Neuro-endocrine and neuropsychological outcome after aneurysmal subarachnoid hemorrhage (aSAH): a prospective cohort study.

OBJECTIVE: Neuropsychological sequelae are common after aneurysmal subarachnoid hemorrhage (aSAH) and may be associated with or caused by supposed hypothalamic-pituitary dysfunction. We evaluated the incidence of neuro-endocrine and neuropsychological deficits after aSAH and their interrelations in a standardized manner. METHODS: 26 patients (20 females) were prospectively screened for neuro-endocrine and neuropsychological deficits 3 and 6 months after aSAH. We measured GH, IGF-1, prolactin, LH, FSH, estradiol, TSH, fT4, total T3, testosterone, ACTH as well as cortisol before and after ACTH-stimulation. Neuropsychological analysis covered verbal comprehension, short term and working memory, visuospatial construction, figural memory, psychomotor speed, attention, and concentration. RESULTS: After 3 months central hypogonadism was observed in 2 patients accompanied by central hypothyroidism in 1 male subject. Central hypogonadism resolved spontaneously after 6 months in both. After 3 months, neuropsychological deficits were detected in 57% of the examined patients (44% attention deficits, 38% memory impairment, 12% psychomotor deficits). Neuropsychological deficits were still present in 53% after 6 months. CONCLUSION: We found a low prevalence of neuro-endocrine and a high prevalence of neuropsychological deficits in patients 3 and 6 months after aSAH. Thus, the absent co-incidence of central hormonal and psychological dysfunction leaves a causal association questionable.

Inhibition of neutrophil-mediated production of reactive oxygen species (ROS) by endothelial cells is not impaired in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis patients.

Leucocyte transendothelial migration is strictly regulated to prevent undesired inflammation and collateral damage of endothelial cells by activated neutrophils/monocytes. We hypothesized that in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) patients' dysregulation of this process might underlie vascular inflammation. Peripheral blood mononuclear cells (PBMC) and neutrophils from AAV patients (n = 12) and healthy controls (HC, n = 12) were isolated. The influence of human umbilical vein endothelial cells (HUVEC) on neutrophil/monocytes function was tested by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP)- and phorbol 12-myristate 13-acetate (PMA)-mediated ROS production, degranulation and interleukin (IL)-8 production. In addition, the ability of lipopolysaccharide (LPS)-stimulated PBMC to produce tumour necrosis factor (TNF)-alpha in the presence or absence of HUVEC was tested. HUVEC inhibited ROS production dose-dependently by fMLP-stimulated neutrophils but did not influence degranulation. No differences between neutrophils from HC and AAV were found. However, in only one active patient was degranulation inhibited significantly by HUVEC only before cyclophosphamide treatment, but not 6 weeks later. Co-cultures of HUVEC with LPS-stimulated neutrophils/monocytes increased IL-8 production while TNF-alpha production was inhibited significantly. There was no apparent difference between AAV patients and HC in this respect. Our findings demonstrate that HUVEC are able to inhibit ROS and modulate cytokine production upon stimulation of neutrophils or monocytes. Our data do not support the hypothesis that endothelial cells inhibit ROS production of neutrophils from AAV patients inadequately. Impaired neutrophil degranulation may exist in active patients, but this finding needs to be confirmed.

Modulation of brain dead induced inflammation by vagus nerve stimulation.

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip-analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFalpha concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFalpha concentrations and resulted in down-regulation of a multiplicity of pro-inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E-selectin, IL1beta and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFalpha through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.

Imatinib mesylate, a new kid on the block for the treatment of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis?

Persistent T cell activation is a common finding in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AAV) patients. Because imatinib, a selective inhibitor of the ABL, ARG, PDGFR and c-KIT tyrosine kinases, inhibits T cell activation, this study was conducted to evaluate the potential use of imatinib for the treatment AAV patients refractory to conventional therapy. In particular, we investigated the inhibition of T cell activation by this drug and its efficacy on activated T cells from anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitides (AASV) patients. T cell stimulation has been induced by anti-CD3/anti-CD28 antibodies or by phorbol myristate acetate (PMA)/ionomycin. T cell proliferation was analysed by tritiumthymidine incorporation. Cell cycle progression was determined by propidium iodide staining using fluorescence activated cell sorter (FACS) analysis and by RNAse protection assay (RPA). Cytokine levels were assessed by enzyme-linked immunosorbent assay. T cell proliferation was inhibited significantly by imatinib, due most probably to cell cycle arrest in the G1-phase. This was paralleled by inhibition in the expression of cyclin-dependent kinases 1 and 2 mRNA. The expression of CD25 in naive and memory T cells was decreased significantly by imatinib in activated T cells. Similarly, conversion from naive to memory T cells after T cell activation was impaired by imatinib. Imatinib did not influence interleukin-2 and tumour necrosis factor-alpha production but increased interferon-gamma production. These observed effects of imatinib were similar in T cells from AASV patients and from healthy individuals. Imatinib might be an alternative therapeutical option for AASV patients refractory to conventional therapy.

Clinical benefit of a short term dietary oatmeal intervention in patients with type 2 diabetes and severe insulin resistance: a pilot study.

AIMS/HYPOTHESIS: To evaluate the potential effectiveness of 'carbohydrate days' as a dietary intervention to overcome insulin resistance in type 2 diabetes. MATERIALS AND METHODS: Patients (n=14) with uncontrolled type 2 diabetes and insulin resistance as defined by a dosage of more than 1 IU/day (*)kg BW were consecutively enrolled in this prospective study. Primary outcomes were daily insulin requirement and mean blood glucose levels which were evaluated before, after, and 4 weeks after the intervention. RESULTS: All patients had a metabolic syndrome, 75% had microvascular and 57.1% macrovascular complications. Hospital setting and diabetes adapted diet alone led to improved glycemic control with a mean blood glucose 158+/-47 mg/dl. Intervention with two days of oatmeal diet further decreased mean blood glucose to 118+/-37 mg/dl (p<0.05). This was associated with a significant reduction of insulin dosage by 42.5% (before: 145+/-68.9 U/d, after 83+/-34.2 U/d, p<0.001) as well as a significant reduction (-26.4%, p<0.01) of serum leptin levels. After the four weeks outpatient period, insulin dosage remained significantly decreased (83+/-20.2 U/kg (*)d, p<0.01). Glycemic control was comparable (mean blood glucose141+/-20.78 mg/dl) to glucose levels within the hospital setting. Adiponectin levels increased significantly by 53.8% (p<0.05). CONCLUSIONS: In this uncontrolled pilot study, hospital admission and diabetes adapted diet followed by oatmeal intervention achieved a approximately 40% reduction of insulin dosage required to achieve controlled glucose levels. This effect was conserved after a 4 week outpatient phase with normal diet.

In vivo effects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis.

15-Deoxyspergualin (DSG) is an alternative treatment modality for Wegener's granulomatosis (WG) patients refractory to conventional treatment. Nevertheless, it is unclear how DSG modulates disease activity in these patients. This study was conducted to investigate which parameters of adaptive and acquired immunity were influenced during two subsequent cycles of DSG treatment. Emphasis was put upon T cell and monocyte activation, neutrophil function and surface expression of proteinase-3 (PR-3). Anti-CD3/anti-CD28 and interleukin (IL)-15/IL-7-mediated T cell proliferation were assessed by fluorescence activated cell sorter (FACS) analysis using carboxyfluorescein succinimidyl ester (CSFE) labelling. Interferon (IFN)-gamma and IL-10 production were determined in the supernatants of these cultures by enzyme-linked immunosorbent assay. Monocyte activation was assessed in lipopolysaccharide (LPS)-stimulated whole blood, using tumour necrosis factor (TNF)-alpha as read-out. Neutrophil function was determined by measuring oxidative burst, chemotaxis and phagocytosis. T cell activation markers and PR3 expression were measured by FACS. All parameters were determined directly before and after each DSG cycle. Anti-CD3/anti-CD28-mediated T cell proliferation was reduced directly after DSG treatment. Directly before a subsequent cycle of DSG was started, T cell proliferation was increased. Similar findings were observed for IFN-gamma and IL-10 production by T cells. DSG did not influence IL-15/IL-7-mediated T cell proliferation. LPS-mediated TNF-alpha production was also impaired directly after DSG treatment. No influence on T cell activation markers, neutrophil function and surface PR-3 expression was observed in peripheral blood of these patients. Our data demonstrate that DSG influences T cell and monocyte activation in a reversible fashion. Although DSG causes neutropenia in these patients, it does not influence neutrophil function.

Abnormalities of CD4 T cell subpopulations in ANCA-associated vasculitis.

In patients with ANCA-associated vasculitis (AAV), CD25 expression is increased on circulating T cells. Although in animal experiments the role of CD4(+) CD25(+) T-regulatory-cells (T(reg)) in protection against autoimmunity is well established, the role of these cells in AAV is unknown. To investigate the hypothesis that an increased expression of CD25 on T cells is related to persistent T cell activation and not to disturbances in T(reg) cells in AAV (34 patients, six of them after renal transplantation), we investigated CD25 expression in different subpopulations of CD4(+) cells and FOXP3 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). In addition, T cell proliferation and cytokine secretion after stimulation with anti-CD3 and anti-CD28 and intracellular cytokine production after stimulation with phorbol myristate acetate (PMA)-ionomycin was determined. Controls were non-vasculitic renal transplant patients (n = 9) and healthy controls (HC) (n = 13). In AAV the total number of lymphocytes, CD4(+) lymphocytes and the percentage of naive T cells are lower than in HC and RTX. An increased percentage of CD25(+) cells was found in AAV and AAV/RTX, irrespective of disease activity, but not in HC or RTX. This was confined to the naive (CD4(+) CD45RB(high)) population only. FOXP3 mRNA expression in CD4(+) T cells did not differ between AAV patients and healthy controls. In vitro T cell proliferation was enhanced in AAV patients compared to HC (P < 0.01). PBMC of AAV patients produced significantly less interleukin (IL)-10 and interferon (IFN)-gamma after anti-CD3/CD28 stimulation. The percentage of IL-10 and IL-12, but not IFN-gamma, IL-4 or tumour necrosis factor (TNF)-alpha-producing cells was significantly higher in patients compared to HC. These findings were confined to the memory population of CD4(+) cells. We conclude that AAV patients are lymphopenic and have low numbers of CD4(+) T cells, which seem to be in a persistent state of activation.

Trichosporon asahii infection of a dialysis PTFE arteriovenous graft.

Trichosporon species are the causative agents of superficial skin infections, such as white piedra. Immunocompromised hosts, particularly those with underlying hematological malignancy, are at risk of developing invasive infection, which usually progresses to disseminated life-threatening disease. Peritonitis caused by Trichosporon has been described in end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis. Here, we report on a Trichosporon infection of an arteriovenous graft in a patient on chronic hemodialysis. The infection was successfully treated with fluconazole and total surgical resection of the graft.

Impact of donor dopamine on immediate graft function after kidney transplantation.

Optimizing medical donor management may have a considerable impact on transplantation outcome. This study investigated the effect of donor dopamine on initial graft function in renal allograft recipients, involving 254 consecutive recipients of a cadaver kidney, aged 18-74 years, transplanted between 1990 and 2003. Immunosuppression was based on cyclosporine. Patients were grouped according to donor use of dopamine during intensive care. Delayed graft function (DGF), and serial creatinine concentrations were compared between the groups. Dopamine-treated and -untreated donors were very similar regarding hemodynamics and renal function. Delayed graft function occurred in 47/158 treated and 48/96 untreated kidneys (p = 0.001). Donor dopamine was associated with a more rapid decrease of s-creatinine, which became obvious on the first postoperative day. Of patients in the treated and untreated group, respectively, 81.9% and 65.8% reached a s-creatinine level less than 2 mg/dL during the first month (p = 0.005). Donor dopamine remained predictive of a normalized s-creatinine level [HR 1.71; 95% CI 1.22-2.41] after controlling for confounding factors by multivariate Cox regression. Donor dopamine is associated with improvements of initial graft function after kidney transplantation. The beneficial effect of dopamine is achievable without side-effects for the recipients, and correlates with superior long-term graft survival.

Expression of somatostatin receptors in inflammatory lesions and diagnostic value of somatostatin receptor scintigraphy in patients with ANCA-associated small vessel vasculitis.

OBJECTIVE: To assess the usefulness of somatostatin receptor (SSTR) scintigraphy for the evaluation of disease activity in the upper and lower respiratory tract in ANCA-associated vasculitis (AASV). METHODS: Thirty-two consecutive patients with AASV were subjected to SSTR scintigraphy as part of their initial diagnostic evaluation and follow-up. The presence of SSTRs in inflammatory lesions was evaluated with immunohistochemistry in selected cases. RESULTS: In AASV, specificity of SSTR scintigraphy for active vs non-active disease was 96% for pulmonary disease and 100% for ear, nose and throat (ENT) involvement, while sensitivity was 86% and 68%, respectively. Absence of previously present tracer accumulation characterized treatment responders, and treatment resistance was reflected by repeated positive scintigraphy. We could demonstrate the expression of SSTRs in lung and mucosal biopsies obtained from patients with active Wegener's granulomatosis and with microscopic polyangiitis. CONCLUSION: SSTR scintigraphy is useful for the assessment of AASV, indicating disease activity, disease extent and treatment efficacy. SSTRs are expressed in both granulomatous as well as non-granulomatous AASV.

[Rapidly progressive glomerulonephritis:classification, pathogenesis and clinical management]. / Rasch progrediente GlomerulonephritidenKlassifikation, Pathogenese und Klinik.

Rapidly progressive glomerulonephritides (RPGN) belong to a heterogeneous group of inflammatory kidney diseases which are commonly associated with systemic vasculitic syndromes. Renal histology is characterized by necrotizing lesions within the glomerual tuft and extracapillary proliferation, in most cases leading rapidly to renal failure. The etiology and pathogenesis are only partly elucidated. Since irreversible renal scaring develops within days to weeks, RPGN represent a nephrological emergency necessitating urgent diagnostic evaluation and rapid institution of effective therapy. New onset nephritic sediment combined with concomitantly deteriorating excretory renal function should lead to immediate nephrological consultation. Autoimmune serology and particularly renal biopsy are of the utmost importance for rapid diagnosis. Most forms of RPGN are treated with immunosuppressive regimens which generally consist of high dose steroids in combination with the alkylating agent cyclophosphamide. Some forms also require the use of plasma exchange therapy. Rapid diagnosis and early therapy improves both renal and overall outcome in the affected patients.

Therapeutic administration of an endothelin-A receptor antagonist after acute ischemic renal failure dose-dependently improves recovery of renal function.

Endothelin (ET) is known to reduce glomerular filtration rate and renal blood flow and is a possible mediator of acute renal failure (ARF). We recently demonstrated that the administration of a very high dose of the ET(A)-receptor antagonist LU 135252 (LU) accelerates recovery from postischemic acute renal failure by an improvement of renal perfusion in a rat model. The aim of this study was to investigate whether this effect of LU is dose dependent. ARF was induced in rats by clamping both renal arteries. Serum creatinine was measured and endogenous creatinine clearance and fractional sodium excretion were calculated up to 4 days after acute ischemia. Rats were treated either with the selective ET(A)-receptor antagonist LU or with vehicle only after reperfusion. LU in doses of 0.5, 1, or 5 mg/kg per day was infused via a femoral vein using an osmotic minipump. Serum creatinine was increased approximately eightfold after induction of ARF. Creatinine clearance decreased from 4.35 +/- 0.26 ml/min before acute renal failure to 0.15 +/- 0.02, 0.54 +/- 0.1, and 1.49 +/- 0.19 ml/min on days 1, 2, and 4 after ischemia (p < 0.05). Fractional sodium excretion increased from baseline 0.77 +/- 0.05% to 7.5 +/- 1.21 % on day 1 and 8.53 +/- 1.34% on day 2 (p < 0.05). Treatment with LU improved kidney function dose relatedly. There was no significant change in creatinine clearance, but compared with controls, with doses of 0.5 mg/kg per day and 1 mg/kg per day (0.28 +/- 0.1, 0.88 +/- 0.22, and 1.93 +/- 0.24 ml/min on days 1, 2, and 4), we noted a significant increase under 5 mg/kg per day (day 1: 0.62 +/- 0.17 ml/min; day 2: 1.38 +/- 0.26 ml/min; and day 4: 2.45 +/- 0.21 ml/min; p < 0.05). Fractional sodium excretion decreased dose-relatedly to a maximally 2.48 +/- 0.58% on day 1 and 2.25 +/- 0.71 % on day 2 after treatment with the highest dose when compared with untreated control rats (p < 0.05). Our data support the hypothesis that ET plays a major role in ARF. It can be concluded from these results that recovery from ischemic ARF is significantly and dose-dependently enhanced by treatment with a selective ET(A)-receptor antagonist.

The renoprotective potential of endothelin receptor antagonists.

The endothelin system has been identified as having a substantial role in renal failure, both acute and chronic. Beside its well characterised haemodynamic effects, its mitogenic and pro-fibrotic properties have gained increased interest in the pathophysiology of chronic renal failure. This review outlines the role of endothelin in the pathogenesis of various renal diseases with a special focus on the potential of blocking this system with endothelin receptor antagonists. So far, most data were derived from animal models, but they provide strong evidence that endothelin receptor antagonists may represent a powerful therapeutic strategy in ameliorating the course of acute and chronic renal failure.

Preferential COX-2 inhibitor, meloxicam, compromises renal perfusion in euvolemic and hypovolemic rats.

Nonsteroidal anti-inflammatory drugs can impair renal perfusion through inhibition of cyclooxygenase (COX)-mediated prostaglandin synthesis. We investigated the influence of the preferential COX-2 inhibitor, meloxicam (MELO), on renal hemodynamics in eu- and hypovolemic rats compared to the nonselective COX inhibitor indomethacin (INDO). The hypovolemic state was obtained in rats by three daily injections of furosemide (2 mg/kg i.p.) followed by a sodium-deficient diet for 7 days. In euvolemic rats (n = 6) neither INDO (5 mg/kg i.v.) nor MELO (1 or 2 mg/kg i.v.) influenced mean arterial blood pressure (MAP) or impaired renal (RBF) and cortical blood flow (CBF). Medullary blood flow (MBF) decreased after INDO (18%; p<0.05), and dose-dependently after MELO (1 mg, 10%; 2 mg, 18%; p<0.05). In hypovolemic rats (n = 6) INDO and MELO had no effect on MAP. RBF and CBF were reduced after INDO (11 or 20%; p<0. 05), but showed no changes after MELO. INDO induced a decrease in MBF (22%; p<0.05) which was less pronounced after MELO (12%; p <0.05). In conclusion the preferential COX-2 inhibitor MELO compromized renal perfusion in the outer medulla both in eu- and hypovolemic animals.