Progressive lipo-lymphedema associated with increased activity of dermal fibroblasts in monoclonal gammopathy of undetermined significance: is there a causal relationship?

The pathophysiology of skin diseases associated with monoclonal gammopathies is generally unknown. Our aim was to investigate whether a monoclonal gammopathy could be a causal factor in progressive lymphedema. We describe a 75 year old patient with a rapidly progressive lipo-lymphedema and a monoclonal gammopathy of unknown significance (MGUS) suspected as a key etiological factor. Dermal fibroblasts were cultured from lesional lower leg skin and non-lesional abdominal skin and compared to healthy control fibroblasts. We found 10-fold elevated basic fibroblast growth factor 2 (FGF-2) in the patient's serum and significantly increased basal FGF-2 production of lesional and non-lesional fibroblasts compared to healthy controls. Upon restimulation with patient or healthy control serum, lesional fibroblasts showed significantly increased proliferation rates and FGF-2 production in vitro. Non-lesional abdominal fibroblasts showed an intermediate phenotype between lesional and control fibroblasts. Our findings provide the first evidence that lesional dermal fibroblasts from lipo-lymphedema with plasma cell infiltration show increased proliferation and FGF-2 production and that both local tissue factors and altered FGF-2 serum levels associated with monoclonal gammopathies might contribute to this phenotype. Thus we propose a possible pathophysiologic link between the gammopathy-associated factors and the generation of lymphedema with initial fibrogenesis aggravating pre-existing lipedema.

Selective regional perfusion of the bilateral external carotid arteries with pegylated liposomal doxorubicin and melphalan to treat metastatic malignant melanoma of the scalp.

We present the case of a 79-year-old patient with extensive metastatic malignant melanoma (MM) of the scalp. Cutaneous MM of the head and neck often presents a therapeutic challenge. Radical surgical procedures and conventional chemotherapy are often unfeasible and contraindicated because of the difficult anatomy, the extent of the tumour process, and systemic toxicity. In our patient, selective intra-arterial perfusion with pegylated liposomal doxorubicin (PLD) and melphalan was performed after catheterization of both bilateral external carotid arteries with an arterial port system. PLD 4.5 mg/m(2) and melphalan (1.35 mg/m(2), followed by 2.7 mg/m(2) after reaching tolerance) were given as short-term infusions at two-weekly intervals into the right and left external carotid arteries, respectively. After eight applications with tolerable side-effects, no MM cells were detected; however, infiltrates of lymphocytes and melanophages were seen. This case suggests that intra-arterial chemotherapy may be a useful treatment for metastatic melanoma of the scalp.

Child abuse - some aspects for neurosurgeons.

Neurosurgeons are mainly concerned with child abuse in cases of severe cranio-cerebral trauma. Aim of the present paper is to highlight the clinical picture and symptoms in cases of child abuse and our multidisciplinary approach to reveal a solid diagnosis. The detection of child abuse requires a high index of suspicion, especially in cases of subtle injuries. Besides reporting to the appropriate agencies primary goals are to terminate suspected abuse and to prevent further harm to the child. All this requires a confirmed diagnosis.

[Professional misconduct in therapeutic relationships: developing critical attitudes in the medical community]. / Missbrauch in therapeutischen Beziehungen : Möglichkeiten zur kritischen Positionierung der Ärzteschaft.

Already the Hippocratic Oath defines maintaining boundaries in the physician-patient relationship as an essential part of medical care: "…In every house where I come I will enter only for the good of my patients, keeping myself far from all intentional ill-doing and all seduction and especially from the pleasures of love with women or men, be they free or slaves…". The World Psychiatric Association's Declaration of Madrid 1996 specifically comments on boundary issues of physician-patient relationships in psychiatry. Boundary violations in any kind of therapeutic relationship - not only regarding psychotherapy - are both relevant and tabooed. There are hardly any options for patients concerned to find appropriate therapeutic and legal support. A public positioning of the medical profession seems to be very important. Apart from raising awareness, further important goals are prevention, guidelines for appropriate handling of victims and offenders, as well as integration of the issue in education and public discourse.

Metastatic squamous cell carcinoma of the ankle in long-standing untreated acrodermatitis chronica atrophicans.

Acrodermatitis chronica atrophicans (ACA) represents the persistent late stage of borreliosis in which Borrelia species may survive for decades. Occasionally, B-cell lymphoma may develop in these patients, and additional neoplastic complications such as basal cell carcinoma or squamous cell carcinoma (SCC) have been reported once each over the past 60 years. Here we describe, to the best of our knowledge, the first case of metastatic SCC in a European patient with long-standing ACA caused by Borrelia burgdorferi sensu stricto. Our case highlights a potential pathophysiological connection of untreated Borrelia infection with the initiation or progression of SCC and should alert dermatologists to this rare complication.

[Livid polycyclic plaques of the lower extremities]. / Livide polyzyklisch begrenzte Plaques an den unteren Extremitäten.

In 10%-55% of patients, leukemia cutis (LC) manifest as a symptom of acute myelomonocytic leukemia and is associated with a poor overall prognosis. Disseminated bluish-violet or red-brownish papules and plaques, nodules and also hemorrhagic ulcers may dominate the initial clinical picture. Importantly, nonspecific infiltrates (leukemids) must be differentiated from specific infiltrates of malignant cells in patients presenting with dermatoses and concomitant underlying hematopoietic neoplasms. The role of the dermatologist is the rapid clinical and dermatohistopathological diagnosis in order to allow immediate, adequate treatment of the patient's underlying systemic disease.

Analysis of the reaction mechanism of the non-specific endonuclease of Serratia marcescens using an artificial minimal substrate.

We have studied the mechanism of action of the Serratia nuclease using deoxythymidine 3',5'-bis-(p-nitrophenyl-phosphate) as a substrate. A comparison of the activity with which the wild-type enzyme and several mutant enzymes attack this artificial substrate and herring sperm DNA, respectively, supports the suggestion that His89 is the general base and a Mg2+ ion bound to Glu127 the general acid in the mechanism of phosphodiester bond hydrolysis by the Serratia nuclease, and that Asn119 directly participates in catalysis, for example by transition state stabilisation. Arg57, Arg87 and Arg131, essential for nuclease activity, are not needed for cleavage of the artificial substrate, suggesting that they are involved in binding and positioning of nucleic acid substrates.

Cleavage experiments with deoxythymidine 3',5'-bis-(p-nitrophenyl phosphate) suggest that the homing endonuclease I-PpoI follows the same mechanism of phosphodiester bond hydrolysis as the non-specific Serratia nuclease.

We show here that two nucleases, Serratia nuclease and I-PpoI, with contrasting specificities, i.e. non-specific vs. highly sequence specific, share a structurally similar active site region with conservation of the catalytically relevant histidine and asparagine residues. On the basis of a comparison of the available structures and biochemical data for wild type and mutant variants of Serratia nuclease and I-PpoI we propose that both enzymes have a common catalytic mechanism, a proposition that is supported by our finding that both enzymes accept deoxythymidine 3',5'-bis-(p-nitrophenyl phosphate) as a substrate and cleave it in an identical manner. According to this mechanism a histidine residue functions as a general base and Mg2+ bound to an asparagine residue as a Lewis acid in phosphodiester bond cleavage.

Genetic engineering, production and characterisation of monomeric variants of the dimeric Serratia marcescens endonuclease.

The Serratia nuclease is a non-specific endonuclease which cleaves single- and double-stranded RNA and DNA. It is a member of a large family of related endonucleases, most of which are dimers of identical subunits, with the notable exception of the Anabaena nuclease which is a monomer. In order to find out whether the dimer state of the Serratia nuclease is essential for its function we have produced variants of this nuclease which based on the crystal structure (Miller, M.D. and Krause, K.L. (1996), Protein Science 5, 24-33) were expected to be unable to dimerise. We demonstrate here that these variants, H184A, H184N, H184T and H184R, are monomers and have the same secondary structure, stability towards chemical denaturation and activity as the wild-type enzyme. This allows to conclude that the dimeric state is not essential for the catalytic function of the Serratia nuclease. In contrast, the S179C variant which is also a monomer shows little activity, presumably because this amino acid substitution changes the structure of the enzyme.

N-Ethyl-17(R,S)-methyl-(6aR,10aR)-delta 8-tetrahydrocannabinol-18-oic amide. Brain pharmacokinetics in mice, triglyceride/phospholipid partitioning and generalization to the discriminative stimulus properties of delta 9-THC in rats.

The title compound, designed as a model for the affinity moiety of a cannabinoid affinity gel was synthesized in tritiated form (sp. act. 7.27 mCi/mmole). To validate the affinity approach to isolate the putative THC receptor, the properties of the amide were studied. Upon i.p. injection in mice the amide reaches peak brain levels of 0.13% of the total dose after 15 min. Following i.v. injection, maximal brain concentrations of 1.9% are observed at 5 min. Compared to delta 9-THC, which distributes almost equally between triglyceride and phospholipid phases (51:49) the amide exhibits a strong preference for phospholipids (5:95) that can be interpreted as high relative membrane affinity. In rats trained in a water maze to discriminate between i.p. injections of 3 mg/kg delta 9-THC (ED50 = 1.8 mg/kg) and its vehicle, the amide was generalized to the training drug, being five times less potent (ED50 = 8.7 mg/kg) than delta 9-THC. This demonstration of cannabis-like activity indicates that the amide retains affinity to the postulated receptor and justifies the choice for the affinity ligand.

Complete remission of a primary cutaneous B-cell lymphoma of the lower leg by first-line monotherapy with the CD20-antibody rituximab.

BACKGROUND: Rituximab is a genetically engineered antibody recognizing the CD20 antigen known to be expressed by more than 95% of B-cell lymphomas. Recently the antibody has been approved for routine administration in primary extracutaneous, treatment-refractory or relapsed low-grade, follicular non-Hodgkin B-cell lymphomas. With regard to the pathogenetically related primary cutaneous lymphomas, the so-called large B-cell lymphoma of the leg represents a distinct, but rare subentity. In an 89-year-old, multimorbid patient who was affected by such a non-resectable CD20+ large B-cell lymphoma limited to the skin of both lower legs, rituximab was used as a first-line monotherapy in order to avoid local or systemic toxicities inevitably linked to conventional treatment modalities, i.e., radio- or chemotherapy. METHODS: Rituximab was administered at a dosage of 375 mg/m(2) i.v. eight times in weekly intervals. As a premedication we used prednisolone 150 mg i.v. as well as loratadine 10 mg p.o. 1 h before each rituximab infusion. RESULTS: The treatment was well tolerated without any adverse reactions, but was accompanied by a mild transient blood eosinophilia. The histologically proven, exophytic, multi-nodular lymphoma showed a substantial regression already at 2 weeks after the onset of the rituximab treatment. At 8 weeks we observed a complete clinical remission which is now stabile for a follow-up period of 6 months without any maintenance therapy. CONCLUSIONS: Our case observation demonstrates that an intensified, i.e. eightfold, rituximab application in weekly intervals may be a highly effective, tumor target cell-specific first-line monotherapy in the management of primary cutaneous large B-cell lymphoma of the leg. Given the rareness of the disease, the result as well as the possible contribution of the prednisolone premedication will have to be evaluated in a future, controlled, multi-centre study.

Immobilization of sugar-non-specific nucleases by utilizing the streptavidin--biotin interaction.

Due to their high enzymatic activity, the sugar-non-specific endonucleases from Serratia marcescens and Anabaena can be used for a number of applications, such as the removal of contaminating genetic material from biological preparations, footprinting studies, and the determination of nucleic acids in biochemical samples. These methods would benefit from immobilized nucleases. For this purpose, a single cysteine residue was added at the N-terminus of the Serratia and Anabaena nucleases and subsequently modified with a maleimide-biotin conjugate. Alternatively, a biotin acceptor domain was fused to the Anabaena nuclease, allowing biotinylation during expression in E. coli without a further chemical step. The attachment of biotin-modified nucleases to streptavidin-coated paramagnetic beads and to streptavidin-coated surface plasmon resonance sensor chips (to study interactions with substrate and inhibitor) worked well when aggregates present in the protein preparations were removed by ultrafiltration. These methods should be of general use for similar enzyme systems.

Demonstration of HPV 24 in long-standing Heck's disease with malignant transformation.

We report on the rare case of a 64-year-old European woman with a viral acanthoma of the oral mucosa of the clinical Heck type with unprecedented molecular-biological proof of HPV 24 DNA and so far undescribed malignant transformation with a long existence of the vegetation. After surgical therapy a circumscribed relapse of viral acanthoma developed, which responded favourably to a combined antiviral and antiproliferative therapy with acitretin perorally and interferon, first subcutaneously, later intralesionally for 3 months.

Cardiopulmonary resuscitation (CPR)-related posterior rib fractures in neonates and infants following recommended changes in CPR techniques.

Posterior rib fractures are highly indicative of non-accidental trauma (NAT) in infants. Since 2000, the "two-thumbs" technique for cardiopulmonary resuscitation (CPR) of newborns and infants has been recommended by the American Heart Association (AHA). This technique is similar to the grip on an infant's thorax while shaking. Is it possible that posterior rib fractures in newborns and infants could be caused by the "two-thumbs" technique? Using computerized databases from three German children's hospitals, we identified all infants less than 12 months old who underwent professional CPR within a 10-year period. We included all infants with anterior-posterior chest radiographs taken after CPR. Exclusion criteria were sternotomy, osteopenia, various other bone diseases and NAT. The radiographs were independently reviewed by the Chief of Pediatric Radiology (MB) and a Senior Pediatrician, Head of the local Child Protection Team (IF). Eighty infants with 546 chest radiographs were identified, and 50 of those infants underwent CPR immediately after birth. Data concerning the length of CPR was available for 41 infants. The mean length of CPR was 11min (range: 1-180min, median: 3min). On average, there were seven radiographs per infant. A total of 39 infants had a follow-up radiograph after at least 10 days. No rib fracture was visible on any chest X-ray. The results of this study suggest rib fracture after the use of the "two-thumbs" CPR technique is uncommon. Thus, there should be careful consideration of abuse when these fractures are identified, regardless of whether CPR was performed and what technique used. The discovery of rib fractures in an infant who has undergone CPR without underlying bone disease or major trauma warrants a full child protection investigation.

[Dose area product of pediatric VCUG with regard to the strongly lowered German diagnostic reference levels]. / Das MCU bei Kindern. Dosiswerte im klinischen Alltag im Hinblick auf die stark gesenkten diagnostischen Referenzwerte.

PURPOSE: To compare the dose area products of pediatric VCUG in daily practice with the dramatically reduced official German diagnostic reference levels, which are based on selected data. MATERIALS AND METHODS: 413 consecutive pediatric VCUG examinations were analyzed. RESULTS: The mean dose area product of all examinations was 0.97 dGycm². This is below the lowest reference level that is valid for neonates. In 12 cases (5.6 %) the achieved dose area product was higher than the corresponding reference level. CONCLUSION: Using the available techniques for radiation protection, it is possible in the daily routine to meet the official diagnostic reference levels for children, which have been reduced by up to 80 %, even though these levels are based on a selected, possibly non-representative data set.