Steroid withdrawal in renal transplant patients: the Irish experience

Background  

Steroid therapy is associated with significant morbidity in renal transplant recipients. However, there is concern that steroid withdrawal will adversely affect outcome.     

Vascular endothelial growth factor delays onset of failure in pressure–overload hypertrophy through matrix metalloproteinase activation and angiogenesis

Objective Pressure–overload hypertrophy is associated with decreased capillary density in myocardium resulting in impaired substrate delivery. Treatment of hypertrophied hearts with vascular endothelial growth factor (VEGF) induces angiogenesis. Since angiogenesis is associated with extracellular matrix degradation, we sought to determine whether VEGF induced angiogenesis in hypertrophy required matrix metalloproteinases (MMP) activation. Methods Newborn rabbits underwent aortic banding. Progression of hypertrophy (mass–to–volume (M/V) ratio) and mid–wall contractility index was monitored by echocardiography. At 4 and 6 weeks, VEGF (2 μg/kg), vehicle or VEGF combined with GM6001 (5 mg/kg), a MMP inhibitor, was administered intrapericardially. CD–31 (indicator of angiogenesis), MMP–2, MT1–MMP and TIMPs (endogenous MMP inhibitors) expression were measured by immunoblotting. MMP–2 activity was determined by gelatin zymography. Results Untreated hypertrophied hearts progressed to ventricular dilatation at 7 wks (M/V ratio: 0.75 ± 0.07), but compensatory hypertrophy was maintained with VEGF (0.91 ± 0.07; p < 0.05). LV contractility declined in untreated hearts from –0.41 ± 0.9 (5 wks) to –0.73 ± 0.5 (7 wks; p < 0.05) but remained normal with VEGF (+1.61 ± 0.6 vs. +0.47 ± 0.2). MMP–2 expression and activity were significantly elevated in VEGF treated hypertrophied hearts (p < 0.05) and were blocked by concomitant administration of GM6001. VEGF induced neovascularization was inhibited by addition of GM6001. MT1–MMP showed a trend to higher levels in VEGF treated hearts. TIMPs were unchanged in all three groups. Conclusions Exogenous VEGF and resultant MMP–2 activation leads to increased capillary formation in severe hypertrophy, preventing progression to ventricular dilation and dysfunction. VEGF and the associated MMP–2 activation play an important and potentially therapeutic role in vascular remodeling of hypertrophied hearts. This work was supported by National Heart, Lung, and Blood Institute Grants HL-075430 (to I. Friehs) and HL-063095 (to P. J. del Nido)     

The steroidogenic effect of single-chain bovine LH analogs in cultured bovine follicular cells

Single-chain gonadotropin analogs had been constructed for the purpose of structure-function studies and analog design. Incorporation of a spacer derived from the carboxyl terminal peptide (CTP) of the choriogonadotropin (CG) beta subunit between the tethered subunit domains of the human gonadotropins is beneficial for the secretion of the single-chain variants without compromising biocactivity. Although the CGbeta subunit containing the CTP domain is expressed only in primates and equids, a CTP-like sequence exists in the untranslated region of the LHbeta gene of several mammalian species, including the bovine species. The CTP encrypted in the bovine LHbeta DNA (designated as 'boCTP') and the CTP derived from the human CGbeta subunit (denoted as 'huCTP') served as a linker sequence in the design of bovine single-chain luteinizing hormone (LH) analogs. The purpose of the present study was to evaluate steroidogenesis in cultured bovine theca cells following stimulation with these single-chain analogs. The concentration of the LHbetaboCTPalpha and LHbetahuCTPalpha analogs in the conditioned media of the expressing CHO cells was three- to six-fold higher than that of the "linkerless" LHbetaalpha and LHbeta111alpha variants. The four analogs induced androstenedione and progesterone secretion from the primary theca cells in a dose-dependent manner, but differences in the steroidogenic response were observed. The LHbetaboCTPalpha analog (10 ng/ml) effectively induced androstenedione and progesterone secretion over unstimulated levels (4.0- and 4.4-fold increase for androstenedione and progesterone, respectively). The response to the pituitary bovine LH standard (10 ng/ml) was less pronounced for both steroids (two- to three-fold increase over basal levels). The activities of LHbetahuCTPalpha, LHbetaalpha and LHbeta111alpha were comparable and sightly reduced relative to the LHbetaboCTPalpha activity. The data suggested that LHbetaboCTPalpha was ranked as the most potent and this was even more prominent when analogs were used at a lower dose (1 ng/ml). These data suggest that the design, including the huCTP or boCTP linker, is favorable for the production of single-chain bovine LH analogs. Furthermore, spacing of the tethered subunit domains with the cryptic boCTP sequence that originated from the bovine LHbeta gene appears advantageous for the purpose of stimulating steroid production in the species-specific bioassay. Thus, an effective strategy to produce bioactive single-chain LH analogs in non-primate, non-equid species would be the mutatation of the LHbeta genes with the aim of expressing the cryptic CTP sequence as a spacer derived from the DNA of the same organism.     

Spontaneous resolution of Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein–Barr virus (EBV‐HLH). Current treatment protocols for EBV‐HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV‐HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV‐HLH who do well with conservative management and can avoid potentially toxic therapies. Pediatr Blood Cancer. 2010;55:754–756. © 2010 Wiley‐Liss, Inc.     

Platelet FcgammaRIIA expression is associated with the alpha2 integrin C807T gene polymorphism in type 2 diabetes

"Patelet" FcgammaRIIA is stably overexpressed in type 2 diabetes and may also play a role in collagen-mediated platelet activation. Platelet surface integrin a(2)ss(1)-collagen interaction is an early step associated with platelet adhesion and activation and plays an important role in arterial thrombosis. The objective of this study was to characterize the relationship in diabetes and non-diabetes platelets between FcgammaRIIA expression and a polymorphism associated with arterial thrombotic events, polymorphism C807T on the gene encoding a(2)ss(1). Platelet flow cytometry and allele-specific PCR revealed a significant correlation in type 2 diabetes between low platelet FcgammaRIIA expression and the 807TT genotype that is associated with increased platelet a(2)ss(1) receptor density. We conclude that uni- or bi-directional modulation of surface expression may exist between the platelet FcgammaRIIA receptor and a a(2)ss(1) thrombogenic polymorphism that could play a role in platelet sensitivity to collagen in type 2 diabetes.     

Apoptosis induction in gastric mucous cells in vitro: lesser potency of Helicobacter pylori than Escherichia coli lipopolysaccharide, but positive interaction with ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) cause peptic ulcer disease, but whether they interact with Helicobacter pylori to promote damage is controversial. Moreover, the reported induction of apoptosis in gastric cells by H. pylori lipopolysaccharide (LPS) (10(-9) g/ml) contrasts with studies showing low immunological potency of this LPS. Therefore, the effects of LPS from H. pylori NCTC 11637 and Escherichia coli O111:B4 on apoptosis in a primary culture of guinea-pig gastric mucous cells were investigated in the presence and absence of the NSAID, ibuprofen. Cell loss was estimated by a crystal violet assay, and apoptosis determined from caspase activity and from condensation and fragmentation of nuclei. Exposure to E. coli LPS for 24 h caused cell loss and enhanced apoptotic activity at concentrations >or= 10(-9) g/ml, but similar effects were only obtained with H. pylori LPS at concentrations >or= 10(-6) g/ml. Although ibuprofen (250 microM) caused cell loss and apoptosis, addition of either E. coli or H. pylori LPSs further enhanced these effects. In conclusion, LPS and ibuprofen interact to enhance gastric cell loss and apoptosis. In such interactions, E. coli LPS is more potent than that of H. pylori. The low potency of H. pylori LPS may contribute to a chronic low-grade gastritis that can be enhanced by the use of NSAIDs.     

Respiratory hygiene in the emergency department

The emergency department (ED) is an essential component of the public health response plan for control of acute respiratory infectious threats. Effective respiratory hygiene in the ED is imperative to limit the spread of dangerous respiratory pathogens, including influenza, severe acute respiratory syndrome, avian influenza, and bioterrorism agents, particularly given that these agents may not be immediately identifiable. Sustaining effective respiratory control measures is especially challenging in the ED because of patient crowding, inadequate staffing and resources, and ever-increasing numbers of immunocompromised patients. Threat of contagion exists not only for ED patients but also for visitors, health care workers, and inpatient populations. Potential physical sites for respiratory disease transmission extend from out-of-hospital care, to triage, waiting room, ED treatment area, and the hospital at large. This article presents a summary of the most current information available in the literature about respiratory hygiene in the ED, including administrative, patient, and legal issues. Wherever possible, specific recommendations and references to practical information from the Centers for Disease Control and Prevention are provided. The "Administrative Issues" section describes coordination with public health departments, procedures for effective facility planning, and measures for health care worker protection (education, staffing optimization, and vaccination). The patient care section addresses the potentially infected ED patient, including emergency medical services concerns, triage planning, and patient transport. "Legal Issues" discusses the interplay between public safety and patient privacy. Emergency physicians play a critical role in early identification, treatment, and containment of potentially lethal respiratory pathogens. This brief synopsis should help clinicians and administrators understand, develop, and implement appropriate policies and procedures to address respiratory hygiene in the ED.     

Does laparoscopy beget underuse of partial nephrectomy for T(1) renal masses? Competing treatment decision pathways may influence utilization

BACKGROUND AND PURPOSE: It has been suggested that renal laparoscopy has resulted in an underuse of partial nephrectomy (PN) for small renal masses in the U.S. In the absence of evidence-based medicine (EBM) guide-lines, multiple-perspective reasoning is required where complete v partial nephrectomy and the laparoscopic v the open surgical approach must be considered. We report on the PN rate in a contemporary laparoscopicera series of patients with T(1) renal masses and examine the potential influence of the management decision tree on the PN rate. PATIENTS AND METHODS: An actively managed database of referred patients with T(1) renal masses was utilized retrospectively. All patients were evaluated by a single fellowship-trained urologic oncologist with formal laparoscopic training. Patients were presented with a management decision tree in which PN v total nephrectomy (TN) was the first decision node, laparoscopy v open surgery was the second decision node, and the actual PN rate was reported. We then constructed a hypothetical decision tree in which the first and second decision nodes were reversed and the criteria for performing laparoscopic nephrectomy remained constant. RESULTS: Seventy consecutive patients were entered during a 36-month period (July 2002-June 2005). The actual PN rate was 60%: 91% for lesions <2.0 cm, 68% for lesions 2.1 to 4.0 cm, and 33% for lesions 4.1 to 7.0 cm; and 62% of patients were treated laparoscopically. When the first and second decision nodes were reversed and this hypothetical model was applied to the study cohort, the projected PN rate was 23%, and 96% of the patients were treated laparoscopically. In the hypothetical model, the PN rate fell when patients who chose laparoscopy at the first decision node were excluded from PN at the second decision node if the criteria for laparoscopic PN were not met. CONCLUSION: Laparoscopy did not appear to result in underuse of PN. We explain this by suggesting that the PN rate may be influenced by variation in the decision tree itself. Such variation is inherent in complex clinical decision making where EBM guidelines are lacking.