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Biomedical subjects

D E Uehlinger

Publications and source records attributed to D E Uehlinger.

At least 19 recordsLinked to original sources
PubMed2006

The prevalence of penicillin-non-susceptible Streptococcus pneumoniae among children aged < 5 years correlates with the biannual epidemic activity of respiratory syncytial virus.

This study investigated whether the epidemiology of penicillin-non-susceptible pneumococci (PNSP) colonising small children correlated with the biannual epidemic activity of respiratory syncytial virus (RSV). Colonisation rates and the prevalence of PNSP among paediatric outpatients aged < 5 years was analysed between January 1998 and September 2003 using an established national surveillance network. Resistance trends were investigated using time-series analysis to assess the correlation with the biannual pattern of RSV infections and national sales of oral paediatric formulations of antibiotics and antibiotic prescriptions to children aged < 5 years for acute respiratory tract infections. PNSP rates exhibited a biannual cycle in phase with the biannual seasonal RSV epidemics (p < 0.05). Resistance rates were higher during the winter seasons of 1998-1999 (20.1%), 2000-2001 (16.0%) and 2002-2003 (19.1%), compared with the winter seasons of 1997-1998 (8.2%), 1999-2000 (11.6%) and 2001-2002 (9.5%). Antibiotic sales and prescriptions showed regular peaks during each winter, with no significant correlation with the biannual pattern of RSV activity and seasonal trends of PNSP. RSV is an important determinant of the spread of PNSP and must be considered in strategies aimed at antimicrobial resistance control.

Anti-Bacterial Agents↗
PubMed2002

DNR orders at a tertiary care hospital--are they appropriate?

QUESTIONS UNDER STUDY: There are no established recommendations in Switzerland on when, how and for what patients DNR orders should be written. Moreover, little is known about current attitudes, patients' preferences, patients' involvement in decision-making and the adequacy of such decisions. The study was conducted in a Swiss tertiary care hospital to investigate the epidemiology, manner of application and appropriateness of DNR orders. METHODS: We performed retrospective chart review of all patients admitted to the department of general internal medicine of a Swiss tertiary care university hospital during four randomly selected months of the year 1998 (group 1) as well as of all patients who died in the department during 1998 (group 2). We assessed the frequency of DNR orders on admission and before death, their association with age, sex, diagnostic category, comorbidity and physical/social dependence, and the frequency of patient and/or family involvement in decision-making. RESULTS: On admission, a DNR order was written for 15% of all hospitalised patients and 54% of the patients dying during the observation period; 93% of patients ultimately dying were the subject of DNR orders before death. There was a significant association between DNR orders and patients' age (p <0.001), physical and/or social dependence (p <0.001) and the admission diagnoses malignancy (p <0.001) or acute stroke (p <0.005). Cardiovascular disease was in inverse ratio to DNR orders (p <0.001). Only 6% of either patients or families were reportedly involved in decisions in the overall group, whereas this was the case in 58% of patients who died in hospital. CONCLUSIONS: The frequency of DNR orders on admission was rather high. Referring to pre-arrest morbidity, DNR orders were often inappropriate on hospital admission but usually became so during hospital stay. After exclusion of confounding factors, age was the main independent factor for DNR orders. Patient and/or surrogate involvement in decision-making for DNR orders was low, thereby raising important ethical issues such as patient autonomy. An urgent national discussion on the topic is needed.

Adult↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

Body mass index: a measure for longevity.

Body mass index has important predictive value for mortality and morbidity both in normal subjects and in those suffering from particular pathologies. However, body mass index was introduced as a measure of body fat, which might not be expected to have such wide implications for various pathological conditions. We argue here that body mass index may actually be a measure for longevity. Our arguments are based on a well-established allometric scaling law for physiological time. The time between heart beats, the time between respirations, and longevity all scale as body weight to the 1/4 power in mammalian species ranging from shrews to blue whales. We find that body mass index also scales with body weight to the 1/4 power in humans from birth to one year of age, and again from approximately 5 to 17 years of age. On the assumption that in these two growth phases humans scale as do species, we postulate that body mass index is a measure of longevity.

Biological Evolution↗
PubMed2000

Novel dialysis cannulas: are they worth the higher price tag?

Accessory hemodialysis equipment, including dialysis cannulas, usually lack controlled and independent testing before being introduced onto the market. The aim of this study is a prospective comparison of a newly designed curved-tip dialysis cannula with a standard dialysis cannula of the same size from the same manufacturer. Fifteen chronic dialysis patients were enrolled onto a prospective 4-month crossover study. All patients had arteriovenous fistulas, except for two patients with polytetrafluoroethylene grafts. The routinely used standard cannulas were replaced by either a curved-tip 15G cannula or a new standard 15G cannula from the same manufacturer. The two cannulas were compared with respect to puncture-related pain and/or problems and bleeding complications, as well as blood-flow dynamics. Venous and arterial access pressures were recorded at blood-flow rates of 100 to 400 mL/min. Linear regression analyses of arterial and venous pressure profiles showed the same regression lines for the standard and curved-tip cannulas. Plasma haptoglobulin levels and occlusion times necessary to stop bleeding after removal of the cannulas did not differ between the two cannulas. Both patients and nurses independently reported equal puncture-related pain and/or problems for both cannulas on visual analogue scales. No correlation was found between puncture problems reported by nurses and puncture pain reported by patients. The curved-tip cannula does not offer an advantage compared with the less expensive standard cannula. Controlled testing of advertised advantages by manufacturers of accessory equipment should be a prerequisite before introduction into routine clinical treatment.

Adult↗
PubMed2000

[Which hypertensive patient requires diuretic therapy?].

Over the last decade the role of diuretics as first-line agents for the treatment of hypertension has diminished substantially. The present review encourages the reader to reconsider the current trend for a decline in the use of these inexpensive antihypertensive drugs whose efficacy is well documented. Diuretics have been used in 16 placebo controlled studies with over 13,000 patients as first-line drugs to lower blood pressure. These drugs were shown to reduce total mortality by 11%, cerebrovascular events by 34% and coronary morbidity by 29%. The magnitude of blood pressure reduction with low-dose thiazide diuretics is comparable to that of a therapy with high-dose thiazides, without the serious metabolic side effects observed with the higher dosage. In combination with other antihypertensive agents, diuretics counteract the compensatory regulatory responses, such as volume expansion and edema formation. Moreover, it has been shown that a combination with low-dose thiazides may not only further decrease blood pressure but also reduce cerebrovascular and coronary mortality. Advantages of diuretics in the treatment of hypertension can be appreciated in special clinical conditions, for instance in patients with edema, heart failure, renal failure, nephrotic syndrome and portal hypertension. Low-dose diuretics still have a place as first-line drugs for the treatment of mild, uncomplicated essential hypertension. Moreover, as opposed to other blood pressure lowering agents, there is sufficient scientific evidence for the primary preventive effect of low-dose thiazide.

Antihypertensive Agents↗
PubMed1999

Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis.

AIMS: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD). METHODS: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days. RESULTS: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session. CONCLUSIONS: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.

Adult↗
PubMed1998

Urea kinetics and dialysis treatment time predict vancomycin elimination during high-flux hemodialysis.

BACKGROUND: Hemodialysis sessions with high-flux filters ask for a reconsideration of the kinetics of xenobiotics. The aim of this study was to analyze whether individual high-flux hemodialysis treatment parameters are of predictive value for dosing guidelines, with use of vancomycin as a model compound. METHODS: Twenty-six patients receiving high-flux hemodialysis were studied prospectively. After an intravenous infusion of 1000 mg or 500 mg vancomycin, respectively, six to eight blood samples were collected within a period of 5 to 9 days, including one hemodialysis session. Serum vancomycin concentrations were measured by HPLC. Nonlinear mixed-effects modeling (NONMEM) was used to fit a two-compartment population pharmacokinetic model to the data of 20 patients; the data of the remaining six patients (group II) were used for a prospective evaluation of the model. RESULTS: A linear relationship was found between vancomycin filter clearance (CLDV) and urea filter clearance (CLDBUN), derived from Kt/V (the product of urea clearance [K] and dialysis treatment time [t], standardized for the urea volume of distribution [V]). Mean (coefficient of variation) steady-state volume of distribution was 1.05 L/kg (22%), CLDV was 0.336.CLDBUN (13%), and residual interdialytic clearance was 2.25 ml/min (90%) in patients with creatinine clearance values (CLCR) below 2 ml/min and 2.25 ml/min + 0.59.CLCR (32%) in patients with CLCR values above 2 ml/min. The model predicted predialysis vancomycin concentrations before the first and the second postinfusion dialysis session in the six patients of group II, with a deviation of 1.8 +/- 1.0 mg/L and 0.8 +/- 0.5 mg/L, respectively. CONCLUSION: The described population pharmacokinetic model allows individualization of vancomycin dosing intervals in patients receiving hemodialysis, based on patient characteristics and urea kinetic modeling.

Adult↗
PubMed1997

Clinical outcome relative to the dose of dialysis is not what you think: the fallacy of the mean.

Several recent retrospective studies of mortality relative to the dose of dialysis have been widely interpreted to indicate that adequate thrice-weekly hemodialysis requires a single pool Kt/V (spKt/V) of at least 1.4 to 1.6 and higher. In these studies, mortality rate has been correlated to the mean delivered spKt/V, (spKt/Vd)m, with coefficient of variation (CV) on the means ranging up to 45%. To evaluate these reported relationships, two large databases were analyzed using population constants to transform urea reduction ratio and spKt/Vd to equilibrated Kt/Vd (eKt/Vd), which expresses dose corrected for treatment time. The eKt/V dose (D) values were correlated to the reported relative risks (RR) of mortality to derive a RR/D function. The RR/D function, derived from these data with stepwise linear regression analysis, is nonlinear, with a steep linear increase in RR for eKt/Vd less than 1.05 and constant RR for eKt/Vd > or = 1.05. This RR/D function is mathematically expressed as RR = 1.96 - 1.03(eKt/Vd) (equation 1) when 0.50 < or = eKt/Vd < or = 1.05, and RR = 0.88 (equation 2) when eKt/V > or = 1.05. We show that regression of RR on (eKt/Vd)m with large CV results in overestimation of RR relative to eKt/Vd for individual patients because of extrapolation of the linear relationship beyond the threshold where the slope becomes zero (see equation 2 above). It is concluded that (1) current clinical data indicate that adequate dialysis is provided with eKt/Vd of 1.0 to 1.1 on a thrice-weekly schedule, (2) it is essential to assure that all patients achieve this level of therapy, which is best accomplished using urea kinetic modeling for both prescription and measurement of delivered eKt/Vd, and (3) the current HEMO study is well designed to determine whether higher levels of eKt/Vd will further improve clinical outcome.

Female↗
PubMed1996

Pharmacokinetics of fleroxacin after multiple oral dosing in patients receiving regular hemodialysis.

The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.

Administration, Oral↗
PubMed1996

Another look at the relationship between protein intake and dialysis dose.

It seems reasonable to postulate that an observed relationship between dialysis dose and protein intake reflects improved nutrition with correction of uremic symptoms. This article demonstrates a purely statistical association between the two parameters--protein intake, expressed as normalized protein catabolic rate (NPCR), and dialysis dose quantified as KT/V [the product of urea clearance (K) and treatment time (T) divided by the distribution volume of urea (V)] in peritoneal dialysis. The use of random samples from independent normal distributions of K, V, and urea generation rate (G) for the calculation of KT/V and NPCR reveals that a statistical association is introduced when both protein intake and dialysis dose are normalized proportional to a common distribution V. Not the normalizing parameter V per se, but rather the variability of V accounts for the introduction of this statistical artifact.

Dietary Proteins↗
PubMed1996

Acute cyclosporine-induced nephrotoxicity in renal transplant recipients: the role of the transplanted kidney.

Cyclosporine A causes an acute reduction in GFR. The interindividual variable reduction in GFR is most likely the result of arteriolar vasoconstriction. Vasoconstriction is attributable either to a local effect of cyclosporine on renal blood vessels (intrinsic mechanism) or to a systemic effect of cyclosporine on circulating and/or neuronal factors (extrinsic mechanism). The aim of the investigation presented here was to establish whether intrinsic or extrinsic mechanisms account for the interindividual differences in the susceptibility to acute cyclosporine-induced nephrotoxicity. For that purpose, this study took advantage of the clinical transplant situation in which two (intrinsically identical) kidneys from a cadaveric donor are transplanted into two (extrinsically) different subjects. The preexisting regular daily cyclosporine doses were raised by 25% for 2 wk and by 50% for another 2 wk in 16 patients with stable renal graft function, representing eight pairs of patients, each of whom had received kidneys from the same donor. In these patients, a mean (+/- SD) maximum cyclosporine-induced increase in serum creatinine concentration of 13 +/- 11% (P < 0.001) and in serum BUN of 27 +/- 33% (P < 0.01), together with a decline in the fractional uric acid excretion of 51 +/- 89% (P < 0.02) were observed. The percentage change in serum creatinine concentrations after increased dosing of cyclosporine paralleled within the subjects receiving their kidneys from the same donor, i.e., when one recipient experienced a large percentage of change after increases of cyclosporine dosing, the corresponding recipient of a kidney from the same donor had a change of the same magnitude. Seven of eight pairs showed a consistent response with respect to a clinically significant increase in serum creatinine concentration of > 15%, with a consistent response purely by chance being < 5%. Thus, the transplanted kidney itself rather than the recipient determines the susceptibility to acute cyclosporine-induced nephrotoxicity.

Acute Kidney Injury↗
PubMed1996

Haemodialysis activates phospholipase A2 enzyme.

BACKGROUND: Clinical and experimental evidence suggest that haemodialysis (HD) procedure is an inflammatory process. For the production of proinflammatory lipid mediators in many inflammatory reactions, the release of arachidonic acid by phospholipase A2 (PLA2) enzyme is a prerequisite. Therefore, the purpose of the present investigation was to establish whether the activity of PLA2 increases during HD and whether the increase depends on the type of dialyser used. METHODS: We performed dialysis in eight chronic HD patients. Blood samples entering and leaving the dialyser were obtained before and at 15, 60, 120 and 180 min after the dialysis was started, on one occasion using a cuprophane and on another occasion a cellulose triacetate dialyser. PLA2 activity was assessed in crude plasma and in plasma extract. RESULTS: PLA2 activity in plasma extract exhibited similar biochemical properties to that of inflammatory human synovial fluid PLA2 enzyme which is of group II PLA2. PLA2 activity in crude plasma represents a type of PLA2 other than the synovial type. In HD patients, baseline PLA2 activities in a crude plasma and plasma extract were significantly increased when compared to normal subjects. An increase in PLA2 activity was observed in crude plasma with a peak appearing at 15 min when the patients were dialysed with cuprophane and cellulose triacetate membranes. This increase was observed in both arterial and venous blood samples and was more pronounced when the patients were dialysed with cuprophane than with cellulose triacetate membranes. When PLA2 was assessed in plasma extract, the activity increased only with cuprophane but not with cellulose triacetate membranes. CONCLUSION: PLA2 activity in plasma is increased in HD patients and increases during the dialysis procedure to a greater extent with a less biocompatible membrane. Continuous activation of PLA2 might be relevant for long-term deleterious consequences of HD.

Adult↗
PubMed1996

Does continuous renal replacement therapy favourably influence the outcome of the patients?

Continuous haemodialysis and continuous haemofiltration are efficient and safe techniques for the treatment of acute renal failure. Theoretical advantages are improved haemodynamic stability and easier fluid removal. All 15 available studies comparing intermittent (522 patients) with continuous (651 patients) renal replacement therapy have been reviewed. From these studies it cannot be established, whether the use of a continuous instead of an intermittent treatment modality improves the outcome in patients with acute renal failure. Reviewing all 67 published studies dealing with continuous renal replacement therapy revealed a trend to a decreasing mortality rate (P<0.08) over the last 11 years, whereas the mean age and the severity of illness of the patients, measured by the APACHE II score, did not change, In order to establish whether the quality of treatment has improved as a function of time, two quality factors (QF) were created, i.e. QF for age (mean age/mean mortality rate of the patients treated) and QF for severity of diseases (mean APACHE II/mean mortality rate). Both QF improved from 1984 until 1994, when analyzed for continuous (P<0.001) or intermittent (P<0.001) treatment modality. Thus the quality of treatment of patients with acute renal failure improved during the last decade. However, there is no evidence with respect to survival rate that a continuous renal replacement therapy is superior to an intermittent one.

Acute Kidney Injury↗
PubMed1995

[Erythropoietin, a milestone in the history of nephrology].

Erythropoietin, a glycoprotein, is synthesized mainly in the kidney. With the destruction of renal tissue, erythropoietin production decreases; this is a major factor in the development of anemia in patients with renal failure. For about ten years now, recombinant human erythropoietin has been available for the treatment of renal anemia. All patients with renal insufficiency, independent of their plan for future renal replacement therapy, may benefit from erythropoietin. At what extent of anemia erythropoietin therapy should be started is still discussed and is certainly dependent on the degree of the patient's impairment by his anemia. Before beginning a therapy with erythropoietin, other forms of anemia observed in patients with renal failure, i.e. mainly iron deficiency, have to be excluded. A strict monitoring of hematocrit during treatment with erythropoietin is mandatory. Hypertension, seizures and cardiovascular complications have been observed with overdosing of erythropoietin. Special emphasis of this review is therefore put on the discussion of the dynamics of the erythropoietin-red cell system.

Anemia, Hypochromic↗
PubMed1993

Epstein-Barr virus infection in HIV-positive patients.

The relationship between Epstein-Barr virus (EBV) viral load in peripheral blood and HIV infection was determined in 103 HIV-infected patients. Epstein-Barr virus was detected by polymerase chain reaction in 75% of the patients, 21% of whom had the more uncommon EBV subtype 2. The highest levels of EBV were found in patients with 100-400 CD4+ cells/mm3 and not in those with more profound immunosuppression. An association was identified between EBV load and HIV proviral levels (p < 0.001), an IgM response to EBV early antigens (p < or = 0.01) and p24 antigenemia (p < 0.01 in patients with > 100 CD4+ cells), but not with other clinical or laboratory parameters. Combinations of different EBV and HIV parameters identified a subgroup of patients with a 2.2- to 4.8-fold risk of > or = 35% decline in CD4+ counts over six months. The association between EBV and HIV markers may reflect a significant pathogenic interaction between the two viruses.

Adult↗
PubMed1992

A pharmacodynamic model of erythropoietin therapy for uremic anemia.

Fifty-seven patients receiving chronic high-flux hemodialysis began receiving recombinant alpha-human erythropoietin (rHuEPO). The mean initial rHuEPO dose used in 54 evaluable patients was 9963 +/- 4364 U/week; the final dose was 8972 +/- 4058 U/week. Treatment over a mean period of 154 +/- 40 days (84 to 224 days) resulted in an average increase in hematocrit from 24.7% +/- 3.7% to 32.5% +/- 4.4%. We present a model for these data that describes changes in hematocrit during rHuEPO therapy and that allows simultaneous estimation of red blood cell lifespan and rHuEPO-induced increases in red blood cell production rate. Analysis of the hematocrit values of the patients with the model, by use of NONMEM, a computer program for analysis of population data, reveals a nonlinear dose-response relationship with large interindividual variability (coefficient of variation) of about 50%. The estimated mean red blood cell lifespan is 64 days, with interindividual variability of about 30% (coefficient of variation). The intraindividual random variability in hematocrit about its prediction is +/- 5% of the prediction. For clinical dose adjustment, we present a method that uses only simple calculations.

Anemia↗