CCR5 or CXCR4 is required for efficient infection of peripheral blood mononuclear cells by promiscuous human immunodeficiency virus type 2 primary isolates

Primary human immunodeficiency virus type 2 (HIV-2) isolates are characterized by their ability to use a broad range of coreceptors, including CCR5, CXCR4, and several alternative coreceptors. However, the in vivo relevance of this in vitro promiscuity in coreceptor usage remains unclear. We set out to evaluate the relative importance of CCR5 and CXCR4 for infection of activated peripheral blood mononuclear cells (PBMC). PBMC from donors homozygous for wild-type CCR5 (CCR5(+/+) or CCR5Delta32 (CCR5(-/-)) were tested for their susceptibility to infection with 10 primary HIV-2 isolates with known coreceptor usage by parallel 50% tissue culture infectious dose (TCID50) titrations. Although all isolates, except one, were able to establish productive infection in CCR5(-/-) PBMC, the infection of these cells was inefficient for all isolates that were unable to use CXCR4. For CXCR4-using isolates there were only minor differences in TCID50 between CCR5(+/+) and CCR5(-/-) PBMC. When we compared the replication kinetics in PBMC from donors of the two genotypes we observed an average delay in replication onset of 9 days in the CCR5(-/-) PBMC. This study shows that HIV-2 can use alternative coreceptors for infection of PBMC, but that this infection is much less efficient than infection mediated by CCR5 or CXCR4. Thus, CCR5 and CXCR4 appear to be the major coreceptors for HIV-2 infection of PBMC.     

TGF-β1 enhances cardiomyogenic differentiation of skeletal muscle-derived adult primitive cells

The optimal medium for cardiac differentiation of adult primitive cells remains to be established. We quantitatively compared the efficacy of IGF-1, dynorphin B, insulin, oxytocin, bFGF, and TGF-β1 in inducing cardiomyogenic differentiation. Adult mouse skeletal muscle-derived Sca1+/CD45-/c-kit-/Thy-1+ (SM+) and Sca1-/CD45-/c-kit-/Thy-1+ (SM-) cells were cultured in basic medium (BM; DMEM, FBS, IGF-1, dynorphin B) alone and BM supplemented with insulin, oxytocin, bFGF, or TGF-β1. Cardiac differentiation was evaluated by the expression of cardiac-specific markers at the mRNA (qRT-PCR) and protein (immunocytochemistry) levels. BM+TGF-β1 upregulated mRNA expression of Nkx2.5 and GATA-4 after 4 days and Myl2 after 9 days. After 30 days, BM+TGF-β1 induced the greatest extent of cardiac differentiation (by morphology and expression of cardiac markers) in SM- cells. We conclude that TGF-β1 enhances cardiomyogenic differentiation in skeletal muscle-derived adult primitive cells. This strategy may be utilized to induce cardiac differentiation as well as to examine the cardiomyogenic potential of adult tissue-derived stem/progenitor cells. Electronic supplementary material  The online version of this article (DOI:) contains supplementary material, which is available to authorized users. Returned for 1. Revision: 8 January 2008 1. Revision received: 8 April 2008 Ahmed Abdel-Latif and Ewa K. Zuba-Surma contributed equally to this work.     

Cytokines and heart rate variability in patients with chronic heart failure

INTRODUCTION: Heart rate variability (HRV) analysis is a non-invasive method of assessment of the autonomic nervous system's effects on heart function. In chronic heart failure (CHF), decreased HRV correlates with the progression of the disease. It is also known that in CHF increased levels of proinflammatory cytokines are present. Because these molecules are believed to influence the nervous system at both the central and peripheral levels, their potential role in HRV reduction in the course of CHF has been proposed. AIM: The study was designed to verify potential relations between cytokines and HRV parameters in CHF patients. The concept of the study was driven by the recognition of controversies in this field and the paucity of published reports. METHODS: Forty-four patients with CHF and stable NYHA class I-IV symptoms and 15 healthy controls were enrolled in the study. Time-domain HRV analysis was performed based on of 24-hour Holter ECG monitoring. Plasma concentrations of soluble TNFalpha receptors sTNF-RI and sTNF-RII and interleukin 6 (IL-6) were measured using commercially available ELISA kits (Quantikine, RD Systems). RESULTS: In patients with CHF, HRV indices included in the analysis were significantly decreased, and the levels of cytokines increased in comparison with the control group. In the whole study population, both in the CHF patients and the control group, significant negative correlations were observed between sTNF-RI level and long-term HRV indices such as SDNN (r=-0.44; p=0.0006), SDANN (r=-0.44; p=0.0005) and short-time index SDNNI (r=-0.37; p=0.004). Similar negative correlations were found between sTNF-RII level and SDNN (r=-0.35; p=0.007), SDANN (r=-0.34; p=0.01), and SDNNI (r=-0.31; p=0.02), as well as between IL-6 level and SDNN (r=-0.41; p=0.001), SDANN (r=-0.44; p=0.0005) and SDNNI (r=-0.34; p=0.009). CONCLUSIONS: Significant negative correlations between TNF-alpha soluble receptors sTNF-RI, sTNF-RII and IL-6 levels and time-domain HRV parameters were observed in the study. Because the results of investigations conducted so far do not elucidate the cause-effect relationship, further studies are needed to clarify the mechanisms of HRV depression in CHF and the role of cytokines in this severe clinical condition.     

Acute infarction of the left ventricular papillary muscle: Electrocardiographic pattern and recognition of its location

Background and hypothesis: ST-segment depression during acute myocardial infarction (AMI) is known to herald serious hemodynamic complications. Since the mechanism of this dependence is not clear, we reinvestigated the old concept of papillary muscle infarction (PMI) as a cause of marked ST depression. Methods: Autopsies and morpho-electrocardiographic correlations were performed in 53 patients with AMI involving one or both left ventricular papillary muscles, and in 10 patients with AMI, but without acute PMI. Results: ST-segment depression ≥l mm in at least two leads (mean 3.6 ± 2.2 mm) was found in 46 (86.8%) patients with, and in one without acute PMI. Thus, the sensitivity and specificity in selecting patients with acute PMI from among those with AMI were 86.8 and 90%, respectively, with an overall accuracy of diagnosis of acute PMI in the course of AMI of 87.3%. Among 26 patients with ST elevation consistent with diagnosis of AMI, ST depression, recorded in 22 patients, was insignificantly greater than in 24 of 27 patients without ST elevation: 4.1 ± 2.9 versus 3.1 ± 1.2 mm. Localization of ST depression in the limb leads allowed recognition of which papillary muscle suffered from acute infarction: ST depression in the inferior leads was seen only in patients with anterolateral PMI, whereas in leads I and/or aVL it was seen only in cases with posteromedial PMI. This rule was also valid in patients without concomitant ST elevation. Conclusion: Patients with acute PMI show marked ST-segment depression. Its location in the limb leads allows recognition of which papillary muscle has undergone necrosis. This cause of marked ST depression in patients with AMI may explain the high mortality in this particular group.     

Lympho- and myeloproliferative disorders in renal transplant recipients--one center's experience and review of the literature

Recipients of renal transplants have an increased risk of developing secondary malignancies. About 4% of patients who underwent kidney transplantation will develop cancer, and 1% of transplanted patients will develop lymphoproliferative disorders. According to clinical analyses and laboratory data, the main reason for increased risk of developing malignant disease in this group of patients, is their immunocompromised status due to immunosuppressive treatment. So called "strong" immunosuppressive drugs like antilymphocytic globulin (ALG), antithymocytic globulin (ATG), or monoclonal globulin OKT3 seem to favor the development of secondary malignancies much more than other drugs, like: corticosteroids, azathioprine (AZA), or cyclosporine (CsA). Secondary lymphoproliferative disorders are usually connected with reactivation of Ebstein-Barr virus infection. Patients with early onset (<1 year after the transplantation) have a favorable clinical course after withdrawal of immunosuppression. The subset of late-onset (>1 year) has usually much more aggressive clinical course and patients require intensive treatment. The general recommendation in these patients is to stop or to reduce the immunosuppressive treatment and to continue the chemotherapy in full dose. This treatment is often complicated by severe infections, but it offers a chance to achieve remission without worsening the function of transplanted organ. In this paper we are presenting five patients with secondary lympho- or myeloproliferative disorders after kidney transplantation and give an overview of the recent literature in this field.     

Endocrine pancreatic function in patients after acute pancreatitis

BACKGROUND/AIMS: The incidence of carbohydrate tolerance disorders in patients after acute pancreatitis has not been clearly established yet. The aim of the study was to estimate the frequency of endocrine pancreatic function impairment in patients after acute pancreatitis and its correlation with acute pancreatitis etiology and clinical course. METHODOLOGY: 82 patients (27 women and 55 men), aged between 28-65 (mean: 47 +/- 8.3), 1-7 (mean: 4.7 +/- 3.6) years after acute pancreatitis were evaluated. Control group consisted of 15 healthy volunteers. Oral glucose tolerance test with RIA insulin level was performed in all examined patients. Patients with any sign of chronic pancreatitis, based on clinical, functional (stool chymotrypsin test) and imaging (US and CT) findings, were excluded from the study. RESULTS: Impaired glucose tolerance was found in 4 patients (4.9%) and overt diabetes in 13 patients (15.8%) recovered from acute pancreatitis, which was not significantly different from those values in the local general population. Mean insulin values fasting and 30, 60 and 90 min after administration of 75 g glucose were significantly lower in patients after acute pancreatitis than in controls (p < 0.001). Endocrine pancreatic function impairment was found significantly more often in patients after severe acute pancreatitis clinical course (p < 0.0001), than in patients after mild pancreatitis. The frequency of impaired glucose tolerance and diabetes after acute alcoholic pancreatitis was 13 (36%), which was significantly higher (p < 0.05), than in cases of gallstone etiology (14%) and other causes (0%). CONCLUSIONS: Pancreatic endocrine function impairment following acute pancreatitis is associated with the decreased plasma insulin levels fasting and after glucose stimulus. Overall, the incidence of diabetes mellitus in patients after acute pancreatitis is similar to the reported values for the general population in this area. Alcoholic pancreatitis is more often complicated with impaired glucose tolerance and diabetes mellitus as regards to other causes of pancreatitis. Endocrine pancreatic function impairment is significantly more common after severe than after mild acute pancreatitis.     

Thoracic impedance measurement in heart stimulation and cardiac arrhythmias

The electrocardiogram (ECG) interpretation in patients with implantable cardioverter defibrillator (ICD) is often a puzzling problem. The difficulty of the device function evaluation further increases in the presence of unfamiliar timing cycles and additional functions. We present an interesting ECG with a special function of a Biotronik ICD devices called the thoracic impedance monitoring, and demonstrate its behavior in a patient with atrial fibrillation, pacing beats, ventricular ectopic beats, and couple of ventricular beats. This report shows unexceptional occurrence of tricky ECG finding in patient with Biotronik ICDs.     

Defensins: Natural component of human innate immunity

The widespread use of antibiotics has contributed to a huge increase in the number of resistant bacteria. New classes of drugs are therefore being developed of which defensins are a potential source. Defensins are a group of antimicrobial peptides found in different living organisms, involved in the first line of defense in their innate immune response against pathogens. This review summarizes the results of studies of this family of human antimicrobial peptides (AMPs). There is a special emphasis on describing the entire group and individual peptides, history of their discovery, their functions and expression sites. The results of the recent studies on the use of the biologically active peptides in human medicine are also presented. The pharmaceutical potential of human defensins cannot be ignored, especially considering their strong antimicrobial activity and properties such as low molecular weight, reduced immunogenicity, broad activity spectrum and resistance to proteolysis, but there are still many challenges and questions regarding the possibilities of their practical application.