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Biomedical subjects

K Peter

Publications and source records attributed to K Peter.

At least 127 records · Page 7Linked to original sources

[Venovenous extracorporeal membrane oxygenation (ECMO) with a heparin-lock bypass system. An effective addition in the treatment of acute respiratory failure (ARDS)].

Mortality of severe acute respiratory distress syndrome (ARDS) in Germany is about 60%. Respiratory therapy can make the lung injury worse by high positive airway pressures, high tidal volumes and high inspiratory oxygen concentrations. Extracorporeal membrane oxygenation (ECMO) was employed to reduce aggressive mechanical ventilation, but it has not been proved to be superior to conventional ventilation. However, encouraged by recently developed improvements in the technique and concept of ECMO, we introduced this therapy into our program for the treatment of ARDS. PATIENTS AND METHODS. All patients with severe ARDS (lung injury score > 2.5) admitted to our multidisciplinary intensive care unit from March 1992 to March 1995 were evaluated prospectively. After admission, the patients first underwent a conventional therapeutic approach, including pressure-controlled inverse-ratio ventilation, permissive hypercapnia, changes in body position (in particular, the prone position), negative fluid balance, anti-biotics, and low-dose hydrocortisone infusion. ECMO via a covalently heparin-coated, venovenous bypass-system with a vortex pump and two membrane lungs was performed if ARDS did not improve after 24-96 h of conventional therapy and if two of three of the slow-entry criteria for ECMO were fulfilled: (1) PaO2/FiO2 < 150 mmHg at PEEP > 5 mbar; (2) semistatic compliance < 30 ml/mbar; (3) right-left shunt > 30%. Only in cases of life-threatening hypoxemia (PaO2 < 50 mmHg at FiO2 1.0 and PEEP > 5 mbar for > 2 h (fast-entry criteria) was ECMO instituted immediately. RESULTS. Sixty patients fulfilled the entry criteria for our study. Thirty-nine patients were treated with a conventional protocol, 37 after improvement of ARDS and 2 who had not improved but in whom there were contraindications to the use of ECMO. ECMO was performed in 10 patients who had not improved, but who fulfilled the slow-entry criteria and in 11 primarily hypoxemic patients who fulfilled the fast-entry criteria. The survival rate was 30/39 (77%) for the conventional therapy group, 6/10 (60%) for the slow-entry group, and 11/11 (100%) for the fast-entry group. The onset of ECMO allowed a significant decrease in peak and mean airway pressures, tidal volume, ventilatory rate, minute volume and inspiratory oxygen concentration. Sufficient gas exchange was provided, and pulmonary artery pressures significantly decreased on bypass. The most frequent complications on bypass were pneumothorax (15/21 patients) and bleeding (7/21 patients). CONCLUSION. In comparison with the historical results at our own institution, the present study demonstrates an improvement in the survival rate from 56% to 78% since ECMO has become available. We conclude that venovenous ECMO with a heparin-bonded bypass circuit is an effective additional option for the treatment of patients with severe ARDS.

Adolescent↗

[Monitoring intraoperative awareness. Vegetative signs, isolated forearm technique, electroencephalogram, and acute evoked potentials].

Several methods have been developed to quantify central anaesthetic effects and monitor awareness during general anaesthesia. The most important of these are the PRST score, calculated from changes in blood pressure, heart rate, sweating, and tear production, the isolated forearm technique, where the patient is allowed to move during surgery, the processed electroencephalogram (EEG) and the derived parameters median frequency (MF) and spectral-edge frequency (SEF), and mid-latency auditory evoked potentials (MLAEP). In clinical practice, the application of individual doses of anaesthetics is generally guided by autonomic vegetative clinical signs such as changes in blood pressure, heart rate, sweating, and tear production, quantified as the PRST score. Unfortunately, these parameters are not very reliable with regard to predicting the suppression of consciousness and awareness, especially when high-dose opioids are used in patients with cardiovascular medications and a variety of accompanying diseases. The PRST score probably indicates mainly the autonomic responses to painful stimuli, and seems to be useful in guiding the individual use of analgesics. The isolated forearm technique is a useful test of the patient's responsiveness during general anaesthesia, and thus an instrument for investigating the incidence of awareness during different anaesthetic regimens and when muscle relaxants are employed. A disadvantage is that it can only be used for 20 to 30 min because of pressure-induced nerve blocks or lesions. It can not be employed when long-term relaxation is necessary and consciousness and awareness are to be monitored continuously. The processed EEG and the derived parameters MF and SEF are important scientific tools to quantify central effects of many anaesthetics and opioid analgesics that allow the development of pharmacodynamic-pharmacokinetic models of anaesthetic action. MF has proven to be useful in monitoring closed-loop feedback of intravenous drug administration. Unfortunately, until now there have been no clinical studies that document the usefulness of MF or SEF with regard to predicting intraoperative arousal or awareness. To the contrary, some experimental data failed to predict imminent arousal and response to surgical incision or verbal commands by MF or SEF. Therefore, the EEG seems to be of limited value for monitoring awareness, consciousness, or memory formation during anaesthesia. MLAEP are suppressed in a dose-dependent fashion by many general anaesthetics and correlate with wakefulness, awareness, and explicit and implicit memory during anaesthesia and seem to be a promising method of monitoring awareness during anaesthesia. Nevertheless, future studies will have to determine threshold values for the different MLAEP parameters for intraoperative awareness and explicit and implicit recall of intraoperatively presented information for the different commonly used anaesthetics. Only then will it be possible to determine the usefulness of the method in clinical practice.

Anesthesia, General↗

[Thromboembolism prevention with low dose heparin and spinal anesthesia--a risky combination?].

UNLABELLED: Spinal or intracranial haematoma is a rare but severe complication of spinal/epidural anaesthesia with an incidence of less than 1:100,000. Coagulation defects, traumatic puncture, and anticoagulant drugs are assumed to be risk factors for the development of this kind of haematoma. Whether the risk of bleeding after spinal/epidural anaesthesia is increased by the administration of low-dose heparin (unfractionated or fractionated) for thromboprophylaxis is currently under discussion. METHODS AND RESULTS: A randomised, prospective trial answering this question is not feasible because of the rarity of the complication. As an alternative, we identified all case reports described in the literature to date and analysed them for possible risk factors. In conjunction with spinal/epidural anaesthesia, we found 4 cases of spinal and 2 cases of intracranial haematoma following treatment with unfractionated heparin and 6 cases of spinal haematoma following treatment with different low-molecular-weight (LMW) heparins. In none of these cases could thromboprophylaxis with heparin be identified as the only risk factor for bleeding: in 11 of the 12 cases a difficult or traumatic puncture was described. Eleven patients showed three or more possible risk factors, e.g., coagulation defects, concomitant therapy with other anticoagulant drugs, or anatomic abnormalities. CONCLUSION: We suggest that the development of spinal or intracranial haematoma after spinal/epidural anaesthesia is a multifactorial event. An influence of low-dose heparin prophylaxis as a cofactor cannot wholly be excluded because of the difficulty of studying the problem in a prospective way. The few case reports have to be seen in the context of millions of patients who have received either unfractionated or LMW heparin and lumbar or thoracic regional anaesthesia without any complication. We conclude that low-dose heparin prophylaxis (fractionated or unfractionated) is not a definite contraindication to spinal/epidural anaesthesia. High-risk (ASA III/IV) patients in particular benefit from effective postoperative analgesia achieved by local anaesthetics in combination with effective heparin thromboprophylaxis. Nevertheless, the absolute contraindications for regional anaesthesia must be respected and an individual risk/benefit analysis should be performed for every patient. An adequate time interval between application of heparin and regional anaesthesia or removal of a spinal/epidural catheter, atraumatic puncture technique, and careful neurologic monitoring during the post-operative period can minimise the risk of complications.

Anesthesia, Spinal↗

Quantification of zidovudine and individual zidovudine phosphates in peripheral blood mononuclear cells by a combined isocratic high performance liquid chromatography radioimmunoassay method.

Zidovudine (ZDV, AZT) is the first clinically effective drug licensed for use in the treatment of human immunodeficiency virus (HIV) infection. Activation of ZDV requires phosphorylation to ZDV triphosphate by cellular kinases. It is important, therefore, to determine the intracellular levels of the active form because measurement of ZDV concentrations in plasma have not reflected any direct relationship with activity or toxicity. In this paper a validated assay for the measurement of both ZDV and its three phosphorylated anabolites, ZDV mono-, di- and triphosphate, in peripheral blood mononuclear cells (PBMCs) is described. The method consisted of a combination of isocratic high performance liquid chromatography (HPLC) separation and radioimmunoassay (RIA). The PBMCs were separated from whole blood and ZDV and ZDV nucleotides were extracted and separated by isocratic elution with an ion-pairing mobile phase on a reversed-phase HPLC column. The collected ZDV and individual ZDV nucleotide fractions were dephosphorylated to ZDV, cleaned by solid phase extraction and assayed by a commercially available RIA kit. The assay developed was successfully used to determine intracellular ZDV and anabolite concentrations of 10 PBMC samples taken from HIV positive patients on ZDV treatment.

Antiviral Agents↗

Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism.

The effects of total parenteral nutrition (TPN) versus enteral nutrition (TEN) were studied in 34 patients following major neurosurgery. Measurements were made of resting energy expenditure (REE), urea production rate (UPR), visceral proteins, parameters of liver and pancreas function, as well as gastrointestinal absorption. To predict nutritional status, nutritional index (NI) was calculated. UPR revealed no significant differences between the groups. After 12 days of TEN, however, synthesis of visceral proteins increased significantly. In addition, NI improved after TEN (p < 0.05), whereas it remained unchanged after TPN. Thrombocyte and lymphocyte counts rose predominately during enteral nutrition. Only in the TEN group was REE increased by 18% and Glasgow Coma Scale (GCS) enhanced from Day 6 on. Exogenous insulin demand was enhanced in the parenterally fed group, and bilirubin (p < 0.05), amylase (p < 0.05), and lipase (p < 0.01) rose significantly, as did gamma-glutamyl-transferase (p < 0.0005) and alkaline phosphatase (p < 0.0005). After 12 d of TPN, vitamin A absorption was significantly attenuated, indicating reduced fat absorption compared to TEN. Carbohydrate absorption did not show significant changes between the groups. Only during TPN did mean values of xylose absorption remain below the normal range. Therefore, enteral nutrition following neurosurgical procedures is associated with an accelerated normalization of nutritional status and an improved substrate tolerance. TEN opposes early postoperative absorption disturbances of the small intestine.

Absorption↗

Zidovudine phosphorylation after short-term and long-term therapy with zidovudine in patients infected with the human immunodeficiency virus.

BACKGROUND: Resistance of human immunodeficiency virus (HIV) to zidovudine (AZT) has been associated with mutations in the viral reverse transcriptase gene. However, recent studies suggest that host cellular factors such as a decreased thymidine kinase activity or an increased cellular P-glycoprotein expression may be important. This study compared concentrations of zidovudine monophosphate, zidovudine diphosphate, and zidovudine triphosphate with P-glycoprotein expression in peripheral blood mononuclear cells from patients receiving long-term (> 18 months) and short-term (< 2 months) zidovudine treatment. METHODS: Ten subjects in the short-term group and 11 subjects in the long-term group with CD4 counts between 300 and 500 received a single oral dose of zidovudine (200 mg) after a 24-hour washout period. Blood samples were collected at 0, 1, 2, 4, and 6 hours. Intracellular nucleotide concentrations were measured by a combined HPLC-radioimmunoassay method, and P-glycoprotein expression was determined by fluorescence activated cell sorting (FACS) analysis with use of the monoclonal mouse antibody MRK-16. RESULTS: Zidovudine monophosphate was the predominant compound, accounting for 73.4% +/- 7.1% (SD) of the total phosphates in the long-term treatment group and 74.2% +/- 15.0% (SD) in the short-term group. Zidovudine diphosphate accounted for 13.3% +/- 3.3% (SD) in the long-term group and 12.5% +/- 6.6% (SD) in the short-term group. Zidovudine triphosphate accounted for 13.4% +/- 4.1% (SD) in the long-term group and 13.5% +/- 8.3% (SD) in the short-term group. Mean peak concentrations for the active zidovudine triphosphate were 0.04 +/- 0.02 (SD) pmol/10(6) cells in both groups. Comparison of the individual zidovudine phosphate concentrations and P-glycoprotein expression revealed no significant difference in the two patient populations. CONCLUSIONS: These data suggest that intracellular phosphorylation does not change over time and that zidovudine does not select for P-glycoprotein expressing cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Dysarthric disorders associated with the neuroleptic malignant syndrome.

There have been two reported cases of neuroleptic malignant syndrome (NMS) in combination with dysarthric disorders. In both cases the NMS was phenomenologically related to the malignant dopamine withdrawal syndrome and to the akinetic crisis of parkinsonism. The reported dysarthric disorders are to be interpreted as a differential-diagnostic sign of the exclusion of a permicious catatonia.

Dysarthria↗

Perioperative mucosal pH and splanchnic endotoxin concentration in orthotopic liver transplantation.

Although impairment of splanchnic perfusion may induce mucosal hypoxia and endotoxaemia during orthotopic liver transplantation (OLT), little is known about the changes in mucosal oxygenation during and after the procedure. To study the effects of liver surgery itself on mucosal pH (pHi) and the response of pHi to acute changes in portal flow, we measured gastric pHi during six liver resections using tonometry: in two patients, after clamping of the hepatoduodenal ligament, pHi decreased within 30 min and recovered promptly after reperfusion. We then investigated gastric and sigmoid pHi (pHig, pHis) during the perioperative phase in 18 OLT. Median pHi values were low before surgery (pHig 7.28 (first/third quartiles 7.22/7.34); pHis 7.27 (7.12/7.36)). Although global oxygen delivery and haemodynamic variables remained constant and veno-venous bypass (VVB) was used to maintain portal flow, pHi declined during the anhepatic phase (pHig 7.19 (7.13/7.23), P < 0.01; pHis 7.13 (7.06/7.24), P < 0.05). After reperfusion of the graft, pHi recovered and did not differ from baseline values by the end of OLT. After operation pHig increased further, reaching the highest values 30 h after ICU admission (7.34 (7.26/7.38)). In the intraoperative period, no significant endotoxaemia was observed either in portal or systemic blood. The maximum reduction in pHi was related neither to the duration of VVB and OLT nor to the number of red cell units transfused. pHi after reperfusion did not correlate with graft viability or dysfunction of the lung or kidney. We conclude that pHi indicates mucosal ischaemia during OLT which is not necessarily associated with endotoxaemia, and intraoperative pHi monitoring does not appear to be a valuable predictor of postoperative graft failure and organ dysfunction.

Adult↗

Spectral edge frequency of the electroencephalogram to monitor "depth" of anaesthesia with isoflurane or propofol.

To determine threshold values, sensitivity and specificity of the spectral edge frequency (SEF) of the electroencephalogram (EEG) that indicate intraoperative movements, we studied 49 patients undergoing, elective laparotomy. Extradural analgesia was used in all patients. To maintain general anaesthesia, patients in group 1 (n = 23) received 0.4-1.2 vol% isoflurane and patients in group 2 (n = 24) propofol 3-5 mg kg-1 h-1 i.v. During operation and emergence from anaesthesia, spontaneous purposeful movements were documented. The EEG was recorded continuously in the awake state until the end of anaesthesia. Power spectral analysis calculated the SEF and power in the delta, theta, alpha and beta bands and the delta ratio. Adequate anaesthesia caused a statistically significant decrease in SEF from 16 to 12 Hz. Power in the beta band decreased and power in the theta band and total power increased compared with the awake state. Before and during movements observed in the intraoperative period or during emergence from general anaesthesia, SEF increased from 12 to 18 Hz, the power in beta band increased and theta power decreased compared with the state of adequate anaesthesia. A threshold value of SEF 14 Hz to predict movements during anaesthesia had a sensitivity of 72% and specificity of 82%.

Adult↗

A deletion in the alpha subunit locks platelet integrin alpha IIb beta 3 into a high affinity state.

The integrin alpha IIb beta 3 (GPIIb/IIIa) mediates platelet aggregation by a change in affinity for the ligand fibrinogen. The amino acids 991-995 (GFFKR) at the NH2-terminus of the cytoplasmic domain are highly conserved in all known integrin alpha subunits. We postulated that the GFFKR-region is important for the inside-out signal transduction and has an influence on the affinity state of integrins. To test this hypothesis, a mutant with a deletion in the GFFKR region was designed. The DNA-constructs were constructed by PCR, sequenced, cotransfected with the beta 3 subunit into CHO cells and cell surface expression was proven with immunoprecipitation and flow cytometry. The GFFKR-deletion mutant demonstrated a high affinity binding of the mAb PAC-1 and I125-labeled fibrinogen. The metabolic inhibitors 2-deoxyglucose and NaN3 did not change the affinity state of the deleted receptor. Neither did the truncation of the cytoplasmic domain of the beta 3 subunit. Additionally, expression of the deleted integrin in the erythropoetic cell line K562 revealed a high affinity state. A deletion of the GFFKR-region in the cytoplasmic domain of the alpha subunit locks integrin alpha IIb beta 3 in a high affinity state. This is an intrinsic property of the deleted receptor since there is no energy dependence and no cell type specifity. Thus, the GFFKR-region is involved in inside-out signaling in alpha IIb beta 3. Furthermore, cell lines expressing this activated alpha IIb beta 3 integrin may be used as models for activated platelets.

Amino Acid Sequence↗

Midlatency auditory evoked potentials during anaesthesia with increasing endexpiratory concentrations of desflurane.

BACKGROUND: Under general anaesthesia with the volatile anaesthetics halothane, enflurane and isoflurane, midlatency auditory evoked potentials (MLAEP) are suppressed dose-dependently. Therefore, MLAEP have been used to measure depth of anaesthesia and to indicate intraoperative awareness. Desflurane is a new volatile anaesthetic and its effect on MLAEP have not been studied previously. METHODS: We have studied MLAEP during general anaesthesia with increasing endexpiratory concentrations of desflurane in 12 patients scheduled for elective gynaecological surgery. Auditory evoked potentials were recorded in the awake state and during anaesthesia with endexpiratory steady state concentrations of 1.5, 3.0, 4.5 and 6.0 vol % of desflurane on vertex (positive) and mastoids on both sides (negative). Latencies of the peaks V, Na, Pa, Nb, Pl (ms) and amplitudes Na/Pa, Pa/Nb and Nb/Pl (micro V) were measured. RESULTS: In the awake state, MLAEP had high peak-to-peak amplitudes and a periodic waveform. During general anaesthesia with increasing endexpiratory concentration of desflurane, the latency of the brainstem response V increased only slightly. In contrast, MLAEP showed a marked dose-dependent and statistically significant increase in latencies of Na, Pa, Nb and Pl and decrease in amplitudes of Na/Pa, Pa/Nb and Nb/Pl. Under 6.0 vol % of desflurane MLAEP were severely attenuated or even abolished. CONCLUSION: Based on these observations, endexpiratory concentrations of > or = 4.5 vol % desflurane should suppress awareness phenomena such as auditory perceptions during anaesthesia.

Adult↗

Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome.

Inhalation of nitric oxide (NO) and prostacyclin (PGI2) may induce selective pulmonary vasodilation and-by improving ventilation-perfusion ratio in ventilated areas of the lung-increase Pao2 in patients with acute lung injury. To assess the therapeutic efficacy of both compounds, dose-response curves were established in patients with adult respiratory distress syndrome (ARDS). Patients received both PGI2 (doses of 1, 10, and 25 ng/kg/min) and NO (concentrations of 1, 4, and 8 ppm). Cardiorespiratory parameters were assessed at control, at each drug concentration, and after withdrawal of NO and PGI2. PGI2 resulted in a significant, dose-dependent and selective reduction of pulmonary artery pressure (PAP) from 35.1 +/- 6.3 mm Hg at control to 33.1 +/- 4.8 (1 ng/kg/min), 31.3 +/- 4.8 mm Hg (10 ng/kg/min) and 29.6 +/- 4.5 mm Hg (25 ng/kg/min), respectively. Inhaled NO reduced PAP from 34.5 +/- 5.6 to 32.1 +/- 5.9 mm Hg at 4 ppm, and to 31.8 +/- 6.1 mm Hg at 8 ppm, respectively, with no effect at 1 ppm. Pao2/Flo2 ratio increased from 105 +/- 37 to 125 +/- 56 mm Hg (range of increase: 0 to 57 mm Hg) at PGI2 10 ng/kg/min and to 131 +/- 63 mm Hg (range: -5 to 89 mm Hg) at 25 ng/kg/min with no effect at 1 ng/kg/min. NO improved Pao2 (e.g., from 116 +/- 47 to 167 +/- 86 mm Hg at 8 ppm) and reduced intrapulmonary shunt at all doses tested. We conclude that both inhaled PGI2 and NO may induce selective pulmonary vasodilation and increase Pao2 in severe ARDS.

APACHE↗

[Fluoride-induced nephrotoxicity: factor fiction?].

In the 1960s, the widespread use of the inhalational anaesthetic methoxyflurane was associated with a significant occurrence of postoperative renal dysfunction. This was attributed to hepatic biotransformation of methoxyflurane and subsequent release of inorganic fluoride ions into the circulation. Based upon the clinical experience with methoxyflurane, serum fluoride concentrations exceeding 50 mumol/l were considered to be nephrotoxic. Without further reevaluation, this 50 mumol/l threshold was subsequently applied to other fluorinated anaesthetics as well. Enflurane and even isoflurane may, when used during prolonged operations, also yield anorganic fluoride levels in excess of 50 mumol/l. Nevertheless, no cases of renal dysfunction attributable to prolonged use of these anesthetics have been reported. About 4% of the new inhalational anaesthetic sevoflurane is metabolized, and fluoride concentrations exceeding those after enflurane are frequently measured. Numerous studies have examined the nephrotoxic potential of sevoflurane degradation products. However, fluoride-related toxicity has been observed neither in animal nor in clinical studies, including prolonged administration and patients with pre-existing renal disease. New insights into the intrarenal metabolisation of volatile anaesthetics may well explain the absence of nephrotoxicity after sevoflurane. The threshold for fluoride nephrotoxicity of 50 mumol/l, still given in many medical text-books, can no longer be applied as an indicator of nephrotoxicity after isoflurane, enflurane or sevoflurane. Therefore, the elevated serum fluoride concentrations consistently recorded following anaesthesia with sevoflurane are devoid of clinical significance.

Anesthetics, Inhalation↗

[Intraoperative awareness and auditory evoked potentials].

Midlatency auditory evoked potentials (MLAEP) are suppressed dose-dependently during anaesthesia with a variety of general anaesthetics. Therefore, MLAEP have been proposed to measure depth of anaesthesia and to indicate intraoperative awareness. Several studies give evidence of a close relationship between MLAEP and motor signs of wakefulness, intraoperative awareness, and explicit and implicit memory functions during general anaesthesia. Summarising these data, one may conclude that there is a close hierarchical relation between cognitive function, memory and wakefulness during anaesthesia, and MLAEP latencies. A short Nb latency below 45 ms is consistent with conscious awareness and unimpaired memory function with explicit recall and adequate response to commands. When Nb latency increases to 45-50 ms, it may be associated with conscious awareness. Patients still respond to commands, but memory formation is impaired and explicit recall is lost. A further increase of Nb latencies seems to be consistent with unconscious awareness, characterised by implicit memory of intraoperative events; 60 ms seems to be the threshold value for motor signs of wakefulness during anaesthesia. With a further increase of MLAEP latency during anaesthesia, conscious awareness and memory formation, explicit and implicit recall, response to commands, and spontaneous purposeful movements during anaesthesia are blocked. The new volatile anaesthetic sevoflurane leads to a dose-dependent increase in MLAEP peak latencies and a decrease in MLAEP amplitudes. At about 1.5 vol.% end-expiratory sevoflurane concentration, MLAEP are significantly suppressed and Nb latency is in the range of 68-80 ms. Therefore, from the present data and those from the literature, one may expect that sevoflurane at concentrations greater than 1.5 vol.% for general anaesthesia would be able to suppress awareness phenomena such as purposeful movements, auditory perception, intraoperative wakefulness and awareness, memory formation, and explicit and implicit recall of intraoperative events.

Anesthetics, Inhalation↗

Investigating the origin of cyclic changes in limb volume using mercury-in-silastic strain gauge plethysmography in man.

1. Vasomotion, a phenomen frequently observed in skeletal muscle microcirculation, has been observed under physiological conditions and found enhanced during critical reduction of tissue perfusion due to hypoxic hypoxia, haemorrhage and local hypotension. We used a computer assisted non-invasive plethysmographic method to investigate periodic changes of limb volume (volumotion), which we previously found in critically ill patients. The current study was designed to investigate the origin of volumotion. 2. Simultaneous recordings of limb circumference of both calves were obtained. In patients with peripheral vascular disease and patients with minor surgery the cross-correlation with spontaneous breathing was investigated. In patients who had undergone major abdominal or vascular surgery we analysed for cross-correlations between MSG plethysmography signals of both legs and changes in central venous, arterial and ventilation pressures. In this group the effects of positive-pressure ventilation and positive end-expiratory pressure (PEEP) were also studied. 3. No ventilation-related volumotion was observed during spontaneous breathing. During positive-pressure ventilation a ventilation-related peak was found in the Fourier transform in agreement with the ventilation frequency applied. The amplitude of ventilation-related volumotion decreased significantly after a pressure cuff applied to the thigh was inflated above central venous pressure. We observed a significant increase in the amplitude of ventilation-related volumotion when PEEP was applied. 4. Ventilation-related volumotion showed significant cross-correlation between both legs. Slow wave volumotion (0.5-7 cycles min-1) was frequently observed, but always appeared unilaterally. Whilst we looked for correlations between slow wave volumotion and changes in central venous pressure and arterial blood pressure, respectively, significant cross-correlation with the MSG plethysmography recordings was only observed at the frequency of the positive-pressure ventilation. 5. The fact that periodic changes of limb circumference matching the frequency of the positive-pressure ventilation were detectable with the MSG plethysmography system demonstrates that small volume changes (less than 0.02 ml (100 ml tissue)-1) can be assessed using this system. As slow wave volumotion was observed unilaterally and revealed no correlation either with breathing, ventilation or arterial and central venous pressure, we suggest that slow wave volumotion is a local event most likely reflecting arteriolar vasomotion.

Aged↗

Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction.

The integrin alpha L beta 2 (leukocyte function-associated molecule 1, CD11a/CD18) mediates activation-dependent adhesion of leukocytes. The cytoplasmic domains of alpha L beta 2 have been demonstrated to modulate adhesiveness of alpha L beta 2. Affinity changes of alpha L beta 2 for its ligand or postreceptor events can be responsible for this modulation of adhesiveness. To investigate the possible role of the alpha L beta 2 cytoplasmic domains in postreceptor events we constructed cDNA encoding chimeric proteins with intracellular alpha L beta 2 domains, which are responsible for alpha L beta 2 specific intracellular interactions, and extracellular alpha IIIb beta 3 (GP IIb/IIIa) domains, which allow the assessment of the receptor affinity state. The cDNA was stably transfected in Chinese hamster ovary cells and chimeric heterodimer formation proven by immunoprecipitations and flow cytometry. The chimeric receptors mediate adhesion to immobilized fibrinogen, and this adhesion is increased by phorbol myristate acetate and abolished by cytochalasin D. However, neither treatment affects the affinity state of the chimeric receptor, suggesting involvement of the cytoskeleton in the regulation of alpha L beta 2 mediated cell adhesion. To exclude the possibility of postoccupancy affinity changes of the chimeric receptors, we locked the receptors into a high affinity state by creating a deletion variant. The region deleted (VGFFK) is highly conserved in integrin alpha subunit cytoplasmic domains. Cotransfection of this deletion variant with a beta subunit truncation (beta 3 delta 724) and a triple mutation at 758-760 (TTT to AAA) of beta 2 abolishes adhesion without changing the affinity state. A single mutation (TTT to TAT) reduces adhesion by half without affinity change. Scanning electron microscopy reveals impaired spreading of these truncated/mutated chimeras. Immunofluorescence microscopy demonstrates a correlation between impaired adhesion and a decrease in the ability to form focal adhesions and to organize the cytoskeleton into stress fibers. These results describe the integrin/cytoskeleton interaction, the organization of the cytoskeleton, and cell spreading as postreceptor events modulating alpha L beta 2 cytoplasmic domain mediated cell adhesion. Furthermore, we demonstrate that the cytoplasmic domain of the beta 2 subunit, and within it the TTT region, are required for these postreceptor events. Additionally, we present a new approach, using deletion variants to lock integrins in a high affinity state without interfering with the investigated integrin/cytoskeleton interaction. This approach may be generally useful to investigate the role of postreceptor events in integrin-mediated cell adhesion and migration.

Amino Acid Sequence↗

Oral and intravenous zidovudine pharmacokinetics: the effect of granulocyte-macrophage colony stimulating factor.

Combination therapy with zidovudine and recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) may be warranted, owing to the bone marrow suppressive effects of zidovudine. A study of 16 patients, 8 of whom had acquired immune deficiency syndrome (AIDS) and 8 of whom were infected with human immunodeficiency virus (HIV) but were asymptomatic, was conducted. The effect of 4 days of rHU GM-CSF versus placebo on intermittent zidovudine therapy (200 mg every 8 hours) was evaluated using a randomized, cross-over study design. Pharmacokinetics of oral and intravenous zidovudine were determined on days 1 (oral), 3 (oral), and 4 (intravenous) of rHu-GM-CSF (placebo) administration. After intravenous dosing, zidovudine plasma clearance for placebo and rHu GM-CSF averaged 1.4 +/- 0.2 and 1.3 +/- 0.2 L/hr/kg, respectively (P = 0.017), mean residence time averaged 1.5 +/- 0.5 and 1.9 +/- 0.6 hours, respectively (P = 0.012), and the steady-state volume of distribution was 2.0 +/- 0.7 and 2.3 +/- 0.7 L/kg, respectively (P = 0.027) for the two treatment arms. Stratified data for patients with AIDS and those with asymptomatic HIV infection revealed no significant difference in plasma clearance or mean residence time between the two patient groups. These pharmacokinetic results indicate that dosage adjustments for zidovudine are not warranted when administered with rHu GM-CSF owing to the small changes observed. However, the statistically significant increase in Vss suggests the possibility of enhanced zidovudine cellular uptake in the presence of rHu GM-CSF.

Acquired Immunodeficiency Syndrome↗