IV/V isolates (χ² = 13.560, P < 0.001). SCCmec-I/II/III MRSA strains were predominantly recovered from blood stream (53.0%, P = 0.014), while SCCmec-IV/V strains were predominately isolated from skin and soft tissue and abscess (55.0%, P < 0.001). The PVL gene was detected in 10.0% of SCCmec-IV/V isolates in contrast to 0.3% in SCCmec-I/II/III (χ² = 25.164, P < 0.001). SCCmec-I/II/III MRSA strains were more resistant to clindamycin (χ² = 5.078, P = 0.024), amoxicillin-clavulanate (χ² = 84.912, P < 0.001), erythromycin (χ² = 4.651, P = 0.031), gentamicin (χ² = 24.869, P < 0.001), and rifampin (χ² = 18.878, P < 0.001) than SCCmec-IV/V MRSA strains. This data indicates that SCCmec-III MRSA strains that do not carry the PVL gene are the predominant MRSA strains in our hospital setting in Ankara, capital of Turkey and that SCCmec-I/II/III MRSA strains may cause serious infections in surgical departments especially those with intensive care units.     

Enhanced brain natriuretic peptide response to peak exercise in heart transplant recipients

We investigatedthe atrial (ANP) and brain natriuretic peptides (BNP), catecholamines,heart rate, and blood pressure responses to graded upright maximalcycling exercise of eight matched healthy subjects andcardiac-denervated heart transplant recipients (HTR). Baseline heart rate and diastolic blood pressure, together with ANP(15.2 ± 3.7 vs. 4.4 ± 0.8 pmol/l;P < 0.01) and BNP (14.3 ± 2.6 vs. 7.4 ± 0.6 pmol/l; P < 0.01), were elevated in HTR, but catecholamine levels were similarin both groups. Peak exercise O₂uptake and heart rate were lower in HTR. Exercise-inducedmaximal ANP increase was similar in both groups (167 ± 34 vs. 216 ± 47%). Enhanced BNP increase was significant only in HTR (37 ± 8 vs. 16 ± 8%; P < 0.05).Similar norepinephrine but lower peak epinephrine levels were observedin HTR. ANP and heart rate changes from rest to 75% peak exercise werenegatively correlated (r = 0.76, P < 0.05),and BNP increase was correlated with left ventricular mass index(r = 0.83, P < 0.01) after hearttransplantation. Although ANP increase was notexaggerated, these data support the idea that the chronotropiclimitation secondary to sinus node denervation might stimulate ANPrelease during early exercise in HTR. Furthermore, the BNPresponse to maximal exercise, which is related to the left ventricularmass index of HTR, is enhanced after heart transplantation.

     

A study of the impact of cytokine gene polymorphism in acute rejection of renal transplant recipients

Acute rejection is a common phenomenon in transplantation. Inflammatory and anti-inflammatory mediators affect the graft microenvironment. Th1 responses cause acute rejection while Th2 immune responses help the survival of the graft. In this study, we evaluated gene polymorphisms of IL-6 G-174C, TGF-β T+869C, IL-4 C-590T, and IFN-γ T+874A cytokines in renal transplant patients. ARMS-PCR method was used to characterize IL-6 G-174C (rs76144090), TGF-β T+869C (rs1800471), and IFN-γ T+874A (rs2430561) polymorphisms and PCR-RFLP, for characterization of IL-4 C-590T (rs2243250) in 100 renal transplant patients. Acute rejection episodes were diagnosed according to the standard criteria. Analysis of the results showed that IL-6-174 GG genotype (P = 0.018, OR = 3.023, 95% CI = 1.183–7.726) and IL-6-174G allele (P = 0.046, OR = 2.114, 95% CI = 1.005–4.447) were more frequent, but IL-6-174GC genotype was less frequent in acute rejection of kidney transplantation in comparison with control group (P = 0.024, OR = 0.302, 95% CI = 0.103–0.883). IFN-γ+874 T allele was associated with a higher risk of acute rejection (P = 0.019, OR = 2.088, 95% CI = 1.124–3.880) while IFN-γ+874 AA genotype was associated with a lower risk of rejection (P = 0.023, OR = 0.318, 95% CI = 0.115–0.875). Frequencies of TGF-β T+869C and IL-4 C-590T were not significantly different (P > 0.05). Consequently, our results show that IL-6 G-174C and IFN-γ T+874A gene polymorphisms have predictive values for acute rejection after renal transplantation in Iranian patients.     

Role of tissue plasminogen activator and plasminogen activator inhibitor polymorphism in myocardial infarction

A case–control association study on 229 Myocardial Infarction (MI) patients and 217 healthy controls was carried out to determine the role of tissue-plasminogen activator (t-PA) (Alu-repeat insertion (I)/deletion (D)) and plasminogen activator inhibitor (PAI-1) (4G/5G insertion/deletion) polymorphisms with MI in the Pakistani population. In MI patients the genotype distribution of the PAI-1 gene was not found to be different when compared with the unaffected controls (P > 0.05, χ² = 1.03). The risk allele 4G was also not associated with MI (P > 0.05, χ² = 0.46, odds ratio (OR) = 1.1 (95% confidence interval (CI) = 0.84–1.43), P > 0.05). Similarly, the genotype frequencies of t-PA I/I, I/D and D/D were not different from the unaffected controls (P > 0.05, χ² = 1.60), and the risk allele “I” was not found to be associated with MI (P > 0.05, χ² = 1.35, OR = 0.86 (95% CI = 0.66–1.11), P > 0.05). However, when the data were distributed along the lines of gender a significant association of the 4G/4G PAI-1 genotype was observed with only the female MI patients (P < 0.05, z-test = 2.21). When the combined genotypes of both the polymorphisms were analyzed, a significant association of MI was observed with the homozygous DD/4G4G genotype (P < 0.01, z-test = 2.61), which was specifically because of the female samples (P = 0.01, z-test = 2.53). In addition smoking (P < 0.001, χ² = 13.52, OR = 3.45 (95% CI = 1.77–6.94)), diabetes (P < 0.001, χ² = 22.45, OR = 8.89 (95% CI = 2.96–29.95)), hypertension (OR = 7.76 (95% CI = 2.88–22.68), P < 0.001) family history (P < 0.001, χ² = 13.72, OR = 3.7 (95% CI = 1.71–8.18)) and lower HDL levels (P < 0.05) were found to be significantly associated with the disease. In conclusion the PAI-1 gene polymorphism was found to have a gender specific role in the female MI patients.     

Familial longevity is characterized by high circadian rhythmicity of serum cholesterol in healthy elderly individuals

The biological clock, whose function deteriorates with increasing age, determines bodily circadian (i.e. 24h) rhythms, including that of cholesterol metabolism. Dampening of circadian rhythms has been associated with aging and disease. Therefore, we hypothesized that individuals with a familial predisposition for longevity have a higher amplitude circadian serum cholesterol concentration rhythm. The aim of this study was to investigate circadian rhythmicity of serum cholesterol concentrations in offspring of nonagenarian siblings and their partners. Offspring from nonagenarian siblings (n = 19), and their partners as controls (n = 18), were recruited from the Leiden Longevity Study. Participants (mean age 65 years) were studied in a controlled in‐hospital setting over a 24‐h period, receiving three isocaloric meals at 9:00 h, 12:00 h and 18:00 h. Lights were off between 23:00 h and 8:00 h. Serum total cholesterol (TC), HDL cholesterol (HDL‐C), non‐HDL‐C and triglycerides (TG) were determined every 30 min over a 24‐h period. Serum TC concentrations were higher during day than during night in offspring (5.2 vs. 4.7 mm , P < 0.001) and in controls (5.3 vs. 5.0 mm , P < 0.001). The difference in TC concentrations between day and night tended to be greater in offspring than in controls (0.5 vs. 0.3 mm , P = 0.109), reaching statistical significance in females (P = 0.045). Notably, the day–night serum differences in non‐HDL‐C were twofold greater in offspring than in controls (0.43 vs. 0.21 mm , P = 0.044) and most explicit in females (0.53 vs. 0.22, P = 0.078). We conclude that familial longevity is characterized by a high circadian rhythmicity of non‐HDL‐C in healthy elderly offspring from nonagenarian siblings.     

Incidence of leukaemia and other malignant diseases following injections of the short-lived α-emitter <Superscript>224</Superscript>Ra into man

We performed an epidemiological study on 1,471 ankylosing spondylitis patients treated with repeated intravenous injections of the short lived α-emitter ²²⁴Ra (excluding radiation therapy with X-rays) between 1948 and 1975. These patients have been followed together with a control group of 1,324 ankylosing spondylitis patients treated neither with radioactive drugs nor with X-rays. The mean follow-up time was 26.3 years in the exposed and 24.6 years in the control group. To date, causes of death have been ascertained for 1,006 exposed patients and 1,072 controls. Special emphasis was placed on the reporting of malignant diseases. Expected numbers of cases were computed for the age, sex and calendar year distribution of both groups using cancer registry incidence rates. In the exposed group 18 cases of kidney cancer (vs. 9.1 cases expected, P < 0.01) and 4 malignant thyroid tumours (vs. 1.2 cases expected, P = 0.03) were observed. In the control group the observed cases for these tumours were not significantly elevated. The most striking observation, however, were the 21 cases of leukaemia in the exposed group (vs. 6.8 cases expected, P < 0.001) compared to 12 cases of leukaemia in the control group (vs. 7.5 cases expected). Further sub-classification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposed group (12 cases observed vs. 2.9 cases expected, P < 0.001), and out of these, especially a high excess of acute myeloid leukaemias (7 cases observed vs. 1.8 expected, P = 0.003). In the controls the observed cases are within the expected range (4 myeloid leukaemias vs. 3.1 cases). This increase in total leukaemias as well as particularly in myeloid leukaemias is significant in direct comparison between the exposed and control groups too (P < 0.05). The enhanced leukaemia incidence in the exposed group is in line with the observation of increased leukaemia incidence in mice injected with ²²⁴Ra.