Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein).

Interleukin 2 (IL-2) is a potent immunostimulant that causes the release of secondary cytokines and the production of lymphokine-activated killer cells. We investigated the cellular and cytokine responses to injection of recombinant human IL-2 into the human cerebrospinal fluid of 11 patients with metastatic tumors involving the spinal or cerebral leptomeninges. After initial intraventricular IL-2 administration (1.25 x 10(5) to 2 x 10(6) Cetus units/injection), cerebrospinal fluid samples were collected at intervals from 0 to 24 h. Enzyme-linked immunosorbent assay results indicated that IL-2 levels gradually decreased during the first 24 h, with an average t1/2 between 4 and 8 h. Induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and interleukin 2 receptor (p55) was also assessed by enzyme-linked immunosorbent assay. Tumor necrosis factor alpha and interleukin 6 levels peaked at 2 to 4 h and 4 to 6 h, with concentrations between 71 to 1,714 pg/ml and 942 to 10,500 pg/ml, respectively. Interleukin 1 beta, gamma-interferon, and soluble IL-2 receptor peaked later, during 6 to 12 h; the levels achieved were 234 pg/ml, 25 NIH units/ml, and 207 units/ml, respectively. All cytokine concentrations returned to near baseline between 12 and 24 h; however, the soluble IL-2 receptor levels remained elevated. Additional observations included a rapid influx of neutrophilic leukocytes, followed by a prolonged presence of lymphocytes. These data indicate a broad and complex potential of the immune response in the central nervous system, as well as further define the cytokine cascade in response to IL-2 alone.

[Injuries and overload-damages at players of the German lady-soccer-national-team]. / Verletzungen und Uberlastungsschäden bei Spielerinnen der deutschen Fussballnationalmannschaft.

30 female soccer-national-players were examined sport-orthopedically in a yearly sport-medical examination. Beside the anamnesis, a clinical and manual-therapeutic examination took place with it, just as an isokinetic-strengh-performance-diagnostics of the thight-musculature. The averaged age of the players amounted to 23.6 +/- 3.6 years, the mean value for the BMI amounted 22.2 +/- 1.34 kg/m (2). The examination shows which injuries and overload-troubles appear at lady-soccer-national-players. The most frequent injuries represented band-capsule-damages and muscle strain. Most overload-damages were located in the area of the knee-joints (Chondromalazia patella, patella-top-syndrome) and the feet (flat/splay foot, hallux rigidus). As a conclusion lady-soccer-players should be examined regularly sport-orthopedically in order to uncover functional deficits and overload-damages early. For prevention there should be a regularly training of coordination and proprioception as well as a strength-training of the thight-flexors.

Induction of maternal behavior in rats: effects of pseudopregnancy termination and placenta-smeared pups.

The onset of maternal behavior in Long-Evans rats was examined after pseudopregnancy (PsP) termination, both with and without exogenous estrogen administration, and in response to either clean or placenta-smeared stimulus pups. Natural (spontaneous) PsP termination was as effective in hastening the onset of maternal behavior as ovariectomy plus estrogen injection. If clean foster pups were presented as soon as pseudopregnancy terminated (first proestrus or cornified smear), maternal behavior was exhibited within 2 days; placenta-smeared foster pups presented at the same time elicited maternal behavior within 2 hr. The combination of initiating maternal-behavior testing immediately after the natural termination of pseudopregnancy and proffering placenta-smeared pups apparently simulates the hormonal milieu as well as the environmental cues present at parturition, noninvasively, producing optimal conditions for the rapid induction of maternal behavior.

Effects of hypothalamic knife cuts and experience on maternal behavior in the rat.

Recent investigations suggest that the disruption of placentophagia, pup-directed maternal behavior, and nestbuilding seen after lesions of the medial preoptic area (MPO) or the lateral hypothalamus may be due to the interruption at different points of a single longitudinal neural system mediating these behaviors. To test this, we compared the effects of knife cuts on the lateral border of the MPO, and of the posterior medial forebrain bundle (MFB), with asymmetrical cuts combining a unilateral MPO cut with a contralateral MFB cut. We observed placentophagia, nestbuilding, and pup-directed maternal behaviors at, and after, parturition in both primiparous and biparous rats. In primiparae, MPO cuts (a) disrupted placentophagia, (b) delayed the onset of crouching and pup-licking, and (c) eliminated retrieval and nestbuilding. MFB cuts (a) disrupted placentophagia, (b) delayed the onset of maternal behavior, and (c) eliminated nestbuilding. Asymmetrical cuts (a) disrupted placentophagia, and (b) delayed the onset of maternal behavior. In biparous rats, MPO cuts eliminated nestbuilding and retrieval. MFB cuts (a) disrupted placentophagia, and (b) eliminated nestbuilding. Asymmetrical cuts (a) delayed nestbuilding. These results suggest the involvement of a longitudinal neural system in the production of immediate pup-directed maternal behavior, placentophagia, and nestbuilding in parturient primiparae, but which is not critical for the eventual display of maternal behavior and nestbuilding in maternally naive rats, nor for the immediate onset of placentophagia and maternal behavior in maternally experienced rats.

Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice.

Hydrocortisone-acetate (HA)-treatment of BALB/c-mice induced a profound suppression of the lymphatic immune system with statistically significant decreases of thymocyte proliferation and maturation rates as well as peripheral blood lymphocyte (PBL) counts. To check its putative immunoprotective/immunorestoring activity, the optimal immunomodulating dosage of commercially available mistletoe extract standardized for the galactoside-specific mistletoe lectin (ML-1) was regularly administered (1 ng ML-1 per kg body weight; subcutaneously). As compared to counts of thymic lymphatic subsets of HA-treated mice, a considerable up regulation of mature cells expressing helper/inducer (L3T4+) as well as cytotoxic/suppressor (Lyt-2+) phenotypes and immature cells expressing both antigens (L3T4+/Lyt-2+) could be found after ML-1 co-administration. Counts of BALB/c-mouse peripheral blood mononuclear cells also revealed statistically significant increases after ML-1 co-administration, as compared to HA-treated animals. Accordingly, ML-1 treatment may be supposed to restore the lymphatic system after immunosuppressive corticoid treatment and thus this treatment may be of great benefit to patients.

Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1.

Commercially available mistletoe extract standardized for the galactoside-specific mistletoe lectin-1 (ML-1) could be shown to induce thymocyte proliferation and maturation in BALB/c-mice after regular subcutaneous administration of the optimal immunomodulating dosage (1ng lectin/kg body weight). The increase in thymocyte numbers per mg organ weight was statistically significant. Determinations of thymic lymphatic subsets revealed considerable up-regulation of mature cells expressing helper/inducer (L3T4) or cytotoxic/suppressor (Lyt-2) phenotype and immature cells presenting both (L3T4/Lyt-2) antigens. Thus, administration of ML-1 accelerated murine thymocyte proliferation and maturation. Counts of BALB/c-mouse peripheral blood lymphocytes (PBL) revealed evident (but statistically non-significant) increases after ML-1 administration. The determination of activated PBL expressing interleukin (Il)-2 receptors proved, however, that ML-1 induced a potent immunostimulation since these cells were significantly enhanced after ML-1 administration.

[Effect of mistletoe lectin therapy on serum level of defined serum proteins (acute phase proteins) in tumor patients]. / Einfluss der Mistellektintherapie auf den Serumspiegel definierter Serumproteine (Akutphaseproteine) bei Tumorpatienten.

The influence of galactoside-specific mistletoe lectin (ML-1) administration on defined acute phase reactants in the serum of cancer patients (mammary carcinoma, n = 4; larynx carcinoma, n = 11; TNM-stages II to IV; after appropriate surgery, chemotherapy, radiation) was studied. Regular subcutaneous injections of the optimal doses of ML-1 (1 mg/kg body weight, twice a week) yielded statistically significant increases of certain acute phase reactants (C-reactive protein, haptoglobin, coeruloplasmin, C3-complement, albumin, immunoglobulin IgM) after four weeks of treatment. However, serum concentrations of transferrin, C4-complement and the immunoglobulins IgG and IgA were found within the biological range (means +/- 2 s). The increase of acute phase reactants after administration of ML-1 correlates positively with the activity of lymphatic cells (e.g. expression of IL-2 and HLA-DR receptors) in FACS (fluorescence-activated cell sorter) staining experiments and indicates the immunoreactive potency of this substance which may be speculated to be cytokine-induced.

[Use of extracorporeal shockwave therapy (ESWT)in sports orthopedics]. / Einsatz der extrakorporalen Stosswellentherapie (ESWT) in der Sportorthopädie.

From 11/97 to 10/99 409 patients have been treated with the extracorporal shockwave therapy (ESWT) in the sport orthopaedic ambulance. An ultrasound controlled treatment was applied in the low and middle energy range, using energy densities of 0.09 to 0.36 mJ/mm2. The ESWT came into application as an operation avoiding procedure after exhausting the conventional conservative therapy measures. Among the 409 patients, 65 persons were competitive sportsmen. Besides the established indications for the application of the shock wave therapy, this method also has been applied with specific sport orthopaedic indications like achillodynia, patella-top-syndrome, medial shin-syndrome, morbus Schlatter or tendinosis of the shoulder. The results were collected three months after the application of the ESWT using a standardized questionnaire. The performed examination exhibits that for conservatively treated tendinoses of the competitive sportsmen, similarly good therapy results concerning the application of ESWT can be reached compared with the classical orthopaedic shockwave therapy. Therefore, for the treatment of a tendinosis, a shock wave therapy should always be taken into account to avoid long exercise and competition breaks due to operative interventions.

[Orthopedic problems in older marathon runners]. / Orthopädische Probleme bei älteren Marathonläufern.

58 marathon runners with an age average of 44.5 years were examined 6 months before the marathon in Berlin orthopedically. The orthopedic examination shows spinal column faulty burdens, muscular dysbalances as well as overload damages in the area of the knee joints and the achilles tendons. 42 probationers began after a biannual training with the marathon, one had to give up. Occurred during the marathon-training with 27 of the probationers orthopedic problems, especially in the area of the knee joint and the area of the achilles tendon. During the marathon 18 of the participants finished with orthopädic troubles. The examination shows, which orthopedic troubles with older marathon runners appears. Beside a sport medical suitability examination, a premature aimed therapy is necessary with the appearance of troubles since normally chronic overload damages and joint-wear threaten. When keeping the corresponding handicaps, a long-time marathon-training is possible also in the higher age without health risks for overuse injuries.

Characterization of sugar receptor expression by neoglycoproteins in oral and oropharyngeal squamous cell carcinomas.

Recognition of the carbohydrate part of cellular glycoconjugates by sugar receptors like lectins may contribute to biosignaling and interactions between normal and transformed cells. Such recognitions may be essential for establishing phenotypic characteristics in neoplastic cells, including metastasis-associated properties. To evaluate various glycoconjugates in tumor diagnosis and clinical therapy, a panel of 18 biotinylated neoglycoproteins was prepared. This included conjugates of a histochemically inert carrier protein and crucial sugar moieties such as D-glucuronic acid, alpha- and beta-N-acetyl-galactosamine, beta-N-acetyl-glucosamine, melibiose, lactose, maltose, cellobiose, mannose, mannose-6-phosphate, fucose, rhamnose, and xylose. In so doing the diazo derivative of the respective p-aminophenyl glycosides was coupled with galactose, beta-N-acetyl-galactosamine or beta-N-acetyl-glucosamine via an epoxy group-containing aliphatic spacer. Other glycoconjugates used were the proteoglycan heparin and the sulfated fucan fucoidan. Labeling was effected with cyanogen bromide activation and aminoalkylation for specific detection of endogeneous sugar receptors, especially lectins. Tissues studied were paraformaldehyde-fixed, paraffin-embedded surgical biopsies from patients with different stages of squamous cell carcinomas (SCCs) of the oral cavity (n = 16) and oropharynx (n = 17), including three lymph node metastases from oropharyngeal primary tumors. Semiquantitative binding differences of probes to tumor stages were evaluated statistically by the Mann-Whitney U-Wilcoxon rank sum W test. Specific binding of a probe to cytoplasmic and nuclear structures was detected with apparent quantitative differences. Overall, the cytoplasmic compartment revealed a higher intensity of histochemical reaction than did nuclear structures, indicating a comparatively higher density of specific carbohydrate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Are differences in the expression of carbohydrate-binding sites (endogenous lectins) responsible for recurrences of benign tumours of the parotid gland?

The expression of endogenous lectins in pleomorphic adenomas and papillary cystadenoma lymphomatosum (Warthin tumour) as well as in the tissue of the normal parotid gland was investigated with the aim to determine the capacity of the different cells to specifically bind carbohydrate ligand structures. The loss of sugar-binding sites of pleomorphic adenomas - lactose (diazonium derivative; diaz.), beta-N-acetylgalactosamine (diaz.), sialic acid [(2,3-epoxypropane)-4-oxybutyric acid linked; epichl.], heparin, mannose-6-phosphate (diaz.), maltose (diaz.), xylose (diaz.), melibiose (diaz.), N-acetylgalactosamine (epichl.) - was detected in the investigated tumours, leading to the hypothesis that altered carbohydrate-protein interactions have been involved in the adhesion of lost pleomorphic adenoma cells after damaging the tumour capsule. The papillary cystadenoma lymphomatosum in its cytoplasmic areas expressed significantly fewer sugar-binding sites for alpha-N-acetylgalactosamine (diaz.) and melibiose (diaz.).

Will neoadjuvant chemotherapy affect the capacity of head and neck squamous cell carcinoma to bind neoglycoproteins?

Evidence is growing that the carbohydrate portion of glycoconjugates is not merely an inert structural addition to the protein or lipid background, but is involved in normal and altered physiological processes. Conjugation of the potentially bioactive carbohydrate ligand to an inert labeled carrier generates the tools to histochemically monitor the presence of sugar receptors like lectins in tissue sections. In head and neck squamous cell carcinoma endogenous lectins have been systematically characterized by a selected panel of conjugates of such synthetic probes. In this investigation we provide evidence that the antineoplastic agents carboplatin and 5-fluorouracil influence the expression of carbohydrate-binding receptors. In cases with a statistically significant alteration, an increasing loss of binding capacity from treatment cycle to cycle was observed in cytoplasmic areas. This means that the extent of binding of beta-N-acetyl-galactosamine, cellobiose, galactose, and sialic acid was affected. The pattern of diminished binding capacity in nuclear structures encompassed beta-N-acetyl-galactosamine, beta-N-acetyl-glucosamine, sialic acid as carbohydrate part of the neoglycoprotein. Thus, exposure to certain chemotherapeutic agents clearly influences the capacity of tumor cells to mediate protein-carbohydrate interactions. Concomitant with the elucidation of the functions of such an interplay the significance of this down-regulation will be apparent.

The C4 beta-chain: evidence for a genetically determined polymorphism.

Using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) five different beta-chain patterns of denaturated human C4 were observed: C4 beta H, beta H greater than L, beta H = L, beta H less than L, and beta L. In 32 families with 174 offspring the segregation of C4 beta-chain types followed that of the other major histocompatibility complex (MHC) markers. It is concluded that the C4 beta-chain patterns represent a genetically determined polymorphism, coded within the known C4A and B gene region.

[Intralesional therapy with natural interferon-beta in refractory squamous epithelial cancers of the ENT area]. / Intraläsionale Therapie mit natürlichem Interferon-beta bei ausbehandelten Patienten mit Plattenepithelkarzinomen im HNO-Bereich.

It has been the aim of the present investigation to study the effect of intratumorally applied human fibroblast interferon (nIFN-beta; Fiblaferon 5 for the first two weeks, and Fiblaferon 3 three times a week) in a phase-II clinical trial of thirteen patients with advanced head and neck squamous cell carcinomas. All of the patients had failed established therapeutic modalities before and could not be treated by conventional procedures. nIFN-beta was injected intratumorally and its effect on tumour size was assessed by an independent, second observer as well as via CT and MR imaging. All assessments were done prior to treatment, 8 weeks after beginning treatment and at 16 weeks. Three female and ten male patients with primary tumours of the hypopharynx (n = 5), the larynx (n = 4), the oropharynx (n = 1), the glandula submandibularis (n = 1), the oral cavity (n = 1) and the oesophagus (n = 1) have undergone outpatient treatment three times a week. Tumour size showed no change in six patients while progressive disease occurred in seven cases after eight weeks of treatment. Radiological findings did not change in the nine patients continuing treatment while five showed progressive disease. There were no serious local or systemic side effects due to the intratumoral nIFN-beta treatment. The survival time was 9.73 months after the onset of nIFN-beta treatment.

Early onset sensorineural hearing loss: association studies with major histocompatibility class III (complement) markers.

In 39 families with at least one child suffering from moderate or severe bilateral sensorineural hearing loss (SNHL), major histocompatibility complex (MHC) class III complement phenotypes were retrospectively determined by standard methods; MHC class I segregation data was also available. The families were treated in the Hospital for Communication Disorders and selected for the HLA-B16 and B18 specificities, respectively. Haplotype and allele frequencies were derived from segregation analysis in the families. From 31 unrelated children with random and familiar forms of SNHL significant deviations in the distribution were seen for the following MHC class III alleles using as a control population 60 German healthy individuals: duplicated C4A alleles (C4"DA") p = 0.009, silent C4A alleles (C4A*Q0) p = 0.006, duplicated heavy C4 beta-chain alleles (C4 beta"DHH") p = 0.0003, and silent C4 beta-chain alleles (C4 beta*Q0) p = 0.0075. In serum samples from patients with an assumed genetic disposition according to clinical criteria indications for an association were found for C4"DA" (p = 0.03), C4A*Q0 (p = 0.003), C4B*3 (p = 0.046), C4 beta"DHH" (p = 0.004), and C4 beta*Q0 (p = 0.02). The underrepresentation of C4A*Q0 may be an indicator for aberrant or duplicated C4 alleles on the same haplotype or exhibit a protection mechanism for acquiring the inheritable forms of early onset SNHL.

Hepatocellular injury inhibits lectin-mediated tumor colonization into BALB/c-mice livers.

Acute (hepatitis) and chronic (cirrhosis) liver injuries were experimentally induced in BALB/c-mice by administration of D-galactosamine and carbon tetrachloride, respectively. In both experimental liver diseases the incidence of hepatic tumor colonization of sarcoma L-1 was significantly reduced as compared to non-treated control animals. Thus, it seems that either dysfunction or loss of organ-characteristic lectins (galactosyl-specific hepatic lectins) prevented liver colonization. Histochemical staining of liver sections from D-galactosamine or carbon tetrachloride-treated mice with appropriate galactose-containing (neo)glycoproteins supported this hypothesis, since the lectin-dependent binding was greatly reduced as compared to sections from non-treated animals.

Playing doctor: application of game theory to medical decision-making.

Decision analysis is an explicit, quantitative and prescriptive means by which the physician can identify optimal clinical strategies under conditions of uncertainty. It is incomplete, however, since it dispenses clinical advice without regard for the fact that the patient--for whatever reason--might choose to reject that advice. Game theory provides a supplementary means to explicate optimal rational strategies in situations where the actual outcome depends on the choices of both the patient and the physician. To determine its potential clinical relevance, we used game theory to reassess a clinical problem which has been used as a textbook exemplar of decision analysis: Should patients with chronic liver failure undergo liver biopsy before being treated? Decision analysis prescribes a pure (deterministic) strategy: the physician should always perform a biopsy. In contrast, given the proper conditions, game theory mandates a mixed (probabilistic) strategy: the physician should (randomly) recommend biopsy to only some fraction of patients, and only some fraction of these should (randomly) accept this advice. Thus, whenever the patient is free to accept or reject the physician's advice, game theory provides a prescriptive decision-making model which is qualitatively and quantitatively different from decision analysis.

Are ABH antigenic determinants on human outer ear canal epithelium responsible for Pseudomonas aeruginosa infections?

The outer ear canal expression of ABH human blood group antigens has been analyzed with a standardized routine histological procedure by monoclonal antibodies in the case of blood groups A and B, and a corresponding lectin in the case of blood group 0, respectively. In all 20 cases the blood groups were histochemically confirmed. Furthermore, Pseudomonas aeruginosa-specific inhibition experiments were performed with different sugar solutions as well as A-like substance incubating outer ear canal tissue sections with P. aeruginosa strain (No. 60) presenting lectin specificity for N-acetyl-galactosamine (GalNAc). P. aeruginosa lectins with GalNAc specificity apparently adhere to GalNAc as terminal blood group A determinant and indicate that patients presenting with blood group A may have a genetic predisposition to this form of otitis externa.