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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.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.

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);P0.05. 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); P0.05. 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.

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.

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.

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.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.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.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.

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 μl 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).

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%; p0.001). 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%; p0.001). 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.

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.

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.

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.

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.

Retinol and Retinol-binding protein are estimated in the plasma of 91 children with hearing impairments of different etiology and 35 normal children of similar age. The concentrations of Retinol and Retinol-binding protein are age-dependent but in a given age class the concentrations of these substances are found to be similar in both groups. It is obvious, however that the concentrations in children with Alport-syndrome lie mainly in the upper range, while these with Pendred-syndrome have values in the lower range of the total distribution curve.

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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.

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.

Two cases of severe poisoning by tricyclic antidepressants (Amitriptylin, Imipramin) are reported. Both patients 3 and 11 years old children, developed a typical clinical picture with cardiovascular, neurological and atropine features. Beside a general supportive management, in one case physostigmin was used as antidote. Alternative treatments of enuresis in childhood are recommended.

Diethylpentenamide (DPA) is a hypnotic which is sold without prescription in W-Germany since 1975. Suicides with this drug have greatly increased in the past two years and will further increase when the bromoureides are under prescription. Measurement of the blood concentration of DPA is necessary for prognosis and therapy. Under the conditions of intensive medicine care there is no danger for the patient’s life up to a drug concentration of 5 mg/100 ml blood. With higher concentration of DPA and additional clinical risks detoxication by haemoperfusion (Haemocol) may be helpful. Its clearance for DPA (118.2 ± 4.1 ml/min, n = 11) is the same as for Carbromal (110.4 ± 3.9, n = 43). The half life of DPA in blood considering low concentrations is 7.7 h. However, in severe poisened patients it will be longer. Drug metabolism is the main route for elimation and the amount of the unchanged drug in the urine extract is very little compaired with the metabolites. Besides 3.3-diethyl-5-hydroxymethyl-tetrahydro-2-furanone, which is already known in literature, 3.3-diethyl-2-pyrrolidone-5-carboxylic acid, 3.3-diethyl-5-hydroxymethyl-2-pyrrolidone, and 2.2-diethyl-4-keto-valeriamylamide have been found. The structures of these new metabolites have been elucidated by GC-MS-measurements with low and high resolution. As a substance which is structure — related to allyl-isopropyl-acetylcarbamide (Sedormid) DPA may as well provoke porphyria. Indeed porphyria was observed in one patient and it must be mentioned that in this case the coma due to overdose of DPA was largely intensified.

An mittlerweile mehr als 150 Patienten mit bisher unbehandeltem Prostatakarzinom konnten wir in den vergangenen 6 Jahren den Kastrationseffekt von pernasal appliziertem Buserelin belegen [1, 2]. Partielle oder komplette Remissionen (objektiviert nach den Kriterien der National Prostatic Cancer Treatment Group oder der EORTC) liegen nach 6 Monaten je nach zugrunde gelegten Ansprechkriterien bei gut 50%, die Progressionsrate bei etwa 20%. Diese Daten konnten mittlerweile von anderen Autoren auch mit anderen LHRH-Analoga als Monotherapie reproduziert werden.

Vorwiegend aus den Vereinigten Staaten wurden in den letzten 5 Jahren zunehmend Daten bekannt, aus denen sich ein Vorteil der Konzentrationsbestimmung (RIA) der sauren Phosphatase gegenuber den Aktivitatsbestimmungen durch konventionelle colorimetrische Methoden bei Patienten mit Prostatakarzinom ableiten last (Tabelle 1).

Drug monitoring for valproic acid (Convulex) was performed in 200 children with a newly developed HPLC procedure and in part with an enzyme immunoassay (EMIT). In addition the activities of the transaminases and the lipase were determined as well as platelet count, prothrombin time, thrombin time, partial thromboplastin time, fibrinogen concentration and in some cases the coagulation factors II, V and X. There is not a higher frequency for pathological laboratory findings with higher serum levels. 81 children exhibited pathological findings, however only in one case therapy had to be stopped. Recommendations when to stop therapy are given.

Decapeptyl ist das dritte derzeit rezeptierbare LHRH-Analogon zur pharmakologischen Kastration beim fortgeschrittenen Prostatakarzinom. Es ist ein synthetisches Decapeptid wie das naturliche Hormon LHRH, lediglich an der 6. Aminosaure-Position ist Glycin durch D-Tryptophan ersetzt.

Retinol and Retinol-binding protein are estimated in the plasma of 91 children with hearing impairments of different etiology and 35 normal children of similar age. The concentrations of Retinol and Retinol-binding protein are age-dependent but in a given age class the concentrations of these substances are found to be similar in both groups. It is obvious, however that the concentrations in children with Alport-syndrome lie mainly in the upper range, while these with Pendred-syndrome have values in the lower range of the total distribution curve.

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. Images Figure 2

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.