Impact of pre-OP independence in patients with limited brain metastases on long-term survival.

BACKGROUND: Brain metastasis represents a major complication with a significantly shorter overall survival of many oncological diseases, in particular of lung cancer, breast cancer and malignant melanoma patients. However, despite the poor prognosis, sometimes clinical decision-making, between on the one hand not to harm the patient and on the other hand not withholding a potential therapeutic option, is very challenging. Thus the aim of this retrospective study was to compare various scores, including scores for activities of daily living (ADL) before resection of brain metastases and to analyse their impact on survival. METHODS: Our single institution retrospective patient cohort (N = 100) with a median age of 63.6 years, which had all undergone resection of one or more brain metastases, was categorized using the original patient files. The cohort includes 52 patients with lung cancer, 27 patients with breast cancer, 8 patients with colorectal carcinoma and 13 patients with kidney cancer. To categorize, we used different score systems which were capable to evaluate the patient in relation to self-sufficiency, activity and self-determination as part of ADL. The retrospective analysis includes the ECOG-Status, Karnofsky-Index, Barthel-Index, ASA-Classification and Katz-Index. Pre-processing and the analysis of the data was implemented using KNIME, where we used the R-plugin nodes to perform the final statistical tests with R. RESULTS: Our analysis reveals that most of the ADL scores we tested are able to give a reliable prediction on overall survival after brain metastasis surgery. The survival rates decrease significantly with a lower score in all tested score systems, with the exception of the ASA-Risk score. In particular, the Katz Index < 6 was identified to have a significant correlation with a lower cancer specific survival (CSS) (HR 3.33, 95%-CI [2.17-5.00]; p-Value = 9.6*10- 9), which is easy to use and has reproducible measurements. CONCLUSIONS: Pre-operative independence assessment by indices of ADL represents a predictor for overall survival after resection of brain metastases. Especially the easily, objectively and rapidly applicable Katz-Score is a very helpful tool to assess the pre-operative status, which could be additionally included in clinical decision making in daily practice.

Pilot study of oxygen transport rate of banked red blood cells.

BACKGROUND AND OBJECTIVES: Dynamic oximetry provides a new way to assess the effect of blood storage on the oxygen transport rate (OTR). MATERIALS AND METHODS: In dynamic oximetry, the rate at which oxyhemoglobin becomes deoxyhemoglobin is measured optically, thereby, indirectly measuring the rate at which oxygen leaves the red blood cell (RBC) making it available for transfer to tissues. Extending the physiologic diffusion time in an in vitro apparatus, consisting of a diffusion system and gas exchanger capable of controlling the surface area and the time of exposure for oxygenation and deoxygenation, makes OTR measurement feasible. Eight normal blood donor units, collected in adenine, dextrose, sorbitol, sodium chloride and mannitol , were stored for 8 weeks under standard conditions and serially sampled for OTR. RESULTS: We report that the OTR at the time of blood bank donation appears to be singular for each donor, that the interdonor differences are maintained over time, and that the individual OTR increased 1.72-fold (95% CI 1.51, 1.95) over 8 weeks, adjusting for sex, age and plasma cholesterol level. CONCLUSION: Oxygen transport rate increases during storage; blood units with similar haemoglobin content may have significant differences in OTR. Studies examining blood parameters at the time of donation and blood storage on patient outcomes should consider measuring OTR, as it may contribute to differences in observed efficacy of tissue oxygenation.

Control of blood glucose in experimental diabetes by means of a totally implantable insulin infusion device.

Near-normal glucose tolerance tests in diabetic dogs were obtained during basal rate insulin infusions in restrained animals by use of extracorporeal infusion pumps and in conscious, unrestrained animals by means of implanted infusion pumps. Even better regulation of blood glucose in diabetic animals was obtained by the addition of predetermined pulses of insulin at higher flow rates than the basal flow rate, accomplished by use of a transcutaneously activated valve mechanism attached to the implanted infusion pump. We conclude that near-normal blood glucose concentrations can be maintained throughout the day in the dog by these means and that similar approaches, using implantable infusion pumps, in man may lead to better long-term control of diabetes than is currently available.

Glycerol prevents insulin precipitation and interruption of flow in an implantable insulin infusion pump.

Insulin precipitation is a major obstacle to the use of implantable insulin infusion pumps. In one such pump (Infusaid, Infusaid Corporation, Norwood, Massachusetts), unprotected insulin precipitated and occluded nine pumps implanted in normal dogs within 43 days. In contrast, two similar pumps containing insulin mixed with 80% glycerol functioned normally for more than 250 days. In human studies, a similar mixture allowed insulin to be delivered to nine diabetic subjects for more than 6 mo in each case; total fluid flow rates from the pump were essentially unchanged after 460 patients-weeks of insulin infusion. A possible drawback of the mixture is a time- and temperature-dependent propensity to cause the formation of soluble, higher-molecular-weight insulin polymers, which apparently have lower biologic activity. Formation of such polymers and maintenance of biologic activity were largely prevented by the addition of phosphate buffer at neutral pH.

A totally implantable drug infusion defice: laboratory and clinical experience using a model with single flow rate and new design for modulated insulin infusion.

The Infusaid implantable infusion pump with a single delivery rate has maintained chronic intravenous heparin infusion in man for greater than 35 mo and for greater than 5 yr in the dog. Intra-arterial infuson of fluorodeoxyuridine has been maintained for greater than 8 mo in man. In a pilot study using a commercially available, transcutaneously controllable, magnetically activated valve for baseline superimposed bolus insulin infusion, the feasibility of maintaining near normal serum glucose in diabetic dogs was demonstrated. The effect of long-term intravenous cannulation was investigated; it was found that the intimal tissues of the vena cava surrounding the cannulae were largely unaltered and microemboli could not be detected in the lungs of the animals studied. Cannula plugging, which occurred on several occasions due to thrombus formation in the final centimeter of the cannula, has been solved by changes in pump design and refilling procedures. The problem of insulin precipitation in flow passages of the pump remains unsolved, but there are indications that substances entering the cannula from the blood may be involved. A new pump design for modulated insulin infusion is described.

The effect of continuous heparin infusion for one year on serum cholesterol and triglyceride concentrations in the dog.

Fourteen normal dogs received continuous infusions of intravenous heparin for one year by means of an implantable infusion pump. Heparin wad admistered at an overall mean rate of 666 units/kg/day, a dose sufficient to prolong the Lee-White clotting time to greater than twice normal. Eight control, animals, under the same dietary and activity regimen, received continuous infusions of bacteriostatic water for one year by means of implanted pumps. Serum cholesterol concentrations rose to 50% above control values after one month of heparin infusion, and remained significantly (P less than 0.05) elevated at this level for the remaining 11 months. Serum triglyceride levels were unchanged. A possible mechanism for this elevation resides in the known effect of heparin to increase plasma free fatty acid concentrations by its activation of lipoprotein lipase. These results may have implications for the long-term use of heparin anticoagulation in the treatment of atherosclerotic states in man.

Long-term, continuous intravenous heparin administration by an implantable infusion pump in ambulatory patients with recurrent venous thrombosis.

We studied the effect of long-term intravenous heparin infusion, delivered by a self-recycling, totally implantable infusion pump developed in our laboratory, in 21 patients with recurrent thromboembolic disease. Continuous infusions were maintained in these patients from 1 to 36 months, during which pumps were refilled by percutaneous needle injection at 4- to 8-week intervals. We maintained plasma heparin levels between 0.1 and 0.3 U/ml plasma. This regimen prevented thromboembolic phenomena in all except one patient, who apparently is refractory to heparin as well as oral anticoagulant drug therapy. Marked reduction of pain and improvement of mobility were reported by several patients with vena cava ligature syndrome. No spontaneous hemorrhagic complications occurred; however, several episodes of pump site hemorrhage were associated with pump refills. Bone mineral densities measured in eight subjects after 1 year of heparin infusion [1.00 +/- 0.06 (SE) gm/cm] were not significantly (P = 0.5) different from baseline values (0.98 +/- 0.08 gm/cm); however, osteoporosis did occur in one subject. Serum calcium, phosphorus, alkaline phosphatase, cholesterol, and triglycerides also remained unchanged in these subjects. These data suggest that continuous long-term heparin infusion is a viable therapeutic alternative in subjects with refractory thromboembolic disease.

A new peritoneovenous shunt.

For today's most common peritoneovenous shunt catheters, the high incidence of complications (disseminated intravascular coagulation [DIC], pulmonary problems, clotting of the intravascular end, and shunt kinking) results in limited use. We have designed a new peritoneovenous shunt catheter in which we improved mechanical biocompatibility with respect to both the peritoneum and the vasculature. The device consists of: a multimicroorifice ascites filter in a double-chambered collecting device, a tubular compression pump with an intratubular check-valve, and a check-valve catheter at the intravascular end for positive exclusion of blood by reflux or back diffusion. This configuration filters the proteinaceous material from the ascites fluid, transports the filtrate into the blood stream, maintains patency, act to prevent DIC by inhibiting the creation and transport of microthrombi into the cardiovascular system, and eliminates clot formation at the intravascular end.

Decreased blood oxygen diffusion in hypercholesterolemia.

BACKGROUND: Improvement of angina pectoris symptoms after cholesterol lowering has raised questions as to the underlying mechanisms. METHODS: Rabbit experiment: We compared arterial blood samples from New Zealand White cholesterol-supplemented rabbits (n = 6) with nonsupplemented rabbit samples (n = 4) in a closed-loop circulation diffusion system. The pH and partial pressures of oxygen (pO2) and carbon dioxide (pCO2) were measured continuously. The samples were first oxygen (O2) saturated (pO2, 160 mm Hg; pCO2, 4 mm Hg) and then desaturated in 100% nitrogen. Cholesterol levels were determined in whole blood, plasma (P Chol), red blood cells (RBCs), and RBC membranes. Human experiment: We exposed quadruple desaturated venous blood samples (n = 4) with P Chol levels of 87 to 400 mg/dL in a gas exchanger to capillary gas conditions (pO2, 23 mm Hg; pCO2, 46 mm Hg). After 15 minutes we performed blood gas analyses and compared our results to baseline values. RESULTS: In the rabbit experiment the cholesterol-supplemented group as compared to the control group showed higher plasma pO2 levels during the saturation phase and lower plasma pO2 levels during the desaturation phase. It also had a markedly increased RBC membrane cholesterol content: 121 +/- 3 (standard error of the mean [SEM]) mg/dL versus 22 +/- 1.7 mg/dL in the control group (P < .05). This barrier to RBC membrane O2 diffusion caused delayed O2 entry into the RBCs during saturation, with a higher plasma pO2, and delayed O2 release from the RBCs during desaturation, with a lower plasma pO2. In the human experiment the P Chol level was inversely correlated with the percentage change of O2 content in milliliters of O2 per deciliter of blood (P < .05). CONCLUSIONS: Increased RBC membrane cholesterol in hypercholesterolemia appears to decrease the transmembrane O2 diffusion rate.

Reduction of plasma cholesterol and LDL-cholesterol by continuous intravenous insulin infusion.

We studied lipid profiles in 10 patients with insulin-requiring type II diabetes. Patients began the study under conventional subcutaneous insulin injection therapy. Treatment was then optimized on subcutaneous therapy and finally converted to continuous intravenous therapy from a single flow rate implantable pump. Pump management proved reliable and safe. Implantable pump therapy showed a statistically significant reduction in the average plasma cholesterol level from 205.7 to 184.7 mg/dl. The mean low-density lipoproteins (LDL)-cholesterol level decreased from 114.6 to 108.1 mg/dl, the high-density lipoproteins (HDL)-cholesterol average changed from 50.6 to 51.0 mg/dl, and the HDL/LDL ratio increased from 0.478 to 0.500. Glycemic control did not improve on single-rate intravenous therapy compared with intensive conventional subcutaneous injection during the short observation period. The authors conclude that additional studies should be performed to confirm the improvement in the lipid profile on intravenous pump therapy.

Impaired muscle glycogen resynthesis after a marathon is not caused by decreased muscle GLUT-4 content.

Our purpose was to investigate whether the slow rate of muscle glycogen resynthesis after a competitive marathon is associated with a decrease in the total muscle content of the muscle glucose transporter (GLUT-4). Seven well-trained marathon runners participated in the study, and muscle biopsies were obtained from the lateral head of the gastrocnemius muscle before, immediately after, and 1, 2, and 7 days after the marathon, as were venous blood samples. Muscle GLUT-4 content was unaltered over the experimental period. Muscle glycogen concentration was 758 +/- 53 mmol/kg dry weight before the marathon and decreased to 148 +/- 39 mmol/kg dry weight immediately afterward. Despite a carbohydrate-rich diet (containing at least 7 g carbohydrate.kg body mass-1.day-1), the muscle glycogen concentration remained 30% lower than before-race values 2 days after the race, whereas it had returned to before-race levels 7 days after the race. We conclude that the total GLUT-4 protein content is unaltered in the lateral gastrocnemius after a competitive marathon and that the slow recovery of muscle glycogen after the race apparently involves factors other than changes in the total content of this protein.

Muscle glycogen accumulation after a marathon: roles of fiber type and pro- and macroglycogen.

Muscle glycogen remains subnormal several days after muscle damaging exercise. The aims of this study were to investigate how muscle acid-soluble macroglycogen (MG) and acid-insoluble proglycogen (PG) pools are restored after a competitive marathon and also to determine whether glycogen accumulates differently in the various muscle fiber types. Six well-trained marathon runners participated in the study, and muscle biopsies were obtained from the vastus lateralis of the quadriceps muscle before, immediately after, and 1, 2, and 7 days (days 1, 2, and 7, respectively) after the marathon. During the race, 56 +/- 3.8% of muscle glycogen was utilized, and a greater fraction of MG (72 +/- 3.7%) was utilized compared with PG (34 +/- 6.5%). On day 2, muscle glycogen and MG values remained lower than prerace values, despite a carbohydrate-rich diet, but they had both returned to prerace levels on day 7. The PG concentration was lower on day 1 compared with before the race, whereas there were no significant differences between the prerace PG concentration and the concentrations on days 2 and 7. On day 2 the glycogen concentration was particularly low in the type I fibers, indicating that local processes are important for the accumulation pattern. We conclude that a greater fraction of human muscle MG than of PG is utilized during a marathon and that accumulation of MG is particularly delayed after the prolonged exercise bout. Furthermore, factors produced locally appear important for the glycogen accumulation pattern.

Effects of glutamine on the immune system: influence of muscular exercise and HIV infection.

Glutamine increased the proliferative response and the lymphokine-activated killer cell activity of blood mononuclear cells isolated from normal healthy subjects (n = 6) in a dose-dependent manner, with optimum at 0.3-1.0 mM. The relative fraction of CD3+, CD4+, CD8+, CD14+, CD16+, and CD19+ cells was not changed by glutamine at a concentration of 0.6 mM, except in the phytohemagglutinin-stimulated proliferation experiment where the fraction of CD4+, and therefore CD3+ cells, increased. The natural killer cell activity was not influenced by glutamine. Human immunodeficiency virus (HIV)-seropositive subjects (n = 8) who performed concentric bicycle exercise for 1 h at 75% of maximal O2 consumption had an overall lower phytohemagglutinin-stimulated proliferative response, compared with the HIV-seronegative control group (n = 7). The proliferation during exercise was lower in both the HIV-seropositive and the HIV-seronegative group. Addition of glutamine in vitro did not normalize the lower proliferation in the HIV-seropositive group or the attenuated proliferation seen during exercise in both groups.

Plasma cholesterol: an influencing factor in red blood cell oxygen release and cellular oxygen availability.

BACKGROUND: A fairly immediate reduction in angina pectoris symptoms after cholesterol lowering has been described. Our previous findings in rabbits and in a four-patient human pilot study indicated the existence of an RBC membrane barrier to oxygen (O2) transport in the presence of hypercholesterolemia. Our current objective was to determine whether, and to what extent, the plasma cholesterol concentration is an influencing factor in RBC O2 release and cellular O2 availability. STUDY DESIGN: In an unique O2 diffusion analysis system, blood samples from 100 patients referred for lipid modification were analyzed. After 1 to 2 minutes of mixing in our diffusion analysis system, the next 1 to 2 minutes of circulation is comparable with 1 to 2 seconds of myocardial capillary flow. RBC O2 diffusion was defined by the depletion rate of total O2 content in blood from full O2 saturation (98%) to desaturation (approximately 60%). Relative tissue O2 availability was defined as the percentage decrease in O2 availability between the high-cholesterol group and the low-cholesterol group. RESULTS: The 100 patients were divided almost equally into two groups on the basis of plasma cholesterol ranges of 175 to 229 mg/dL (n=49) and 230 to 299 mg/dL (n = 51). The mean cholesterol concentrations and percentage increases in the high-cholesterol group over the low-cholesterol group were: for plasma, 206 +/- 0.3 and 256 +/- 0.4 mg/dL, 24.3% (p < 0.001); for RBCs, 93 +/- 0.2 and 106 +/- 0.2mg/dL, 14.0% (p < 0.001); and for RBC membranes, 41 +/- 0.1 and 54 +/- 0.2mg/dL, 31.7% (p < 0.001). The blood O2 diffusion curves were distinctly different between the high- and the low-cholesterol groups (p < 0.05). Blood O2 diffusion, defined by the blood O2 diffusion curves, was inversely proportional to the plasma, RBC, and RBC-membrane cholesterol concentrations. The relative tissue O2 availability, after a circulation period of more than 3 minutes in the diffusion system, showed a decrease of 17.5% (p < 0.05) between the plasma cholesterol groups. In comparing the two plasma cholesterol concentration extremes of less than 200mg/dL (n= 14) and greater than 275 mg/dL (n= 11) after a circulation period of more than 3 minutes in the diffusion system, we found a decrease in relative tissue O2 availability of 35.8% (p < 0.05). CONCLUSIONS: The plasma cholesterol concentration may be an influencing factor in RBC-membrane cholesterol content, which, in turn, may regulate RBC-membrane O2 transport, RBC O2 release, and cellular O2 availability. The implications of this work include the addition of angina pectoris control to the indications for appropriate lipid modification and the development of an in vitro blood stress test to replace patient cardiac stress testing.

Glutamine, exercise, and the immune system--is there a link?

Glutamine is known to be important for cells replicating in culture. It has been proposed that the decrease in plasma glutamine concentration in relation to catabolic conditions, including strenuous exercise, resulting in a lack of glutamine for cells of the immune system, is responsible for the transient postexercise immunosuppression. This review discusses the potential role of glutamine on the postexercise in-vitro changes in immune parameters. Furthermore, the value of glutamine as a nutritional supplement to athletes and the possible influence on these parameters is reviewed.

Effect of glutamine supplementation on changes in the immune system induced by repeated exercise.

UNLABELLED: The ability of lymphocytes to proliferate and generate lymphokine activated killer (LAK) cell activity in vitro is dependent on glutamine. In relation to intense exercise the lymphocyte concentration, the proliferative response, the natural killer and LAK cell activity, and the plasma glutamine concentration decline. It has been hypothesized that in relation to physical activity a lack of glutamine may temporarily affect the function of the immune system. PURPOSE: The purpose of this study was to examine the influence of glutamine supplementation on exercise-induced immune changes. METHODS: In a randomized cross-over placebo-controlled study, eight healthy male subjects performed three bouts of ergometer bicycle exercise lasting 60, 45, and 30 min at 75% of their VO2max separated by 2 h of rest. RESULTS: The arterial plasma glutamine concentration declined from 508 +/- 35 (pre-exercise) to 402 +/- 38 microM (2 h after the last exercise bout) in the placebo trial and was maintained above pre-exercise levels in the glutamine supplementation trial. The numbers of circulating lymphocytes and the phytohemagglutinin-stimulated lymphocyte proliferative response declined 2 h after, respectively, during each bout of exercise, whereas the LAK cell activity declined 2 h after the third bout. Glutamine supplementation in vivo, given in the described doses at the specific times, did not influence these changes. CONCLUSION: The present study does not appear to support the hypothesis that those aspects of postexercise immune changes studied are caused by decreased plasma glutamine concentrations.

An in vitro evaluation of microleakage of a new root canal sealer.

An in vitro dye leakage study was performed to compare the apical microleakage of Ketac-Endo root canal sealer with that of Roth's 801E and AH26 sealers. Sixty-four single-rooted human teeth were instrumented and randomly divided into four groups. Three groups were obturated with laterally condensed gutta-percha and either Roth's 801E, AH26, or Ketac-Endo as the sealer. A fourth group was obturated using a single master cone and the Ketac-Endo sealer. The teeth were suspended in 1% methylene blue dye for 6 days. The teeth were then longitudinally sectioned and evaluated for linear apical dye penetration. In general, Ketac-Endo root canal sealer showed greater dye penetration than Roth's 801E and AH26. There was no statistical difference in leakage between the laterally condensed Ketac-Endo group and the single-cone-obturated Ketac-Endo group.

Implantable pumps. Recent progress and anticipated future advances.

The implantable pump field is now more than 20 years old. The original goal of developing a totally artificial beta-cell remains unrealized, but programmable insulin pumps that contain all of the elements of the artificial beta-cell except the glucose sensor are involved in clinical trials in the United States and are commercially available in Europe. Currently, both single-rate and programmable implantable pumps are in general clinical use in the United States for the treatment of pain and spasticity, cancer, and osteomyelitis. Only a few of the potential applications of implantable pumps have been developed to the stage of commercial availability. This is, in part, because drug companies have traditionally developed parenteral drug applications only as a last resort and, in part, because of the complexity of the regulatory process for implantable pumps, often requiring review by both the drug and device branches of the Food and Drug Administration.

The spring-driven implantable pump. A low-cost alternative.

In the current era of cost containment in medicine, manufacturing economics have become increasingly important. The authors devised an implantable pump powered by spring force from an elastomeric Belleville washer, which is also the outer flexible wall of the drug reservoir. Use of formed and injection molded parts provides for low-cost manufacturing, in contrast to the precision welded alternative designs. Additional advantages include insensitivity to changes in ambient temperature and pressure. Finite element modeling of the elastomer spring allows prediction of the effects of parameter changes on performance, so that expansions and reductions of scale can be made without compromising the uniform spring rate of the device. A concern that subcutaneous fibrous encapsulation might markedly alter reservoir pressure was not supported by experimental data. In a unit implanted subcutaneously in a dog, reservoir pressures measured over a 4 year period were stable. This new, simple, implantable infusion pump can serve as an economical vehicle for prolonged parenteral drug treatment of ambulatory subjects in circumstances where continuous single-rate infusion is appropriate.

A peritoneovenous shunt with an access port enables non surgical reversal of intraperitoneal catheter occlusion.

Management of chronic peritoneal ascites by transfer of the fluid to the right atrium via peritoneovenous shunt (PVS) is often complicated by occlusion of the peritoneal catheter by one, or a combination, of the following: 1) omental plugging of drain holes, 2) fibrin obstruction of the lumen, and 3) encapsulation of the peritoneal segment by a cocoon. A PVS design that includes an access port facilitates the reversal of fibrin obstruction by urokinase. Eight dogs with implanted PVS were tested weekly for patency (indicated by the flow rate of saline into the peritoneum via the access port) and performance (indicated by the percent transfer of saline from the peritoneum to the vasculature). In 256 test sessions performed to date, 15 catheter occlusions occurred. Nine of these were reversed by one or two flushes with 5,000 units of urokinase via the access port. The remaining six were found to be occluded by cocoons (two), omentum (three), and fibrin (one). Although it is an effective treatment for ascites, the PVS is not in common use, because it has a relatively high occlusion rate. The access port and other features of the authors' PVS are designed to reduce the incidence of PVS occlusion.