Chronic lymphocytic leukemia presenting in the marrow of a phalanx

Systemic disease may present first in the foot. The authors present a case in which the marrow of resected bone tissue from a phalanx showed the changes of chronic lymphocytic leukemia (CLL). Subsequent blood examination confirmed this diagnosis.     

Low molecular weight heparin plus dihydroergotamine for prophylaxis of postoperative deep vein thrombosis

In a prospective, double-blind investigation of the prophylaxis of deep vein thrombosis (DVT) in patients undergoing elective major abdominal surgery, 269 patients were randomized into two groups. One hundred and thirty-two patients received a fixed combination of heparin sodium 5000 units plus dihydroergotamine mesylate 0.5 mg (H/DHE) twice a day and 137 patients received a fixed combination of low molecular weight heparin 1500 units plus dihydroergotamine mesylate 0.5 mg (LMWH/DHE) once a day as well as one injection of placebo per day. Treatment was initiated 2 h pre-operatively in both groups and continued for 7-10 days. The frequency of DVT determined by the 125I-labelled fibrinogen uptake test and phlebography was 10.3 per cent in patients receiving H/DHE and 10.4 per cent in those receiving LMWH/DHE. DVT of the femoral vein was detected in four patients of the H/DHE group and in none of the LMWH/DHE group. Intra- and postoperative blood loss did not differ significantly between both groups. Also no difference in the development of wound haematoma and injection site haematoma was found. While intra-operative volume substitution was comparable in both groups, significantly more patients under H/DHE prophylaxis received volume substitution during the postoperative phase. These results show that once-daily prophylaxis with the combination of low molecular weight heparin and dihydroergotamine is equally as effective and as safe as the twice-daily regimen using a combination of unfractionated heparin and dihydroergotamine in patients undergoing elective, major abdominal surgery. The advantages of the once-daily regimen of LMWH/DHE include greater patient acceptance, less nursing time and greater cost effectiveness, provided the new combination can be sold at a cost which maintains this advantage.     

Zur Problematik des Leistungssports bei Heranwachsenden

Ohne Zusammenfassung     

Importance of spinal noradrenergic pathways in cardiovascular reflexes and central actions of clonidine and alpha-methyldopa in the rabbit

We have examined in conscious rabbits the chronic effects of 6-hydroxydopamine (6-OHDA)-induced local lesions of the spinal noradrenaline (NA) pathways on (i) resting mean arterial pressure (MAP) and heart rate (HR), (ii) the nasopharyngeal pressor response, (iii) the sympathetic component of the baroreceptor-heart rate reflex (iv) the acute responses to intracisternal (i.c.) clonidine and alpha-methyldopa (alpha-MD), and (v) the acute NA release response produced by i.e. 6-OHDA. One month after injection of 6-OHDA (40 nmol in 4 microliters) into the first cervical spinal cord segment (C1), the NA content was reduced to 29% in C2, 45% in T4 and 61% in L3 with little non-specific damage. Basal MAP was 14% higher (P less than 0.05) than in sham-operated rabbits suggesting increased vasoconstrictor tone. Basal cardiac sympathetic tone was enhanced, but a corresponding increase in cardiac vagal tone resulted in little net effect on resting HR in the spinal NA-depleted group. Spinal NA lesions attenuated the nasopharyngeal pressor reflex by 27% in baroreceptor-intact rabbits and by 38% in sino-aortically denervated (SAD) animals. The lesion did not affect HR range, gain and BP50 of the sympathetic baroreflex. In SAD rabbits, the acute MAP responses to i.c. 6-OHDA (early hypotension, late hypertension) were not affected by spinal NA depletion, but the early fall in HR (cardiac sympathetic inhibition) was abolished. The hypotension produced by i.c. clonidine or alpha-MD was not affected by the lesion, probably because many of the NA terminals in the lower thoracic and upper lumbar cord were still intact. Our results suggest that intraspinal NA fibers have a tonic inhibitory action on spinal preganglionic vasoconstrictor and cardiac motoneurons. The spinal NA neurons affecting vasomotor tone (but not cardiac sympathetic tone) are in turn inhibited by higher vasomotor centers receiving projections from the arterial and trigeminal afferents and thereby participate in vasoconstrictor reflexes.     

Development of cytochrome P-450-altered preneoplastic and neoplastic lesions during nitrosamine-induced hepatocarcinogenesis in the rat

The expression of four cytochrome (cyt.) P-450 isoenzymes has been studied in preneoplastic and neoplastic lesions during the course of nitrosamine-induced hepatocarcinogenesis in the female Wistar rat. Following exposure to diethylnitrosamine (50 or 100 ppm in the drinking water) for 10 days, animals were taken sequentially, and the livers were analyzed for the evolution of adenosine triphosphatase deficient focal lesions. These lesions were subdivided into different phenotypes with regard to their cyt. P-450 isoenzyme expression using serial frozen sections. Our results demonstrate that about 40% of the adenosine triphosphatase-deficient lesions show concomitant alterations in their cyt. P-450 isoenzyme contents. Of these lesions, islets which are characterized by decreased levels of at least three cyt. P-450 isoenzymes show a dramatic increase in their volumetric fraction of liver tissue with progression of time. Although only very few lesions express this phenotype, the contribution to the volumetric fraction of islet tissue raises from about 2% at 10 weeks to about 60% at 35 weeks after cessation of diethylnitrosamine treatment. By contrast, lesions which express less than two alterations in cyt. P-450 isoenzyme levels develop relatively slowly. Similar results were obtained when animals were exposed continuously to diethylnitrosamine for a period of up to 8 weeks. Following treatment of islet-bearing animals with phenobarbital, an induction of cyt. P-450 isoenzymes and NADPH-cyt. P-450-reductase was observed within preneoplastic and neoplastic lesions. This induction was most pronounced in large, expansively growing nodules, a type of lesion which displayed decreased levels of these enzymes in livers of animals not treated with phenobarbital. The elevation of the cyt. P-450 isoenzymes disappeared within 2 to 3 weeks after cessation of inducer treatment. Our results indicate that a high proportion of rapidly growing lesions has assumed a constitutive deficiency in cyt. P-450 isoenzyme expression during nitrosamine-induced hepatocarcinogenesis. This deficiency, however, is not an irreversible quality, since individual cyt. P-450 isoenzymes can be markedly induced by treatment with an enzyme inducer like phenobarbital. Thus, the observed decrease in cyt. P-450 expression during development of malignancy does not result from alterations in the cyt. P-450 encoding structural genes but may rather be related to abnormalities in the function of regulatory systems of a higher order which may play a central role in the maintenance of cell homeostasis.     

Phage-displayed recombinant single-chain antibody fragments with high affinity for cholesteryl ester transfer protein (CETP): cDNA cloning, characterization and CETP quantification.

Cholesteryl ester transfer protein (CETP) greatly affects the metabolism of all lipoprotein classes including low-density lipoprotein (LDL) and high-density lipoprotein (HDL), both known to constitute powerful risk factors for coronary artery disease (CAD). We now report the successful first cloning and characterization of single-chain antibody fragments specific for CETP. A recombinant phage display library was generated using spleen mRNA isolated from BALB/c mice that had been immunized with highly purified CETP. Screening of the library yielded two single-chain antibody fragments with high affinity for CETP, termed 1CL8 and 1CL10, displaying respective KD values of 4.36 x 10(-9) M and 4.64 x 10(-9) M as determined by affinity sensor technology. Amino acid sequence comparison indicated the complementarity-determining regions of the respective heavy chains to be responsible for CETP high affinity binding. Fragment 1CL8 was successfully employed in clinical chemical quantification systems that uncovered an association in humans between plasma CETP concentration and total body fat mass (r=0.50, p<0.002). Because of the demonstrated superb CETP capturing capacity, combined with high binding affinity to CETP, ready access and unlimited supply, 1CL8 and 1CL10 are expected to prove powerful tools for studies on the role of CETP in atherogenesis.     

Clinical efficacy, safety and pharmacokinetic properties of the factor VIII concentrate Haemoctin® SDH in previously treated patients with severe haemophilia A

Clinical efficacy, safety and pharmacokinetic properties of the high-purity double-virus inactivated plasma-derived factor VIII concentrate Haemoctin SDH (pdFVIII) were evaluated in three prospective open-label uncontrolled studies in previously treated patients (PTPs) with severe haemophilia A. The pharmacokinetic properties assessed at baseline and after 3 months of treatment are in accurate accordance with published data and remain unchanged over time (study A, n = 12). Mean terminal elimination half-life was 11.8 and 11.9 h, mean incremental recovery (IU dL(-1)/IU kg(-1)) was 2.3 and 2.0, respectively. Long-term efficacy and safety, in particular the potential immunogenicity, were investigated in a total of 53 PTPs (studies A and B) treated prophylactically and on-demand, as required. PdFVIII has shown to be effective in preventing and controlling bleeding episodes; 23.5% of patients were free of bleeding events. A total of 177 haemorrhages occurred with 74.0% resolving after a single infusion, 87.6% within two infusions. 98.3% of responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy has been demonstrated in 10 surgical procedures including general and severe orthopaedic interventions (study C). No complication occurred in any surgery. Few adverse events were reported, one patient developed a high-titre FVIII inhibitor without clinical relevance. In all three studies, over 6 million units were administered in nearly 4300 infusions, approximately 94% units or infusions were given for prophylaxis and only 6% for treatment on-demand. In conclusion, pdFVIII has shown to be effective, safe and well tolerated in long-term prophylaxis and treatment on-demand as well as after minor and major surgical procedures.