Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

[Impairment of safety in navigation caused by alcohol: impact on visual function]. / Beeinträchtigung der Sicherheit im Schiffsverkehr durch Alkohol. Einfluss auf das Visuelle System.

BACKGROUND: So far in Germany, no legally binding standards for blood alcohol concentration exist that prove an impairment of navigability. The aim of our interdisciplinary project was to obtain data in order to identify critical blood alcohol limits. In this context the visual system seems to be of decisive importance. MATERIALS AND METHODS: 21 professional skippers underwent realistic navigational demands soberly and alcoholized in a sea traffic simulator. The following parameters were considered: visual acuity, stereopsis, color vision, and accommodation. RESULTS: Under the influence of alcohol (average blood alcohol concentration: 1.08 per thousand ) each skipper considered himself to be completely capable of navigating. While simulations were running, all of the skippers made nautical mistakes or underestimated dangerous situations. Severe impairment in visual acuity or binocular function were not observed. Accommodation decreased by an average of 18% ( p=0.0001). In the test of color vision skippers made more mistakes ( p=0.017) and the time needed for this test was prolonged ( p=0.004). CONCLUSIONS: Changes in visual function as well as vegetative and psychological reactions could be the cause of mistakes and alcohol should therefore be regarded as a severe risk factor for security in sea navigation.

[Impairment of safety in navigation caused by alcohol: pupillography and measurement of pupil movements]. / Beeinträchtigung der Sicherheit im Schiffsverkehr durch Alkohol. Pupillographie und Augenbewegungsmessungen.

OBJECTIVE: To evaluate data in an interdisciplinary project (ophthalmology, forensic medicine, internal medicine, psychology,and nautical science) in order to identify critical blood alcohol limits in sea navigation. METHODS: A sea traffic simulator was employed for realistic nautical demands on 21 professional experienced skippers under sober and alcoholized conditions (target blood alcohol concentration: 1.0 per thousand ). After simulated navigation, pupil light reflex, spontaneous pupil movements,nystagmus,and saccades were evaluated by pupillography. Modification of the pupillograph enabled us also to measure optokinetic nystagmus. RESULTS: Evaluation of the pupil light reflex revealed obvious changes in the extent of relative contraction and in redilatation time under the influence of alcohol. Diminished vigilance could be observed in all of the skippers when optokinetic nystagmus was tested. CONCLUSION: The pupillograph represents a suitable device for measuring functions of the visual and vegetative systems. Thus, the impact of these functions on nautical capability can be demonstrated. If further investigations such as ophthalmological, medical, psychological, and nautical evaluations are taken into account, it could be determined that blood alcohol levels of 1.0 per thousand may exclude safe navigation.

[Alcohol-induced morphologic and biochemical corneal changes]. / Alkoholinduzierte morphologische und biochemische Hornhautveränderungen.

In our cornea bank, it was noticed that corneas from donors with alcoholism seemed to be of lower quality than corneas from other donors. High blood ethanol concentrations can induce high alcohol concentrations in aqueous and vitreous humor. This could be demonstrated in the case of a lethal alcohol intoxication. We conducted in vitro experiments to clarify the question of alcohol-induced changes of corneas. The corneas were stored in a standardized culture medium including ethanol, formic acid, methanol, and acetaldehyde in concentrations to be expected in chronic alcoholism. During cultivation over 4 weeks, endothelial morphology and extent of aspartic acid racemization in stromal proteins were evaluated. The extent of aspartic acid racemization served as a biochemical parameter of alcohol-induced protein changes of the corneas. In the in vitro experiments, a drop in the endothelial cell counts could be seen in corneas stored in culture medium with acetaldehyde. The extent of aspartic acid racemization increases in corneas stored in medium containing ethanol, which obviously is the result of alcohol-induced protein degradation. High concentrations of ethanol and its metabolics can be detected in vitreous and aqueous humor in chronic alcoholism. Clearly, these concentrations have a direct toxic effect on the corneal endothelium (acetaldehyde) and on the stromal proteins (ethanol).

[Astigmatism-oriented perforating keratoplasty. A possibility for minimizing postoperative astigmatism?]. / Astigmatismusorientierte perforierende Keratoplastik. Eine Möglichkeit zur Minimierung des postoperativen Astigmatismus?

BACKGROUND: This pilot study examined whether astigmatism of donor corneas can be evaluated postmortem, and whether there is an effect on the astigmatism following keratoplasty. METHODS: The corneoscleral rims of donors were marked after measurement by a hand keratometer in the 12 o'clock position. We examined 38 patients after penetrating keratoplasty and divided them into three groups. The 12 o'clock position of the donor cornea was fixed in the same position as the recipient (group A, n = 12), or the donor corneas were transplanted with the axis in opposition to the axis of the recipient (group B, n = 12) or in the same orientation (group C, n = 14). Development of postoperative astigmatism was compared with controls (group D, n = 40). RESULTS: In group B we found a new orientation of the astigmatism axis within 2-4 months; in group C the axis maintained the original orientation of the recipient. Mean postoperative astigmatism was 3.5 +/- 1.5 dpt in group A, 2.1 +/- 1.3 dpt in group B, 5.8 +/- 1.6 dpt in group C, and 3.4 +/- 1.5 dpt in group D. After suture removal the axis orientation persisted in all groups. CONCLUSION: This study shows the possibility of evaluating corneal astigmatism in donor eyes. The astigmatism of the donor cornea itself directly influences the postoperative axis of astigmatism in recipient eyes. Astigmatism after corneal grafting can be reduced by orienting the donor astigmatism against the axis of the recipient.

[Postmortem evaluation of corneal astigmatism after astigmatism oriented penetrating keratoplasty]. / Postmortale Evaluation des kornealen Astigmatismus nach Astigmatismus-orientierter perforierender Keratoplastik (AOpKP).

BACKGROUND: Reduction of astigmatism following penetrating keratoplasty can be achieved if the graft is oriented according to astigmatism parameters in donor and host (AOPKP). Postmortem evaluation of these parameters is therefore essential. The aim of our investigation was to compare postmortem measurements using a hand-held keratometer with those of the living donor's astigmatism. METHOD: The 72-year-old female patient had undergone AOPKP on her right eye. After death the astigmatism in the right eye was evaluated 4.5 h postmortem using a hand-held keratometer. After explantation, the eyeball was examined by computer-assisted topography (TMS-1). RESULTS/CONCLUSION: We could show that hand keratometry in situ is reliable for evaluating astigmatism in donor eyes after death. As far as our AOPKP study is concerned, these results are of great interest. Reduction of postoperative astigmatism following penetrating keratoplasty is only possible if data on astigmatism of the donor and host corneas are available.

[Wound or suture insufficiency complicating penetrating keratoplasty]. / Schwerwiegende Wund- und Nahtinsuffizienzen nach perforierender Keratoplastik.

BACKGROUND: With regard to penetrating keratoplasty methods to culture corneal donor tissues, microsurgical techniques, HLA typing and understanding of basic mechanisms in inflammation and especially graft rejection, and postoperative treatment schedules have been improved in recent years. This now enables successful penetrating keratoplasty in many more patients than previously performed. However, in rare cases relevant problems in wound closure may appear. PATIENTS AND METHODS: A standardized treatment protocol was applied to 1,253 penetrating keratoplasties performed in a single center. Patients were continuously followed up. Simple leakage after corneal grafting was not further analyzed if conservative treatment or additional sutures achieved sufficient wound closure. In 21 cases, however, the causes of large wound dehiscence after corneal grafting were analyzed. RESULTS: During the first week early problems in suturing penetrating keratoplasty in five patients were associated with the instability of the recipients' corneal stroma (stromal thinning in keratoconus or corneal herpes, suture problems in keratomalacia, active herpes keratitis, corneal burns, or rheumatic diseases). Long-term complications in 16 patients were associated with alcoholism, herpes keratitis, rheumatic disorders or traumatic suture defects. Overall, nine patients lost functionally or even anatomically one eye because of wound dehiscence after corneal grafting. CONCLUSIONS: When penetrating keratoplasty is indicated, special attention should be given to (1) the compliance of the patient, (2) sufficient treatment of herpes keratitis or other infections, (3) adequate immunosuppression in autoimmune corneal inflammation, (4) double running continuous sutures as primary suture with sometimes additional single sutures to stabilize the graft, and (5) surgery in time.

High energy shock waves induced increase in the local concentration of systemically given TNF-alpha.

The influence of high energy shock waves (HESW) on the local concentration of systemically given TNF-alpha was studied in a syngeneic rat bladder tumor model. 125I-TNF-alpha was injected intravenously and within 1 minute was followed by HESW tumor exposure. High energy shock waves were generated using an experimental shock wave emitter based on the Siemens Lithostar Plus. Administration of HESW to RBT323 tumors resulted in a 3-fold increase in uptake of 125I-TNF-alpha in the tumor compared with nontreated tumors, whereas the tissue distribution and pharmacokinetics of nontumor tissue were similar irrespective of HESW exposure. These results demonstrate that HESW administration leads to an increase in the local concentration of a systemically given drug. The capacity of HESW to increase local drug concentrations will be of importance in designing more effective combined treatment strategies.

Fate of antigen after intravenous and intraarticular injection into mice. Role of molecular weight and charge.

The role of the charge of differently sized proteins in their penetration, persistence and localization in murine joint tissues was studied. Radiolabeled proteins of variable molecular weight (14-150 kDa) and charge (isoelectric point (pI) 4.5-10) were administered by intravenous and intraarticular routes, and localization studies in the first 2 and at 24 h were done with autoradiography. Small cationic proteins rapidly penetrated joint tissues after intravenous injection and persisted in larger amounts compared to anionic proteins of corresponding size. Small cationic proteins easily penetrated the matrices of both epiphysial and articular cartilage. In contrast larger cationic proteins (cBSA, cIgG) persisted for the greater part in the tissues just around the vessels and cartilage association was less striking. After intraarticular injection it was found that low molecular weight proteins (14 to 47 kDa) are rapidly cleared from the joint. Small cationic proteins persisted somewhat better than anionic ones, but impressive retention was only found with cationic proteins with higher molecular weight (67 to 150 kDa). Our data help to define prerequisite properties of proteins for penetration and interaction with joint structures after systemic supply or local production.

Quantitative urine collection in renal clearance studies in the dog.

A double-walled urinary catheter is described which allows rapid and quantitative urine collection at short time intervals. The catheter consists of a polyurethane outer cannula in which a small Teflon cannula is inserted. The essential of the catheter is that at the end of a collection period, residual urine in the bladder can be collected completely via the outer cannula by flushing the bladder with physiological salt through the inner cannula. In this manner urine can be collected in a very reproducible way at intervals down to 5 min. The use of the catheter was illustrated in a study on the renal clearance of hippuric acid in the dog. Plasma concentration and renal excretion rate were followed after i.v. injection of 0.9 g sodium hippurate. In accordance with previous studies, it was found that the renal excretion of hippuric acid consisted of glomerular filtration and active tubular secretion. A large variability was observed in the tubular transport maximum (3,800-11,600 micrograms/min) and the Michaelis-Menten constant (22-190 micrograms/ml), which were used to characterize the secretory system. The interpretation and value of these transport parameters is discussed briefly.

Uteroplacental blood flow during pregnancy in chronically catheterized guinea pigs.

Uterine blood flow and its distribution to uterus, placenta and subplacental structures was measured in 18 pregnant guinea pigs studied under chronic steady-state conditions. Maternal cardiac output averaged 266 +/- 14 ml/min. Placental blood flow (PBF) remained less than 4 ml/min until 50 days gestation, after which it increased rapidly, attaining flows of 16 ml/min at term. PBF also increased linearly with placental weight (r = 0.76, P less than 0.001); however, the increase in PBF with gestational age is evident even in narrow weight ranges, indicating hyperperfusion of term placentas relative to those earlier in gestation. Fetal weight correlated with measured placental blood flow supplying the corresponding placenta after 50 days gestation (r = 0.72, P less than 0.001).

Distribution of cardiac output in the unstressed pregnant guinea pig.

Cardiac output (CO) and organ flows were measured in five nonpregnant and 14 pregnant unstressed guinea pigs between the thirty-ninth and sixty-fifth postconceptional day by means of radionuclide-labeled microspheres. Blood pressure, heart rate, and cardiac output in nonpregnant animals were 60 torr, 234 bpm, and 248 ml/min, respectively. These parameters did not change significantly during pregnancy. The uterine fraction of cardiac output increased to approximately 18% at term and there was an equivalent decrease in the CO fractions to the carcass and skin. Blood flow per gram of wet weight increased during pregnancy by approximately 140% and 70% for the thyroid and gastrointestinal tract, respectively, but did not change significantly for the heart, brain, kidneys, and adrenals. In pregnant animals near term the weight of the heart, kidneys, intestines, and lungs was approximately 25% lower than that observed in nonpregnant guinea pigs.