Testicular leiomyosarcoma and marked alopecia in a cryptorchid ferret (Mustela putorius furo).

A 3.5-year-old male ferret, bought as male castrated, was presented to the veterinarian with marked alopecia of back, neck, abdomen and tail, a pronounced sexual behaviour and weight loss. An inguinal mass of about 2.5 cm in diameter was diagnosed as potentially tumorous inguinal testicle by ultrasound and fine-needle aspiration. Adrenal glands and prostate were ultrasonographically unremarkable. The surgically removed cryptorchid testicle contained a greyish tumour that was histologically composed of spindle-shaped cells with elongated nuclei, embedded in a fibro-vascular stroma. Up to two mitotic figures per high power field were noted. Additionally, an interstitial cell hyperplasia and marked reactive proliferation of a collagen-rich fibrous tissue were observed. Tumour cells were positive for α-smooth muscle actin, desmin, and occasionally vimentin and S-100, leading to the diagnosis of an intratesticular leiomyosarcoma. As an adrenal-associated endocrinopathy was excluded and a complete fur recovery was observed after removal of the cryptorchid testicle the alopecia was eventually due to hormones produced by the hyperplastic interstitial (Leydig) cells.

Serum bactericidal activity of trovafloxacin, in combination with cefepime or amikacin, in healthy volunteers.

OBJECTIVE: To investigate the phamacokinetics and serum bactericidal activities (SBAs) of trovafloxacin, cefepime and amikacin alone and trovafloxacin in combination with cefepime or amikacin, so that the most favorable combination with trovafloxacin can be determined. METHODS: In this open, randomized, crossover study, 12 healthy volunteers (six females, six males; mean age +/- SD, 25.1 +/- 2.6 years) received an infusion of either 300 mg of alatrovafloxacin or 2000 mg of cefepime or 6 mg/kg body weight amikacin alone, or 300 mg of alatrovafloxacin plus 2000 mg of cefepime or plus 6 mg/kg body weight amikacin. The SBAs against Pseudomonas aeruginosa, Staphylococcus aureus (11 strains each), Citrobacter freundii and Acinetobacter spp. (10 strains each) 1, 10 and 24 h after drug administration were measured by a standard microdilution method. Concentrations of trovafloxacin, cefepime and amikacin in serum and urine were analyzed before and up to 10 and 12 h, respectively, after drug infusion. RESULTS: Significant synergistic effects on SBA were observed with the combination of trovafloxacin and cefepime against P. aeruginosa, S. aureus and Acinetobacter spp. 1 h after drug administration, and against Citrobacter freundii 1, 10 and 24 h after drug administration. The combination of trovafloxacin and amikacin showed significant synergistic effects against P. aeruginosa, S. aureus and C. freundii 1 h after drug administration. The combination of trovafloxacin and cefepime was, in general, more active than the combination of trovafloxacin and amikacin. No significant differences in the serum concentrations of trovafloxacin were observed between single and combined administration. However, the maximal concentration of cefepime was significantly lower when it was used in combination with trovafloxacin. CONCLUSION: Our study suggests a favorable interaction between trovafloxacin and cefepime. This combination showed more synergistic bactericidal activity against most of the test strains compared to the combination of trovafloxacin and amikacin. However, for P. aeruginosa, the bactericidal activity of cepefime alone was higher than that of the combination with trovafloxacin.

Ecological effects of linezolid versus amoxicillin/clavulanic acid on the normal intestinal microflora.

Twelve healthy subjects (6 females, 6 males; age range 18-40 y) participated in this trial. Linezolid was given as 600 mg tablets b.i.d. for 7 d and amoxicillin/clavulanic acid as 1000 mg tablets o.d. for 7 d. The washout period between the administration of the 2 antibacterial agents was 4 weeks. Faecal samples were collected prior to administration (Days -2 and -1), during administration (Days 4 and 8) and after administration (Days 14, 21 and 35) for microbiological analyses. The samples were diluted in pre-reduced media and inoculated aerobically and anaerobically on non-selective and selective media. Different colony types were identified to genus level by morphological, biochemical and molecular analyses. During the administration of linezolid, enterococci in the intestinal aerobic microflora were markedly suppressed while Klebsiella organisms increased in number. In the anaerobic microflora, the numbers of bifidobacteria, lactobacilli, clostridia and Bacteroides decreased markedly while no impact on the other anaerobic bacteria was observed. The microflora was normalized in all volunteers after 35 d. Amoxicillin/clavulanic acid administration caused increased numbers of enterococci and Escherichia coli in the aerobic intestinal microflora while numbers of bifidobacteria, lactobacilli and clostridia decreased significantly. Clostridium difficile strains were recovered from 3 of the volunteers. At the last visit, the intestinal microflora of the volunteers had returned to normal levels. The administration of linezolid mainly had an impact on the gram-positive bacteria and linezolid thus had an ecological profile different from that of amoxicillin/clavulanic acid.

Impact of moxifloxacin versus clarithromycin on normal oropharyngeal microflora.

A multiple-dose, randomized, double-blind, controlled, cross-over trial was performed in 12 healthy male subjects in order to investigate the effect of a 7-day treatment with moxifloxacin (400 mg orally, once daily) versus clarithromycin (500 mg orally, twice daily) on the normal oropharyngeal microflora. Moxifloxacin caused significant reductions in levels of alpha-streptococci and Neisseria cocci during the treatment period, while the numbers of gram-negative anaerobic bacteria increased markedly during moxifloxacin administration. Clarithromycin administration caused a suppression of micrococci and corynebacteria, while no significant changes were recorded in the anaerobic microflora. No new colonizing moxifloxacin-resistant strains were isolated during the investigation period.

In vitro effects of interleukin-10, prednisolone, and GM-CSF on the non-specific immune function of human polymorphonuclear leucocytes and monocytes.

A wide range of immune-modulating effects make IL-10 a potential therapeutic option in the treatment of numerous diseases pathophysiological based on a dysregulation of cytokine production. The background of this study was to investigate, whether the beneficial effects of a therapeutic immunosuppression with IL-10 may be countered by an increased risk for infections due to impaired effector cell functions of unspecific immunity. We demonstrated the in vitro effects of IL-10 on phagocytosis (P), intracellular killing (K), and chemotactic activity (C) by human neutrophils (PMN) and monocytes (MON) using Candida albicans as test strain and compared the results to the effects of prednisolone and GM-CSF. IL-10 reduced significantly the intracellular killing rate of PMN compared to untreated phagocytes (60 +/- 16% versus 68 +/- 13%, mean +/- SD, p = 0.0002). High dose IL-10 (100 ng/ml) had a stimulating effect on the percentage of phagocytizing MON (70.2 +/- 12.7% vs. 66.9 +/- 14.2%, p = 0.0436), without impairing intracellular killing. Prednisolone reduced significantly the Candida uptake by MON (57 +/- 18.1% vs. 66. 9 +/- 14.2%, p = 0.0019). In contrast to prednisolone, neither MON nor PMN chemotaxis was suppressed by IL-10. In conclusion, IL-10 had only marginal immunosuppressive effects on the unspecific immunity compared to prednisolone.

Comparative effects of moxifloxacin and clarithromycin on the normal intestinal microflora.

Twelve healthy male subjects age range 24-40 y participated in the investigation. The trial was divided into 2 35-d periods. The 2 treatment regimens were: (i) 1 x 400 mg moxifloxacin tablet in the morning and 1 placebo tablet in the evening for 7 d; and (ii) 1 x 500 mg clarithromycin tablet in the morning and 1 x 500 mg clarithromycin tablet in the evening for 7 d. Each subject received firstly I treatment regimen and secondly the other treatment regimen. The wash-out period was 6 weeks between the two treatment regimens. Moxifloxacin caused significant decreases of enterococci and enterobacteria during the administration period while the numbers of staphylococci, streptococci, Bacillus and Candida were not affected. No impact on peptostreptococci, lactobacilli, Veillonella, Bacteroides or fusobacteria was observed, while bifidobacteria and clostridia decreased during moxifloxacin administration. The microflora was normalized after 35 d. Clarithromycin caused significant reduction of Escherichia coli while the numbers of enterococci, Enterobacter, Citrobacter, Klebsiella and Pseudomonas increased markedly. No significant changes in the numbers of staphylococci, streptococci, Bacillus and Candida were noticed. In the anaerobic microflora bifidobacteria, lactobacilli and clostridia were suppressed, while no changes in peptostreptococci, Veillonella, Bacteroides and fusobacteria were found. The microflora was normalized in all volunteers after 35 d.

Pharmacokinetics of gatifloxacin and interaction with an antacid containing aluminum and magnesium.

The pharmacokinetics of gatifloxacin (400 mg orally) and the influence of the antacid aluminum magnesium hydroxide (20 ml of Maalox 70) on the bioavailability of gatifloxacin in 24 healthy volunteers were assessed. In an open, randomized, six-period crossover study, the volunteers received either gatifloxacin alone (treatments A and D); aluminum magnesium hydroxide concomitant with gatifloxacin (treatment C); or aluminum magnesium hydroxide 2 h before (treatment B), 2 h after (treatment E), or 4 h after gatifloxacin administration (treatment F). Gatifloxacin concentrations were measured by a validated bioassay and high-performance liquid chromatography. Pharmacokinetics of a single 400-mg dose of gatifloxacin alone were characterized as follows (mean +/- standard deviation): peak concentration (Cmax), 3.8 +/- 0. 5 (treatment A) and 3.4 +/- 0.9 (treatment D) microgram/ml; time to Cmax, 1.4 +/- 0.8 (treatment A) and 1.7 +/- 0.7 (treatment D) h; area under the curve from time zero to infinity (AUC0-infinity), 33. 5 +/- 5.9 (treatment A) and 31.4 +/- 3.4 (treatment D) microgram. h/ml; urine recovery, (83 +/- 6)% (treatment A) and (84 +/- 8)% (treatment D). Comparison of the results obtained by bioassay showed a good correlation. Aluminum magnesium hydroxide administration 2 h before (treatment B) or concomitant with (treatment C) gatifloxacin decreased the Cmax by 45% (2.1 +/- 1.2 microgram/ml) or even 68% (1.2 +/- 0.4 microgram/ml) highly significantly (P < 0.01). AUC0-infinity was significantly reduced from 33.5 +/- 5.9 to 19.4 +/- 6.9 microgram. h/ml (by 42%) or even to 11.9 +/- 3.3 microgram. h/ml (by 64%) (P < 0. 01). If aluminum magnesium hydroxide was given 2 h after gatifloxacin (treatment E), there was no significant reduction of concentration in serum but AUC0-infinity was significantly reduced from 31.4 +/- 3.4 to 25.9 +/- 5.3 microgram. h/ml (18%) (P < 0.01). Aluminum magnesium hydroxide given 4 h after gatifloxacin (treatment F) showed no influence on the gatifloxacin pharmacokinetics. Therefore, the optimal time between gatifloxacin application and the intake of an aluminum-containing antacid should be 4 h.

Interleukin-10: effects on phagocytosis and adhesion molecule expression of granulocytes and monocytes in a comparison with prednisolone.

Interleukin-10 (IL-10) has potent anti-inflammatory and immunosuppressive properties. The potential therapeutic benefit may be compromised by the down-regulation of the non-specific immune system and an increased risk of infection. We studied the effects of IL-10 on important functions of native and granulocyte-macrophage colony-stimulating factor (GM-CSF) activated neutrophils and monocytes, namely phagocytosis and membrane expression of the beta superset2-integrins and of the intercellular adhesion molecule-1 (ICAM-1). In order to simulate the in vivo situation closely, we used whole blood flowcytometric assays. The effects of IL-10 (0.05, 1, 10, 100 ng/ml) were compared to those of prednisolone (10 superset-8-10 superset-5 Mol/l), an approved immunosuppressive drug which is known to impair phagocyte function. - Incubation with IL-10 for three hours significantly attenuated the ability of neutrophils to phagocytose E.coli, particularly in lower concentrations. On the other hand, high IL-10 concentrations (10, 100 ng/ml) slightly augmented monocyte phagocytosis. Similarly, expression of the beta subset2-integrins and of ICAM-1 on monocytes was markedly enhanced with IL-10 concentrations in the range from 1 to 100 ng/ml and IL-10 showed strong synergistic effects with GM-CSF in the enhancement of monocyte receptor expression. Neutrophil adhesion molecule expression was not affected. Prednisolone suppressed the phagocytosis of both cell types in a dose-dependent fashion but hardly altered the receptor numbers. Our study indicates that IL-10 can behave as a de-activator as well as an activator on the non-specific immune system, depending on the cell type and the concentration.

Synergetic interpretation of patterned vasomotor activity in microvascular perfusion: discrete effects of myogenic and neurogenic vasoconstriction as well as arterial and venous pressure fluctuations.

Synergetic concepts allow to identify emergent coordination phenomena between interacting physiological systems, for example between the cutaneous microcirculation, the sympathetic nervous system and the cardiac and pulmonary systems. The temporal patterns (oscillations of various frequencies) that are found in the data obtained with laser-Doppler anemometers (LDA; e.g. Periflux 2 used in the study) can be investigated by simultaneous recording of photoplethysmographic data obtained in the identical region of interest, as well as in cutaneous regions treated with vasoparalytic procedures which permit to record the dynamics of the arterial system. These strategies were applied to studies in the cutaneous microcirculation (volar side of the index fingers) as well as to mucosal microcirculation (maxillar gingiva) in healthy subjects and in patients suffering from autonomic dysfunction (cutaneous microcirculation) or gingivitis. By this procedure, it could be corroborated that - contrary to popular notions - the temporal fluctuations in the LDA records do not necessarily reflect myogenic vasomotion, but can have multiple causes. In a confirming recent study [Schmid-Schönbein et al., J Auton Nerv Syst, 57, 136-140, 1996], we have demonstrated that the LDA fluctuations under conditions of normal ambient temperature and hand position most likely reflect neurogenic vasoconstriction. Under exceptional conditions, different patterns emerge. Prolonged exposure to ambient temperature (18 degrees C) leads to marked vasoconstriction, with occasional vasodilator escape ('miniature hunting reaction'). Normal subjects under gravitational load and in warm environment (28 degrees C ambient) silence their neurogenetic vasoconstriction reactions, which allows sinusoidal vasomotion to dominate. A similar phenomenon is seen in neuropathic patients at 21-24 degrees C (presumably due to structural defects). Fluctuations in LDA signal taken from the healthy gingiva are entrained to arterial, those taken from inflamed gingiva to respiratory activity. The theory and practice of nonlinear analysis is discussed, and data compression procedures allowing to portray characteristic temporal patterns for future diagnostic procedures are presented.

Long-term registration of cutaneous microcirculation during general anesthesia.

The temporal dynamics of the systemic arterial pressure can be monitored noninvasively from the skin of the earlobe or forehead by photoplethysmography under the provision that the active control of the microcirculatory perfusion is eliminated. Using this approach, we have been able to detect a highly stable blood pressure rhythm in the range of 0.15 Hz during psychophysical relaxation or sleep. The aim of the present study was to investigate the occurrence and behavior of blood pressure rhythms below 0.2 Hz during general anesthesia. In 30 patients (ASA groups I-II) undergoing basic surgical procedures, photoplethysmographic recordings from the earlobe were made during the whole time of anesthesia. The recorded signals were divided into segments of 200 s of duration, the temporal structure of which was analyzed by fast Fourier transform. Different characteristic patterns of rhythmical behavior were detected: (1) absence of activity below 0.2 Hz ('low-frequency range'); (2) slow sinusoidal rhythmicity below 0.05 Hz; (3) 'chaotic' behavior, i.e. multiple incoherent fluctuations without stationary periods or amplitudes; (4) short-term rhythmical activity at about 0.15 Hz, and (5) long-term rhythmical activity at about 0.15 Hz. In patients sufficiently sedated to eliminate low-frequency activity, rhythmicity could sometimes be triggered by certain surgical stimuli, the response to which was suppressed by injection of opioids. The data presented strongly suggest that rhythmical perfusion patterns of the cutaneous microcirculation could serve as an indicator for the depth of anesthesia.

Attractors and quasi-attractors in the cutaneous perfusion in human subjects and patients: "chaotic" or adaptive behaviour?

The causes of the aperiodic fluctuations in the perfusion of the skin (volar hand, measured by the Laser-Doppler (LD) technique) of healthy human subjects were studied were studied by simultaneous recording of the fluctuations of local blood content (reflectiophotoplethysmography (rPPG)) and those in the skin of the glabella. Various thermoregulatory situations were provoked by exposing 12 subjects to 18, 21, 24 and 27 degrees C ambient temperature; in addition, the hands were placed at, below and above heart level. In mentally relaxed subjects (evidenced by a stable approx. 0.015-Hz rhythm in the glabellar rPPG signal), there was perfect temporal correlation between aperiodic LDA and rPPG signal under all thermoregulatory conditions. Clearly identifiable episodes of retardation associated with skin bleaching, asymmetrical shape of LDA and rPPG signals were taken as indicators of episodic sympathetic skin constrictor (SSC) activity. In synergetic terms, the modulated SSC activity operates as transient "quasi-attractor'. A notable exception occurred: when the hand was placed below heart at 27 degrees C ambient temperature, a sinusoidal periodic fluctuation (approx. 0.03 Hz) in the LDA evolved. These were not seen the rPPG signal, i.e., coherence between LDA and rPPG dynamics was lost). Lack of coherency between LDA-rPPG, also observed in patients with autonomic neuropathy and decompensated forms of peripheral arterial disease, suggesting predominance of spontaneously oscillating myogenic vasomotion after removal of temporally variable SSC drive. Stable vasomotion is regarded as a synergetically stereotyped reaction rather than as "well-ordered' stable attractor mode of operation.

Active and passive modulation of cutaneous red cell flux as measured by laser Doppler anemometry.

1) We have found that the fluctuations in blood motion and blood content in cutaneous microvessels in man can be related to either active vasomotion (an order parameter for this system) or to a passive penetration of arterial (or venous, not shown) pressure waves (the control parameters for the microvascular blood motion). Arterial, respiratory (not shown), neuronal and myogenic rhythms can be clearly differentiated. 2) Spectral analysis of the signal fluctuations of a LDA method (monitoring phasic shifts in blood velocity) in combination with a photoplethysmographic method (monitoring shifts in blood content) can be used to identify the "normal state". In normal human subjects, it is characterized by broad band synergetic liberty (a wide spectrum of rhythmic activities between 0.01 and 5 Hz). The spectrum readily responds to changes in thermoregulatory state and/or myogenic activation by positional changes of the extremity. 3) The spectral analysis of LDA and photoplethysmographic records of the volar finger reveals predominance of active vasoconstriction during heat conserving thermoregulatory reflexes (18 degrees C ambient), predominantly passive reactions are seen at 27 degrees C. At 21-24 degrees C ("thermoregulatory indifference temperature range"), a mixed reaction pattern is seen. 4) Functional or irreversible elimination of the activity of subsystems leads to the elimination of circumscript spectral bands and/or potentiation of others. The functional differentiation of active and passive components can be utilized in the future for differential diagnosis of vascular and nervous disease state on the basis of spectral shifts and/or spectral narrowing.