Production of tailored hydroxylated prodiginine showing combinatorial activity with rhamnolipids against plant-parasitic nematodes.

Bacterial secondary metabolites exhibit diverse remarkable bioactivities and are thus the subject of study for different applications. Recently, the individual effectiveness of tripyrrolic prodiginines and rhamnolipids against the plant-parasitic nematode Heterodera schachtii, which causes tremendous losses in crop plants, was described. Notably, rhamnolipid production in engineered Pseudomonas putida strains has already reached industrial implementation. However, the non-natural hydroxyl-decorated prodiginines, which are of particular interest in this study due to a previously described particularly good plant compatibility and low toxicity, are not as readily accessible. In the present study, a new effective hybrid synthetic route was established. This included the engineering of a novel P. putida strain to provide enhanced levels of a bipyrrole precursor and an optimization of mutasynthesis, i.e., the conversion of chemically synthesized and supplemented monopyrroles to tripyrrolic compounds. Subsequent semisynthesis provided the hydroxylated prodiginine. The prodiginines caused reduced infectiousness of H. schachtii for Arabidopsis thaliana plants resulting from impaired motility and stylet thrusting, providing the first insights on the mode of action in this context. Furthermore, the combined application with rhamnolipids was assessed for the first time and found to be more effective against nematode parasitism than the individual compounds. To obtain, for instance, 50% nematode control, it was sufficient to apply 7.8 µM hydroxylated prodiginine together with 0.7 µg/ml (~ 1.1 µM) di-rhamnolipids, which corresponded to ca. » of the individual EC50 values. In summary, a hybrid synthetic route toward a hydroxylated prodiginine was established and its effects and combinatorial activity with rhamnolipids on plant-parasitic nematode H. schachtii are presented, demonstrating potential application as antinematodal agents. Graphical Abstract.

Therapy of IgA nephropathy with mycophenolate mofetil--report of 3 cases.

Mycophenolate mofetil is an immunosuppressive agent in transplantation which inhibits the purin neogenesis. Proliferating lymphocytes are suppressed and antibody production is decreased. Many cases of successful therapy in different kidney diseases are reported, such as diffuse proliferative lupus nephritis, pauci-immune necrotizing glomerulonephritis, focal segmental glomerular sclerosis and IgA nephropathy. We report 3 patients with IgA nephropathy who were treated with mycophenolate mofetil for more than 1 year. In all patients, proteinuria decreased significantly and the renal function remained stable. In 2 patients, kidney biopsy was repeated after 12 months and 18 months, respectively. There were no histological signs of progression of the disease. Two patients developed infections during treatment. One patient had a pneumonia, and a second patient an infection with varizella zoster. Based on our data, mycophenolate mofetil can be a potential treatment of IgA nephropathy. Further controlled studys are warranted to investigate the role of mycophenolate mofetil in IgA nephropathy.

[A rare cause of hepatic coma]. / Seltene Ursache eines hepatisch bedingten Komas.

CASE REPORT: A 65-year-old female patient was admitted to the hospital in somnolent state. During physical examination, she had an increase in blood pressure and a positive bilateral Babinski's sign. Laboratory findings showed elevated liver enzymes, metabolic alkalosis and slightly elevated kidney values. 3 h hours later she lapsed into a hepatic coma (ammonia > 400 micrograms/dl). Subsequently, indirect anamnesis revealed the following affections: ureterosigmoidostomy in 1942, cystectomy in 1943, and right-sided nephrectomy in 1950. DISCUSSION: This case presents with an uncommon origin of the hepatic encephalopathy: in the operated colon, bacterial overgrowth (bacteriogenic ureapoiesis) developed, which led to a hyperammonemia. Furthermore, in mild alcoholic liver disease--as in this case--ammonia cannot be metabolized to urea and leads to hepatic encephalopathy. We considered making this part of the colon poor in bacteria (by consequent administration of antibiotics), thus reducing the formation of ammonia.

[Kidney involvement in hypocomplementemic urticaria-vasculitis syndrome--a simulated systemic lupus erythematosis]. / Nierenbeteiligung bei hypokomplementärem Urtikaria-Vaskulitis-Syndrom--einer Spielart des systemischen Lupus erythematodes.

We report a case of hypocomplementemic urticarial vasculitis (HUV). The clinical course was characterized by urticaria, angio-edema, pericarditis, joint pain and conjunctivitis. The laboratory findings revealed moderate proteinuria, erythrocyturia, normal renal function, normotension, reduction of C3, C4 and C1q complement with elevated C1q antibodies. Antinuclear antibodies were inconstantly positive. Renal biopsy showed a mild form of membranous glomerulonephritis. Despite intensive therapeutic measures (dapsone, immunosuppressives and immunoglobulins), relapses of urticaria occurred frequently. HUV is probably a minor form of systemic lupus erythematosus.

Clinical course and symptomatic prediagnostic period of patients with Wegener's granulomatosis and microscopic polyangiitis.

The clinical course of 15 patients with Wegener's granulomatosis (WG) and eight patients with microscopic polyangiitis (MPA) from one nephrological clinical center is presented for the period from 1984 to 1993, when testing for antineutrophil cytoplasmic antibodies (ANCA) was gradually introduced into routine clinical practice. We found a high degree of prolonged time periods with symptoms attributable to WG or MPA until the specific diagnosis was made. Nine patients with WG and one patient with MPA had symptomatic prediagnostic periods of more than three years, which extended in one case up to twenty years. In these prediagnostic periods, often even severe flares of vasculitic activity resulted in spontaneous remission without immunosuppressive therapy. One patient on chronic dialysis for four months because of rapidly progressive glomerulonephritis, experienced sufficient spontaneous regain of residual renal function to stay off dialysis for 6 years. Despite a high amount of spontaneous recovery, recurrent flares of disease eventually led to death in those cases without sufficient immunosuppressive therapy. Contrary to long courses of disease, one patient with WG had a fulminate exacerbation of disease with lethal hemoptysis after a prediagnostic period of only three months. Renal disease, respiratory and other symptoms did not occur sequentially, but each could precede the other. We conclude in agreement with published former experience, that WG and MPA show a highly variable spontaneous disease course, that requires extended observational periods for evaluating maintenance therapies.

Transferrin receptor assay and zinc protoporphyrin as markers of iron-deficient erythropoiesis in end-stage renal disease patients.

To evaluate storage iron deficiency and iron-deficient erythropoiesis we determined, in a cross-sectional study of 95 patients mainly including end-stage renal disease patients (ESRD) with (32) and without rh-EPO therapy (55), the following parameters: hemoglobin, mean corpuscular red cell volume, ferritin, transferrin saturation (TS), zinc protoporphyrin (ZPP) and soluble transferrin receptor (TfR). In the dialysis group the percentage of positive samples with each marker of tissue iron supply defined as TS < 20%, ZPP > 40 mumol/mol Heme and TfR > 3.05 microgram/ml was as follows: TS 43.7% and 32.2% at a diagnostic threshold level of < 16%, ZPP 33.3% and TfR 17.2%. Manifest storage iron deficiency defined as ferritin < 30 ng/ml was observed in 5.7% of the samples while the mean ferritin concentration of the rh-Epo treated dialysis patients was 509.3 ng/ml compared to 262.5 ng/ml in the group without rh-EPO therapy. These data reflect a generous iron substitution in our series taking a TS < 20% as an intervention criterion. Looking at the different results of the three markers the best correspondence was found between ZPP and TfR resulting in a weak positive correlation (+0.64). In conclusion, we found quite different results with different assays when evaluating endogenous iron availability in our series of mainly ESRD patients in a cross-sectional study. Because a gold-standard is not defined further firm conclusions cannot be drawn from this type of study. The adequacy of the different parameters of iron metabolism including threshold levels and, consequently, the decision and route of iron substitution deserve an evaluation in a longitudinal study to characterize the best marker or marker combination in this setting.

Morbidity in 565 type 2 diabetic patients according to stage of nephropathy.

Between 1988 and 1992, 565 type 2 diabetic patients were examined for nephropathy and diabetes-associated diseases during hospital treatment. Stages of nephropathy were defined as no clinical sign of nephropathy (N = 280), microalbuminuria (N = 38), overt proteinuria (N = 105), impaired renal function (N = 55), and chronic dialysis therapy (N = 87). In dialyzed patients, HbA1c averaged 6.8%, and, in the other groups, HbA1c was between 7.6% and 8.3% (normal range, 3.8%-6.1%). Cataract was not associated with the severity of nephropathy. Stroke was most common in the stage of renal insufficiency (34%). The following complications, as found in medical history or as current event, showed a significant association with the stage of nephropathy and occurred most frequently in dialysis patients (percentage is displayed for patients with nephropathy in comparison to diabetic dialysis patients): hypertension (53%-89%), left ventricular hypertrophy (39%-81%), myocardial infarction (14%-36%), peripheral vascular disease (27%-77%), foot lesions (7%-75%), minor or major amputations (3%-23%), proliferative retinopathy (6%-46%), blindness (2.9%-16.1%), and internal carotid artery stenosis (15%-36%). In this preselected cohort of diabetic patients, a high morbidity was found already without nephropathy that increased several-fold in the course of the development of nephropathy. Our data identify patients with diabetic nephropathy as a high-risk group for excess morbidity.

[Brucellosis with fatal endotoxic shock]. / Bruzellose mit tödlichem Endotoxinschock.

BACKGROUND: Brucellosis is a zoonosis with good prognosis in cases of early diagnosis. To make the diagnosis is still a problem today. CASE REPORT: A 60-year-old butcher was admitted with undulating fever, sweats, arthralgia and weight loss. Further examination revealed hepatosplenomegaly with laboratory findings of a hepatitis and multiple focal liver lesions shown by abdominal ultrasound and CT. Histologically, these lesions corresponded to caseous granulomas. Diagnosis of brucellosis was confirmed by detection of brucella species in prolonged incubation in blood culture. After the beginning of antibiotic resistance-tested therapy with tetracycline and quinolones, an endotoxic shock occurred during the first 24 hours of treatment and the patient died after multiorgan failure with disseminated intravascular coagulation. CONCLUSION: In cases of undulating fever with liver involvement, a brucellosis should be considered. Good teamwork of the internal, pathological and microbiological departments is necessary for early and correct diagnosis. This is the first report of human brucellosis in association with lethal endotoxic shock.

Twenty-four-hour blood pressure monitoring, diurnal blood pressure profile and drug therapy under hospital care conditions.

OBJECTIVES: To elucidate the prevalence of nondipping in 24 h blood pressure monitoring (BPM) during hospital care with respect to antihypertensive drug therapy, diabetes, renal artery stenosis, and inverse diurnal blood pressure profiles. METHODS: Prospective, consecutive categorization of routine 24 h BPM was performed according to nondipping, drug therapy, normotension, severity of hypertension, diabetes, and inverse diurnal profile for 2 years. Retrospective analysis of patients examined by intraarterial renal artery angiography were performed. Nondipping was defined as a drop in night-time blood pressure (2200-0600 h) by less than 10% of the daytime values. Normotension was considered a daytime 24 h BPM value below 135/85 mmHg without antihypertensive therapy. RESULTS: We categorized 2105 24 h BPM protocols for patients of mean age 59 years. Nondipping was found for 26% of the normotensives, 38% of hypertensive patients not being administered medication, and 48% of drug-treated hypertensives. The significant increase in nondipping among patients under drug therapy applied for patients with daytime blood pressures below and above 135/85 mmHg and was thus independent of the severity of hypertension. Among the subgroup of 561 predominantly type 2 diabetic patients the prevalence of nondipping was increased significantly only for those patients who were hypertensive and being administered antihypertensive drugs. Subgroup analysis of patients using intraarterial angiography did not find different prevalences of nondipping for patients with and without renal artery stenosis. Patients with an inverse diurnal blood pressure profile and an increase in night-time blood pressure by more than 5% of the daytime values presented as a high-risk group because of morbidity associated with renal, cardiac, and cerebral disease. CONCLUSION: Nondipping is a common phenomenon among hospital patients. Drug therapy of hypertension should be directed not only towards the daytime blood pressure, but also toward alleviation of night-time hypertension.

Experience with zinc protoporphyrin as a marker of endogenous iron availability in chronic haemodialysis patients.

BACKGROUND: Ferritin and the percentage of transferrin saturation (TS) are established parameters with which to evaluate endogenous iron availability during treatment of renal anaemia with recombinant human erythropoietin (rHuEpo). Zinc protoporphyrin (ZPP) has been proposed as another valid marker in this setting. METHODS: We determined the following parameters in 127 patients, including 117 haemodialysis patients: haemoglobin, erythrocytes, haematocrit, mean corpuscular volume (MCV), iron, ferritin, transferrin saturation and ZPP. Of the patients treated in a cross-sectional study, 38.5% were treated with rHuEpo; 30.7% with intravenous iron; and 13.6% with intravenous iron and rHuEpo simultaneously. Median ferritin was 304 ng/ml and median transferrin saturation was 21.2%. RESULTS: Including cases with manifest storage iron deficiency, a concordant elevated ZPP ( > 40 mumol/mol haem) and a decreased transferrin saturation ( < 20%) were found in 23 of our dialysis patients (19.6%) while 55 cases (47%) were classified as concordantly negative. However, as many as 39 cases (33.3%) showed discrepant results: in 16 cases (13.6%) ZPP was elevated but transferrin saturation was in the normal range, while in 23 cases (19.6%) the opposite results were observed. CONCLUSIONS: We conclude that beyond the border of manifest storage iron deficiency, defined as a ferritin < 30 ng/ml in male and < 15 ng/ml in female patients, ZPP and TS cover different ranges of functional iron deficiency which is reflected in the lack of a correlation of ZPP to any other of the above-mentioned parameters. Our data suggest that a TS < 20% as a diagnostic, and thus intervention, criterion in the evaluation of functional iron deficiency and iron substitution beyond manifest storage iron deficiency might result in overestimation of iron requirements. It remains to be shown in a longitudinal study, also reflecting the course of haemoglobin and the mean rHuEpo dose, whether ZPP or TS is the more appropriate parameter in the evaluation of functional iron availability.

Primary bilateral renal centrocytic non-Hodgkin's lymphoma as a cause of renal failure.

We present a patient whose cause of renal failure was primary and isolated bilateral renal manifestation of centrocytic non-Hodgkin's lymphoma. The treatment options for bilateral primary renal lymphoma are discussed against the background of published data concerning this topic.

A case of pure red cell aplasia: follow-up on different immunosuppressive regimens.

A 66-year-old patient was admitted to our hospital in January 1992 for further evaluation of severe normocytic anemia. Hemoglobin (Hb) was 3.5 g/dl, reticulocyte count 1%. Bone marrow showed a nearly complete lack of red cell precursors, thus favoring the diagnosis of acquired pure red cell aplasia (PRCA). Immunosuppressive therapy with prednisolone was started but had to be supplemented with azathioprine because of a further rapid decrease in Hb to 3.7 g/dl after an initial transfusion of 6 U red blood cells. However, with this regimen a renewed decrease in Hb to 6.6 g/dl was noted, and further transfusions were required. Therefore therapy was switched to cyclosporine A (CyA) while tapering off prednisolone. Four months after the initial diagnosis a positive parvovirus B19 IgM antibody was found. After the failure of hematological remission with three immunosuppressive regimens a course of high-dose intravenous immunoglobulins (IVIG) was administered in July 1992. Six weeks after IVIG therapy a peak hemoglobin concentration of 12.3 g/dl was noted, and further transfusion was not required. CyA was tapered off in October 1992. One month later CyA was reinstituted because of a relapse of PRCA but was unsuccessful until January 1993. At this time immunosuppressive CyA therapy was discontinued because of a periodontal abscess. In February 1993 a second IVIG infusion was given, and a second remission of PRCA was noted, showing an increase in hemoglobin up to 14.5 g/dl by November 1993. At the last follow-up visit in February 1994 our patient was still in complete hematological remission.

Endothelin and atrial natriuretic peptide in non-insulin-dependent diabetic versus nondiabetic patients on chronic hemodialysis.

Plasma levels of endothelin (ET) and atrial natriuretic peptide (ANP) are known to be elevated in patients on chronic hemodialysis. Since ET and ANP plasma levels are found to be raised in nonuremic diabetic versus nondiabetic subjects, we wanted to detect a possible difference in plasma levels of these hormones in diabetic versus nondiabetic patients who were on chronic renal replacement therapy. ET is a possible marker of increased vascular atherogenic activity. We measured plasma levels of ET and ANP pre- and posthemodialysis in 23 non-insulin-dependent (NIDDM) diabetic versus 23 nondiabetic patients who were matched according to age and time of day of hemodialysis, and who did not show clinical signs of overt cardiac decompensation. Mean plasma levels of ET and ANP did not differ in diabetic from nondiabetic patients, neither pre- nor postdialysis. In both patient groups, mean ET levels were twice the upper normal limit, did not change significantly pre- versus postdialysis, and did not correlate with blood pressure or with volume ultrafiltration during dialysis. Calcium channel blocker therapy was accompanied by a significant rise of ET pre- and postdialysis in nondiabetic patients but not in diabetic patients. In diabetic patients, ET plasma levels correlated positively with fructosamine levels as an indicator of short-term blood glucose control. Mean ANP plasma levels were about three times the upper normal limit and decreased significantly during dialysis, but this decrease correlated neither with volume ultrafiltration nor with blood pressure. In conclusion, we could not find a difference in plasma levels of ET and ANP for diabetic versus nondiabetic dialysis patients, but impaired short-term blood glucose control in diabetic and calcium channel blocker therapy in only nondiabetic dialysis patients showed concomitant increases in plasma ET levels and thus possibly different mechanisms of ET regulating pathways.

Plasminogen activator inhibitor 1 activity and lipoprotein(a) in nephropathic patients with non-insulin-dependent diabetes mellitus versus patients with nondiabetic nephropathy.

Increased plasma activity of plasminogen activator inhibitor 1 (PAI-1) is considered as a risk factor for thrombosis associated with atherosclerosis by reduction of fibrinolysis. Since nephropathic patients with non-insulin-dependent diabetes mellitus (NIDDM) are a cardiovascular high-risk group, which has yielded only controversial results as to the regulation of PAI-1, we compared 19 overt nephropathic NIDDM patients (mean age 63 years, serum creatinine 1.9 mg/dl, proteinuria 4.2 g/day) to 17 nondiabetic nephropathic patients with various causes of renal insufficiency (mean age 63 years, serum creatinine 2.8 mg/dl, proteinuria 3.9 g/day). We found normal PAI-1 levels for patients with diabetic nephropathy and significantly elevated PAI-1 levels within the upper normal range for nondiabetic nephropathic patients. Common risk factors in both groups were very high levels of fibrinogen, lipoprotein(a), serum cholesterol, and LDL cholesterol.