[Fulminant pulmonary edema in falciparum malaria [corrected]]. / Fulminantes Lungenödembei Malaria tropica.

HISTORY AND ADMISSION FINDINGS: A 54-year-old man was admitted because of intermittent fever for 2 days. Ten days earlier he had returned from Kenya. He had not taken any antimalarial drugs prophylactically. INVESTIGATIONS: Initial blood smears showed Plasmodium falciparum in 10.4% of erythrocytes. Laboratory tests indicated hyponatremia and disseminated intravascular coagulation. Also, laboratory markers of infection and hemolysis were clearly positive and accompanied by a low-grade normocyticanaemia. Chest radiograph showed the heart size to be at the upper limit of normal and no signs of congestion, pleural effusion or inflammatory infiltrates. Sonography demonstrated hepatosplenomegaly with diffusely increased echogenicity of the liver. TREATMENT AND COURSE: Falciparum malaria [corrected] with quartan fever was diagnosed and treatment with quinine and doxycycline was initiated. Despite the successful elimination of parasites and a negative fluid balance the patient died two days after admission from pulmonary edema and heart failure. CONCLUSIONS: A negative fluid balance failed to prevent acute pulmonary edema in this case of severe malaria,supporting the view that fluid imbalance is not an essential feature in malaria-induced lung injury and that cytokines play and important role.

Immunologic findings in workers formerly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

One hundred ninety-two workers in a German pesticide factory who were exposed to polychlorinated dibenzodioxins and -furans (PCDD/PCDF) were investigated for former and present diseases and laboratory changes of the immune system. Moreover, in a subgroup of 29 highly exposed and 28 control persons, proliferation studies were performed. In addition to assays such as blood count, immunoglobulins, serum electrophoresis, monoclonal bands, surface markers, autoantibodies, and lymphocyte proliferation, two new methods, the rise of tetanus antibody concentration after vaccination and the in vitro resistance of lymphocytes to chromate, were used to diagnose the morphologic and functional state of the immune system. There was no stringent correlation of actual PCDD/PCDF concentrations with the occurrence of infections or with one of the immune parameters. In addition, outcomes of the tetanus vaccination and the chromate resistance test were not correlated with PCDD/PCDF. However, the chromate resistance of lymphocytes stimulated by phytohemagglutinin of highly exposed persons was significantly lower than that for the control group. These findings indicate that the function of lymphocytes can be stressed and possibly impaired by high exposure to PCDD/PCDF.

Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate.

UNLABELLED: This report describes the successful use of protein C concentrate to treat severe purpura fulminans in a homozygous protein C-deficient infant for 8 months until oral anticoagulation was initiated. While fresh frozen plasma was previously used in such cases to replace protein C in the acute phase, the availability of a monoclonal antibody purified protein C concentrate now allows specific replacement of protein C, avoiding problems of fluid overload. An occlusive-hydrocolloid bandage proved to be effective in local treatment of skin lesions. D-dimer, fibrin monomer, thrombin-antithrombin complex and prothrombin fragment 1 + 2 were useful markers in monitoring and optimizing protein C replacement therapy. CONCLUSION: Diagnosis of protein C deficiency should be considered in a newborn with purpura fulminans. Early diagnosis and adequate replacement therapy is life-saving. Today, administration of protein C is the acute as well as long-term therapy of choice.

Biochemical bone markers compared with bone density measurement by dual energy X-ray absorptiometry.

In contrast to medical imaging, the biochemical markers allow a more frequent determination and are not as invasive as histomorphometric methods. We investigated biochemical markers of type I collagen compared with bone density measurements in 85 females between 41 and 89 years of age (median: 57 years). The bone density measurements were performed by dual energy X-ray absorptiometry (DXA) on the lumbar spine (L1-4). The bone density measurements were stated as a percentage of the norm. All patients were divided into three groups: I = <80%; II = 80-130%; III = >120%. Based on this classification the median concentration of the I-carboxyterminal propeptide of type I collagen in serum (S-PICP) as an anabolic marker of type-I collagen increased significantly with rising bone density: I 65.0 micrograms/liter (interquartile range: 52.1-78.0 micrograms/liter); II 85.9 micrograms/liter (52.1-115.5 micrograms/liter); III 81.4 micrograms/liter (62.0-101.0 micrograms/liter);P < 0.05. The concentration of urinary pyridinolines (U-PYR) as a marker for degradation of type I collagen decreased. The I-carboxyterminal telopeptide (S-ICTP) and osteocalcin (S-BGP) did not change. The multivariate regression analysis showed no relationship between between bone density and biochemical bone markers. Only the age significantly correlated negatively with bone density measurement. For a better assessment of type I collagen metabolism we created a "b-quotient" by dividing the sum of S-PICP and S-BGP by U-PYR. The median b-quotient increased significantly: I 1.55 (0.97-2.04); II 2.09 (1.57-2.86): III 2.46 (1.58-3.22); P < 0.05. Changes in bone metabolism cannot be identified by the determination of a single marker. However, the improved biochemical diagnostic measurement using the b-quotient may provide early information about the progression of a metabolic disorder within the interval of imaging.

Evaluation of an automated chromogenic substrate assay for the rapid determination of hirudin in plasma.

A fully mechanized chromogenic substrate assay method for the rapid and specific determination of recombinant hirudin (r-hirudin) in citrated plasma on clinical chemistry analyzers (Hitachi 911 and Cobas Mira) is described. In a first step, 12 microliters sample volume is mixed with the chromogenic substrate. Due to the almost immediate action of hirudin the inhibitory reaction and the cleavage of the substrate is started simultaneously when bovine thrombin is added in excess. This excludes interferences by antithrombin III or heparin cofactor II. The change in absorbance/min is recorded at 405 nm. The measuring range is about 0.2-4.0 mg/l r-hirudin on both analyzers. Precision is characterized by intraassay coefficients of variation between 0.63% and 2.78% on the Hitachi 911 and 1.51% and 7.84% on the Cobas Mira, respectively and interassay coefficients of variation of 3.57% to 9.15% (Hitachi 911) and 3.72% to 12.99% (Cobas Mira) for the same r-hirudin plasma concentrations. The described determination of r-hirudin correlates well with an enzyme linked immunosorbent assay method for r-hirudin (Hitachi 911: r = 0.964, y = 0.978x + 0.038, n = 323; Cobas Mira: r = 0.964, y = 0.959x-0.003, n = 323).

Laboratory control of minimal heparinization during haemodialysis in patients with a risk of haemorrhage.

For patients undergoing dialysis with a high risk of haemorrhage there is no standardized procedure for anticoagulation during extracorporeal circulation. Minimal heparinization with a dose equivalent to half that used for chronic haemodialysis was employed in 49 patients (125 haemodialyses) performed after operative interventions (83.3%), after haemorrhagic events (5.2%) and after invasive investigations (11.5%). Using a biocompatible membrane and a low molecular weight heparin (bolus dose 500-1300 U; continuous infusion 100-400 U) it was possible to complete haemodialysis in 74 cases (Group 0) without clots appearing in the venous bubble trap of the tubing system. In 30 cases (Group 1) only small clots were detected at the end of haemodialysis, and in 13 cases (Group 2) larger clots (exceeding a diameter of 1 cm) were found. In eight cases (Group 3) partial or complete clot formation occurred in the tubing. No haemorrhagic complications were observed. Anti-Xa activity, thrombin-antithrombin III complex (TAT) and D-dimer were determined before haemodialysis, 2 h after the start of haemodialysis and on completion of the procedure. The anti-Xa activities ranged between < 0.2 and 0.56 U/ml. In contrast, at 2 h there were significant differences (P < 0.05) in the TAT concentrations between Group 0 and the other groups, as well as between Group 1 and Group 2 and 3. Significant differences (P < 0.05) in D-dimer levels occurred only at the end of haemodialysis. Minimal heparinization in haemodialysis is a practicable alternative in patients with a high risk of haemorrhage and extended coagulation monitoring is helpful in adjusting heparin dosage.

Influence of blood sampling from venipunctures and catheter systems on serial determinations of prothrombin activation fragment 1 + 2 and thrombin-antithrombin III complex.

To evaluate the influence of different blood sampling techniques on test results of thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2) serial determinations were performed. In six groups of nonrandomized patients (ten patients each) the concentrations of the coagulation markers of blood samples from central catheters (internal jugular, caval, Shaldon, pulmonary artery) and peripheral cannulas (17G and 18G) were compared with those of blood samples obtained simultaneously from direct venipunctures of the contralateral arm. Medians and 25th-75th percentiles of TAT and F1 + 2 concentrations of plasmas obtained from central catheters were not different from those taken from venipunctures. When delta mean values (catheter - venipuncture) were calculated negative results were obtained, indicating lower concentrations measured from blood sampled through central catheters with the exception of blood that taken from Shaldon catheters. Only for TAT concentrations significantly were lower values measured in blood samples taken from internal jugular catheters when compared with blood samples obtained from direct venipunctures. Significantly higher TAT concentrations were determined in blood samples obtained from Shaldon catheters. For both coagulation markers correlations were found between concentrations in blood samples from central catheters and venipunctures. In blood samples taken from peripheral venous cannulas only F1 + 2 concentrations correlated with the concentrations found in samples from direct venipuncture. In contrast to F1 + 2, TAT concentrations measured from blood samples via peripheral cannulas were determined significantly higher than those taken from direct venipunctures.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunonephelometric determination of the C4b-binding protein.

A fully mechanised immunonephelometric method for the rapid and specific determination of C4b-binding protein (C4b-BP) in citrated plasma is described. The method utilizes commercially available rabbit antiserum against human C4b-BP and a nephelometer analyser. A single determination can be performed within 6 min, requiring 80 microliters sample volume. The measuring range is about 10 to 200% of normal C4b-BP. Precision is characterized by intraassay coefficients of variation between 1.5% and 2.8%, and interassay coefficients of variation between 4.0% and 4.6% for the same C4b-BP concentrations. The nephelometry of C4b-BP was correlated with electroimmunodiffusion (Laurell technique; r = 0.863, y = 0.909x+7.091, n = 79). C4b-BP concentrations (143%, 96-223%; median and 2.5th-97.5th percentile) from 83 subjects with increased inflammation markers C-reactive protein (> 10 mg/l), and fibrinogen (> 4.5 g/l) showing significantly higher C4b-BP concentrations compared to 151 obviously healthy subjects (97%, 68-141%; p < 0.001). In contrast to 81 patients with therapeutic heparinisation (90%, 60-131%) significant decreased concentrations were found in 90 subjects under oral anticoagulant therapy (OAT) in the stable state (78%, 44-125%; p < 0.001). Depending on different INR levels (< 2.5, n = 40: 71%, 63-85%; > 2.5, n = 50: 81%, 68-92%; median and 25th-75th percentile) no significant differences of C4b-BP concentrations could be measured.

Monitoring prothrombin fragment 1 + 2 during initiation of oral anticoagulant therapy after intracoronary stenting.

Patients with intracoronary stent implantation are treated with aggressive anticoagulant and antiplatelet therapy consisting of high-dose heparin, phenprocoumon, acetylsalicylic acid, dipyridamole, and the infusion of dextran to prevent a subacute thrombotic occlusion of the stented segment. In an effort to optimize this treatment by reducing both imminent bleeding complications and subacute thrombotic occlusion, the concentrations of prothrombin fragment 1 + 2 (F 1 + 2) were determined after intracoronary Palmaz-Schatz stent implantation in 19 consecutive patients. The F 1 + 2 concentrations after stent implantation and before the initiation of oral anticoagulant therapy (OAT) were 0.35 nm/l and 0.25-0.53 nm/l (median and 25th-75th percentile), versus 0.74 nm/l and 0.52-0.78 nm/l, in healthy subjects and 0.61 nm/l and 0.30-1.02 nm/l in 15 patients with ongoing proximal DVT. Nine days after initiation of OAT, F 1 + 2 concentrations in both patient groups had not yet reached levels observed in patients with OAT in the stable state (0.16 nm/l, 0.12-0.26 nm/l; n = 76; P less than 0.0001 compared with healthy subjects; INR 2.0-4.5). Despite an INR greater than 2.0, accompanying heparinization was terminated on day 9. In two stented patients a minor bleeding complication arose after the removal of the arterial catheter. Subacute thrombotic occlusions were not observed. Since F 1 + 2 concentrations did not exceed the upper limit of normal range (1.11 nm/l) in any of the 19 patients, the therapeutic regimen was not changed. Monitoring F 1 + 2 may thus be helpful in introducing a more individual treatment if aggressive anticoagulation has to be performed.

The control of anti-coagulation in acute dialyses with sensitive laboratory parameters.

In seven patients who had to be dialysed between four and 13 times due to acute renal failure, low molecular weight heparin (LMWH) Fragmin was used for anticoagulation. According to dose-finding studies, 80-90 U kg-1 body weight of LMWH as a single bolus were administered initially, producing dose-related levels of 0.3-1.5 anti-factor Xa U ml-1 in plasma. Apart from the anti-Xa activity in the plasma, the thrombin anti-thrombin III complex (TAT complex) and a fibrin degradation product (D-dimer) were measured as parameters of a coagulation activation. A sufficient anti-coagulation during dialysis was supposed to exist at a normal range (5.0 micrograms l-1 or below) of TAT complex. Pathological TAT concentrations at the end of dialysis indicated the requirement of an increased dose for the next dialysis. These concentrations reflected a need for more heparin if, for example, inflammation, indicated by increasing C-reactive protein levels (CRP), occurred. The increase of TAT complex and D-dimer during dialysis showed a good agreement (p less than 0.001). Due to a single bolus application before dialysis, one measurement of TAT at the end of the dialysis was sufficient. The determination of the TAT complex concentration enabled a heparinization better adapted to the clinical situation of intensive-care patients undergoing acute dialyses, so that the coagulation system was not additionally activated by the extracorporeal circulation.

Nonradical oxidants of the phagocyte type induce the activation of plasmatic single chain- urokinase.

Single chain- urokinase (scu-PA) is the proenzyme of the plasminogen activator urokinase (tcu-PA). In human blood scu-PA is of great stability. Activated phagocytes generate large amounts of single chain- urokinase and of reactive oxidants (chloramines and HOCl). Since these cells participate in physiologic fibrinolysis, we were interested in the interaction between plasmatic scu-PA and chloramines. The oxidants dose dependently induce the activation of plasmatic scu-PA. Optimal activation of scu-PA occurs at about 3-5 mmol/l of chloramine-T. The findings suggest a control mechanism of scu-PA stability/activity by oxidatively modifiable plasma proteins, such as alpha-2-antiplasmin. The oxidation mechanism seems to be mediated by singlet molecular oxygen, an excited oxygen species. Basing on this scu-PA/oxidant synergism a sensitive and fast functional assay of scu-PA in human plasma is presented. Plasmatic inhibitors normally interfering with functional scu-PA measurements are inactivated by addition of chloramine-T, imitating the physiological oxidants generated by activated phagocytes. The scu-PA concentration in plasma of n = 36 healthy individuals has been determined to be 5.8 +/- 1.6 ng/ml. The lower detection limit of plasma scu-PA by the procedure described is about 1.5 ng/ml of plasma. By means of this technique scu-PA concentration during thrombolytic therapy can be measured within minutes in undiluted (direct) plasma samples, allowing adjustments of the scu-PA dosage. The present study gives further credence for a role of singlet molecular oxygen, possibly a new type of locally acting hormones (autacoid), in the regulation of the fibrinolytic pathway.

Determination of human granulocyte elastase by the immunoactivation method on the Hitachi 717 automated analyser.

This paper describes a fully mechanized homogeneous immunoassay using the immunoactivation method for the rapid and specific determination of human granulocyte elastase (EC 3.4.21.37) in plasma. The method uses anti-elastase antibody fragments from sheep, conjugated to horseradish peroxidase. These enzyme-antibody conjugates bind to the elastase-alpha 1-proteinase inhibitor complex present in plasma. A separate sample blank with non-specific sheep antibody fragments conjugated to horseradish peroxidase corrects for errors introduced by the sample matrix. Measurements were performed with the clinical chemistry analyser Hitachi 717. A single determination can be performed in 10 min, requiring 24 microliters sample volume. The measuring range is about 20 to 1000 micrograms/l elastase. For within-run precision the coefficients of variation are 4.77%, 4.48% and 1.85% for elastase concentrations of 45.7, 89.1 and 385.4 micrograms/l; for day-to-day precision the coefficients of variation are 15.81%, 7.19% and 4.12% for elastase concentrations of 31.1, 65.5 and 440.2 micrograms/l, respectively. Correlation (y = bx + a) of results with those from the heterogeneous immunoassay showed a good agreement (r = 0.93, b = 1.11, a = -27.0, N = 121). Interferences by endogeneous substances and by drugs at therapeutic doses were not observed. The reference interval, determined by using plasma from 215 healthy individuals (C-reactive protein less than 5 mg/l, leukocyte count 4-8 x 10(9)/l), was 9-56 micrograms/l (2.5th to 97.5th percentile), with a median of 27 micrograms/l.

Acute dialysis: PMN-elastase as a new parameter for controlling individual anticoagulation with low molecular weight heparin (Fragmin).

Despite the improvements in the development of dialyzer membranes with greater hemocompatibility, an activation of the coagulation system occurs when blood comes into contact with exogenous surfaces. The large number of heparin dosage regimens demonstrated the difficulty to adapt general therapeutic guidelines. Low molecular weight heparin (Fragmin) was administered as a single bolus dose for anticoagulation during 58 acute dialyses. Anti-Xa-activity, the plasma levels of the lysosomal elastase of the polymorphonuclear granulocytes ("PMN-elastase") and of the thrombin-antithrombin III-complex (TAT) were measured at hourly intervals. Therapeutic anti-Xa-levels did not show evidence of sufficient inhibition of thrombin formation. The PMN-elastase increased by 180 ng/ml 3 h after administration of the bolus dose, with no further increase occurring (plateau phase). This was considered to reflect adequate anticoagulative activity. Where anticoagulation was inadequate, the elastase values rose consistently. After 2 h the increase of the PMN-elastase showed that--and to what extent--coagulation had been activated. The determination of PMN-elastase, using the IMAC-principle, is a method which can be performed quickly with any conventional autoanalyzer. It makes it possible to monitor adequate anticoagulation, but PMN-elastase results must be proven during routine use before recommendation as a routine test.

Direct tubular effect on calcium retention by hydrochlorothiazide.

Previous studies with hydrochlorothiazide revealed a calcium retaining effect of this substance. The mechanism by what this is done is still matter of controverse discussion. Effects of hydrochlorothiazide on vitamin D metabolism have been reported as well as those on parathyroid function. To further clarify the calcium retaining potency of hydrochlorothiazide (HCTZ) we treated 10 healthy young volunteers for four weeks with 2 x 50 mg HCTZ. In all volunteers we observed a marked decrease in urinary calcium excretion as well as in calcium clearance. Furthermore, we found a slight rise in ionized serum calcium (6.7%) and in intact PTH, as well as a 36% drop in 1,25-(OH)2-D3-levels. These effects were reversible after discontinuation of the treatment. No change was observed in urinary cAMP, phosphate excretion, serum anorganic phosphate levels, serum calcitonin and magnesium levels. Data presented here suggest that treatment with HCTZ causes a persistent reduction in calcium excretion through direct tubular effects, inhibits hydroxylation of vitamin D, and does not affect parathyroid function.

Endocrine and clinical evaluation of 107 patients with advanced prostatic carcinoma under long-term pernasal buserelin or intramuscular decapeptyl depot treatment.

Three major assumptions emerged from these clinical and endocrine long-term studies. First, buserelin, given pernasally in the conventional doses, and Decapeptyl microcapsules administered intramuscularly in 5-week intervals are equally effective in terms of their long-term castration effect in previously untreated patients with prostatic carcinoma. However, Decapeptyl causes complete LH and subsequent testosterone down-regulation 1 week earlier than buserelin. Furthermore, this treatment is more convenient, and the compliance is better. Both LHRH analogues are equally well tolerated. Second, in groups of prostate cancer patients with far advanced disease treated with palliative intention, only true subjective or objective remission should be considered a positive treatment response. Third, our results comparing PAP and PSA as the two most useful tumor markers with the corresponding testosterone levels suggest a close correlation.

Detection of spontaneous echocardiographic contrast within the left atrium by transesophageal echocardiography: spontaneous echocardiographic contrast.

Transesophageal echocardiography was performed in 314 patients over a period of 24 months using a 3.5 MHz phased-array system fitted to the distal end of a conventional 12 mm endoscope. In 12 patients (2.6%) transesophageal echocardiography could not be performed because of adverse reaction to the gastroscopic procedure. Side effects were a transient A-V block in one patient and asthmatic attack in another. Mitral valve lesions were found in 99 of 314 patients. In 9 of these 99 patients (11%), including 1 patient with mitral valve stenosis and sinus rhythm, 2 with atrial fibrillation, 3 with disc, and 3 with porcine mitral prosthesis, spontaneous echocardiographic contrast was found within the left atrium, described as faint echoes in 2 patients and dense echoes filling the whole left atrium and following turbulent flow in the other 7 patients. Only in 2 patients was left atrium shown to have additional echoes within its cavity in the four-chamber view by transthoracic echocardiography. Signs of cerebral emboli were found in 5 of 9 patients and of peripheral embolism in 3 of 9 patients. Their mechanism seems to involve red cell aggregation, which is greatest at low flow velocity such as in dilated left atria in the case of mitral valve stenosis or prosthesis. The additional effect of platelet aggregation must be discussed because increased platelet aggregation was detected in all patients with spontaneous echocardiographic contrast. Transesophageal echocardiography seems to be of great diagnostic value in patients with mitral valve lesions and cerebral and peripheral embolism, giving new insight into the pathophysiologic mechanism and possibly improving the therapeutic approach in the near future.

Rapid determination of retinol (vitamin A) in serum by high pressure liquid chromatography (HPLC).

A simple, fast, and specific HPLC-method to estimate retinol (vitamin A) in serum is reported. In the presence of small amounts of acetonitrile retinol is extracted quantitatively with n-hexane from serum. Neither the use of an internal standard nor evaporation to concentrate the extract is necessary. The HPLC-method avoids interferences of substances like phytofluenes, carotinoids or retinyl palmitate which is present in serum to a fraction of about 2-5%. The HPLC-method was applied to healthy adults and healthy children. The method allows about 100 determinations per day and operator.