Paclitaxel drug-coated balloon angioplasty for the treatment of failing arteriovenous fistulas: a single-center experience.

Objectives: To report our experience of angioplasty with Lutonix (Bard Peripheral Vascular, Inc., Tempe, AZ) drug-coated balloon (DCB) for the treatment of failing arteriovenous fistulas (AVF).Materials and methods: Retrospective, single-center analysis consisting of 14 patients treated with Lutonix paclitaxel DCBs in the period from July 2015 through April 2017. We analyzed technical success, clinical success, primary patency of the target lesion, primary patency of the dialysis circuit, and the rate of complications. Regular follow-up of AVF patency was realized by clinical examination and duplex ultrasonography. The Kaplan-Meier survival method was applied to determine the cumulative primary patency of the target lesion and the dialysis circuit.Results: Technical success was 100% and clinical success 92.9%. There were no major or minor complications. Cumulative target lesion primary patency after DCB was 69.2% at 6 months and 31.6% at 12 months. Cumulative vascular circuit primary patency was 61.5% at 6 months and 31.6% at 12 months.Conclusion: Compared to results reported in literature with plain old balloon angioplasty (POBA), Lutonix paclitaxel DCB angioplasty proved a short-term patency benefit in treatment of dialysis AVF stenosis.

Effect of whey storage on biogas produced by co-digestion of sewage sludge and whey.

Biogas production from municipal anaerobic digesters could potentially be boosted via co-digestion with organic wastes such as whey. The challenge is that whey production is seasonal. This research examined the effect of storing whey at ambient temperature on: (1) whey composition; (2) biogas production from co-digestion of the stored whey with municipal primary sludge. Whey storage resulted in acidification with formation of acetate, propionate and butyrate and a 9% reduction in total chemical oxygen demand (COD) over the 9-month trial. A control digester fed with primary sludge produced 0.18-0.23 m3 CH4/kgCOD(added). Co-digestion of fresh whey and sludge increased biogas production and the methane contribution from the whey was 0.29 m3CH4/kgCOD(added). When the fresh whey was substituted with stored whey, methane production by the whey remained at 0.29 m3CH4/kgCOD(added). The ability to store whey at ambient temperature and allow co-digestion year round will significantly improve the economics of biogas production from whey.

Enhanced biogas production using cow manure to stabilize co-digestion of whey and primary sludge.

Increasing biogas production from municipal anaerobic digesters via additional loading with industrial/agricultural wastes offers a low-cost, sustainable energy generation option of significant untapped potential. In this work, bench-top reactors were used to mimic a full-scale primary sludge digester operating at an organic loading rate (OLR) of 2.4 kg COD/m3 d and a 20 d hydraulic retention time (HRT). Co-digestion of whey with primary sludge was sustained at a loading rate of 3.2 kg COD/m3 d (17 d HRT) and boosted gas production to 151% compared to primary sludge digestion alone. Addition of chemical alkalinity enabled co-digestion of whey with primary sludge to be maintained at an elevated OLR of 6.4 kg COD/m3 d (11 d HRT) with gas production increased to 208%. However, when the chemical addition was simply replaced by cow manure, stable operation was maintained at OLRs of 5.2-6.9 kg COD/m3 d (11-14 d HRT) with gas production boosted up to 268%.

Thrombotic microangiopathy induced by long-term interferon-ß therapy for multiple sclerosis: a case report.

We report the case of a 53-year-old woman treated for 8 years with Betaferon® (interferon-ß-1b), who developed mild renal failure with hypertension, proteinuria and glomerular hematuria. Kidney biopsy was consistent with thrombotic microangiopathy (TMA). Considering the strong evidence of interferon-α causing TMA and the numerous immunomodulatory activities shared by INF-α and -ß, we incriminated Betaferon as the etiological agent of TMA in our patient. To our knowledge, it is the first time such an association has been published.

Effects of energy delivery via a His bundle catheter during closed chest ablation of the atrioventricular conduction system.

In this paper we summarize our experience and report the characteristics of energy delivery in 23 patients who have undergone closed chest ablation of the normal atrioventricular (AV) conduction system for the treatment of refractory supraventricular arrhythmias. The induction of AV block was achieved by the synchronous delivery of electrical energy with a damped sinusoidal waveform utilizing a standard direct current defibrillator and a standard tripolar His bundle catheter. The procedure was well tolerated, though one patient experienced ventricular fibrillation, which was uneventfully converted with external paddles. Complete AV block was achieved in 20 of 23 patients and all were rendered arrhythmia free, though two still required antiarrhythmic drugs. A stable escape rhythm was seen in all patients with a cycle length of 1,294 +/- 243 ms. Creatine phosphokinase-MB was positive at low levels in 19 of 23 patients and cleared within 24 h. 99mTc pyrophosphate scans were faintly positive in only 2 of 22 patients. Left ventricular wall motion and ejection fractions were unchanged in 19 of 19 patients, two-dimensional echocardiography with microcavitation technique was unchanged in 12 of 12 patients, and a slight increase in pulmonary artery wedge pressure was seen in only 1 of 11 patients. Current, voltage, and their product (power) waveforms were recorded in 12 patients (12 recordings at a defibrillator setting of 200 J and 5 recordings at a defibrillator setting of 300 J) and revealed a complex voltage-current relationship due to changes occurring at the catheter electrode-tissue interface. At 200 J the peak values were 42.2 +/- 3.3 A, 2.16 +/- 0.11 kV, and 87.9 +/- 4.7 kW, while at 300 J the peak values were 58.2 +/- 2.8 A, 2.40 +/- 0.10 kV, and 134.4 +/- 6.7 kW, respectively. No instance of catheter disruption was seen, though "pitting" of the distal electrode (through which current passed) occurred in all but one catheter.

Radioimmunoassay of bleomycin.

A radioimmunoassay for bleomycin has been produced using 125l-labeled bleomycin and antisera raised in rabbits against a carbodiimide-catalyzed bleomycin-bovine serum albumin conjugate. 125l-Labeled bleomycin was synthesized by direct iodination of the drug using the chloramine-T technique. The standard curve of the assay was linear on a logit-log plot and the lower limit of sensitivity was 250 pg bleomycin sulfate. A mean recovery of 102.6% (+/- 3.3% S.E.) was obtained using bleomycin added to normal sera. No significant decrease in bleomycin immunoreactivity was observed following 24 hr incubation of the drug in serum at 37 degrees. The radioimmunoassay was also suitable for measuring bleomycin in the presence of other drugs since the assay was not significantly affected by the other antineoplastic agents tested. The sensitivity and specificity of the radioimmunoassay for bleomycin should provide a new means for pharmacokinetic and toxicity studies of bleomycin.

Adverse consequences of high sympathetic nervous activity in the failing human heart.

OBJECTIVES: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. BACKGROUND: Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. METHODS: Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. RESULTS: The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. CONCLUSIONS: These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.

Estimation of maximum left ventricular inotropic response from changes in isovolumic indices of contractility in the dog.

The effects of catecholamine infusion on three isovolumic indices of left ventricular (LV) contractility were studied under "steady-state" conditions in open-chest dogs with left atrial pressure held constant. The indices studied were (dP/dt)max; (dP/dt)DP40 where DP40 = developed LV pressure (LVP) of 5.3 kPa (40 mmHg) and dP/dt/TP)max, where TP = total LVP above atmospheric. There was a curvilinear relationship between dose of noradrenaline and the rise of each index, but the magnitude of the rise differed considerably. When heart rate was allowed to rise (dP/dt)max rose to about 800% of the basal value, whilst the other two indices both increased to about 300% of basal. The reason for the difference appeared to be related to the earlier timing of (dP/dt)DP40 and (dP/dt/TP)max. When heart rate was controlled (dP/dt)max increased to about 500% of basal, similar to findings reported by others in the maximum rate of isometric force development in isolated myocardium. During noradrenaline infusion (dP/dt)max always occurred before aortic valve opening and provided a satisfactory measure of inotropic change whilst the other indices apparently occurred too early in systole to reflect full ventricular "activation". However, during isoprenaline infusion blood pressure fell and estimates of inotropic reserve using (dP/dt)max were 40 to 100% in error due to early aortic valve opening until blood pressure was raised using methoxamine.

Comparison of left and right ventricular blood flow responses during arterial pressure reduction in the autonomically blocked dog: evidence for right ventricular autoregulation.

The effect of reducing systemic arterial pressure with an arteriovenous fistula on left and right ventricular myocardial blood flow was studied in 17 anaesthetised, open chest, autonomically blocked dogs. Global and regional myocardial blood flows were measured with radioactive microspheres. As mean arterial pressure was reduced from 133 mmHg to 78 mmHg left ventricular myocardial blood flow and the left ventricular inner to outer flow ratio decreased progressively. By contrast, right ventricular myocardial blood flow remained constant (range 78-81 ml.min-1.100 g-1) whereas right ventricular vascular resistance fell linearly (from 235 to 130 kPa.litre-1.min.100 g-1). The inner to outer right ventricular free wall flow ratio (range 1.04-1.10) and blood flow to the right side of the interventricular septum also did not change significantly. It is concluded that the right ventricular myocardium shows effective autoregulation of total and regional tissue blood flow during changes in coronary perfusion pressure.

Left ventricular blood flow during aortic pressure reduction in hypertensive dogs.

We measured left ventricular blood flow with radioactive microspheres during aortic pressure reduction in 10 open-chest, anesthetized dogs with left ventricular hypertrophy due to chronic hypertension and in 10 matched normotensive dogs. Heart rate and left atrial pressure were held constant, and autonomic reflexes were abolished with ganglionic blockade. Aortic diastolic pressure was lowered from baseline to 90, 75, and 60 mm Hg with an arteriovenous fistula. During aortic pressure reduction, a stepwise decline in the endocardial-to-epicardial flow ratio in hypertrophied hearts from 1.23 +/- 0.04 at baseline to 0.96 +/- 0.09 at a diastolic pressure of 75 mm Hg parallelled that in normal hearts and was not associated with any deterioration in left ventricular performance. However, a further fall in the endocardial-to-epicardial flow ratio to 0.76 +/- 0.10 at a diastolic pressure of 60 mm Hg in hypertrophied hearts exceeded that in normal hearts (0.92 +/- 0.05, p less than 0.05) and was accompanied by evidence of left ventricular isovolumic and end-systolic dysfunction. We conclude that in hearts with pressure-overload left ventricular hypertrophy, aortic pressure reduction causes a transmural blood flow redistribution from subendocardial to subepicardial muscle layers. At moderately low aortic pressures, this redistribution is more pronounced than in normal hearts and is associated with functional evidence of myocardial ischemia.

Differentiation of septal from free wall accessory pathway location: observations during bundle branch block in reciprocating tachycardia in the presence of type I antiarrhythmic drugs.

In patients with Wolff-Parkinson-White syndrome, observations during bundle branch block (BBB) in reciprocating tachycardia are of value in accessory pathway localization. Most importantly, an increase in the ventriculoatrial (VA) interval of greater than or equal to 35 ms has indicated an ipsilateral free wall location and excluded a septal location. The present study examined whether data collected in the presence of type I antiarrhythmic drugs retained localizing value. Review of retrospective data showed that observations in the drug-free state were precluded by the need to suppress atrial arrhythmia during electrophysiologic study in 20% of patients with Wolff-Parkinson-White syndrome who underwent preoperative workup. Prospectively, in 15 patients with left free wall or posteroseptal pathways, we observed transient left BBB during tachycardia before and after administration of procainamide, disopyramide or quinidine. Serum drug levels ranged from 4.6 to 6.9 mg/liter, except in 1 patient with a serum procainamide level of 18 mg/liter. Drugs increased the VA interval during narrow QRS tachycardia by 17% (p less than 0.01). However, the change in the VA interval with left BBB was not significantly affected. The baseline and drug values averaged 73 ms (range 39 to 94) and 70 ms (range 39 to 90), respectively, for left free wall pathways (n = 8), and 19 ms (range 0 to 28) and 21 ms (range 2 to 35), respectively, for posteroseptal pathways (n = 7). Among the latter, the interval increased less than 30 ms during left BBB except in the patient with the high serum procainamide level, in whom the increase was 35 ms. Thus, the VA interval change that accompanied left BBB remained of localizing value with moderate blood levels of type I drugs, and an increase greater than or equal to 35 ms indicated a left free wall rather than posteroseptal pathway.

Effects of exercise and isoproterenol during atrial fibrillation in patients with Wolff-Parkinson-White syndrome.

The effects of exercise and isoproterenol on atrial fibrillation (AF) were studied in 17 patients with Wolff-Parkinson-White syndrome (WPW) to assess the risk of developing a rapid ventricular response. Mean cycle length (R-R interval) and shortest R-R interval between both preexcited and nonpreexcited QRS complexes were recorded, as well as the percentage of preexcited complexes during control periods, during bicycle exercise, and during isoproterenol infusion. Exercise resulted in significantly shorter mean cycle length and the shortest R-R interval between nonpreexcited complexes. Exercise also resulted in a significantly lower percentage of preexcited complexes during AF, but had no effect on the R-R intervals between preexcited complexes. Isoproterenol had a variable effect on the percentage of preexcited QRS complexes, but resulted in significant shortening of mean cycle length and the shortest R-R interval between both normal and preexcited complexes. With isoproterenol, 12 of 17 patients had shortest preexcited R-R intervals less than or equal to 215 ms, compared with 6 of 17 in the control state. Isoproterenol infusion increased the rate of conduction over the accessory pathway during AF and allowed better assessment of the risk of excessively rapid rates occurring during AF. Exercise is not an adequate test for this purpose.

Immunologic biomarkers associated with an acute exposure to exothermic byproducts of a ureaformaldehyde spill.

A community was exposed for several days to formaldehyde (HCHO), hexamethylenetetramine, trimethylamine, and paraformaldehyde emitted from an overheated tanker car containing ureaformaldehyde resin. Residents experienced acute HCHO symptoms at the time of the accident. Many developed chronic, multiple organ health complaints. Three years following the accident, exposed subjects were compared to residents of a nearby unexposed community for the following immunological parameters: white blood cell count, total lymphocyte count, percent and total lymphocyte subsets (CD5, CD4, CD8, CD19, CD25, and CD26 cells), prevalence of autoantibodies, and antibodies to HCHO-human serum albumin (HCHO-HSA) conjugate. The data were adjusted for gender, age, history of smoking, mobile home residency, and use of wood stoves. There was a statistically significant difference for the following: elevated percent and absolute numbers of CD26 cells (p less than 0.0001); autoantibodies (p less than 0.004), and greater titers of isotypes IgG (p less than 0.0005) and IgM (p less than 0.005) to HCHO-HSA. It is concluded that the exposed subjects had an activated immune system in addition to the elevated autoantibodies. Also, isotypes to HCHO-HSA resulted from the exposure and no other sources, such as smoking, mobile home residency, and use of wood stoves.

Application of adrenocorticotropin assays in a routine clinical laboratory.

The radioimmunoassay of ACTH was used in a routine laboratory to localize the site of the lesion in 20 patients with Cushing's syndrome. Eight of the patients had no detectable circulating ACTH and had adrenal tumors removed, 12 had high levels and were diagnosed as having pituitary Cushing's syndrome. Very high levels of plasma ACTH were found in eight patients who had primary adrenal insufficiency, while ACTH was undetectable in ten patients with secondary hypoadrenalism. The routine use of this assay in endocrinology should reduce the hospitalization of patients under investigation for disorders of the pituitary--adrenal axis. Eight patients who had the ectopic ACTH syndrome and carcinoma of the lung were found to have very high levels of ACTH with no diurnal variation. Forty-seven patients with oat-cell carcinoma but without evidence of the ectopic ACTH syndrome had normal ACTH levels. A possible role of ACTH and other peptide hormones as tumor markers is mentioned.

The pharmacokinetics of bleomycin in man.

A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.

Clinical pharmacology of the anticancer polypeptide neocarzinostatin.

The clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400-3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7 h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3 l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearance, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1-5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.

Bleomycin clinical pharmacology by radioimmunoassay.

Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7-30 U intravenously (IV) and eight patients who received 4-30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m2 and the volume of distribution was 13.2 l/m2. Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m2 and the volume of distribution was 19.2 l/m2. Bleomycin plasma clearance correlated well with serum creatinine (r2 = 0.72). Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.

Radioimmunoassay of iodinated gentamicin.

A radioimmunoassay is described for the aminoglycoside antibiotic, gentamicin. Iodinated gentamicin was prepared using an 125I-labeled acylating agent: 3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester which spontaneously reacts with gentamicin to produce an iodinated conjugate. The radioimmunoassay with iodinated gentamicin produced a straight line on a logit/log plot yielding an assay sensitivity of 80 pg. A Scatchard plot plus an equilibrium technique were used to estimate the affinity constant at 8 X 10(9) 1 mol-1 and 10.5 X 10(9) 1 mol-1, respectively. Kanamycin and neomycin, two chemically related aminoglycoside antibiotics, did not crossreact with gentamicin until concentrations were 10(5) greater than those found in blood. Assay of patients' serum samples by both a microbial assay and radioimmunoassay resulted in a statistically significant (p less than 0.001) correlation between the two methods.

Salivary creatinine assays as a potential screen for renal disease.

Salivary creatinine concentrations are 10-15% of serum creatinine concentrations in healthy populations but have not previously been measured in patients with renal disease. The Cobas Mira automated Jaffé method was adapted to measure salivary creatinine concentration. The method was linear to 1200 mumol/L, had a mean recovery of 78% and a detection limit of 6 mumol/L. Intra-assay variability was 13.5, 5.5 and 1.4% at 10.6, 17.8 and 128.4 mumol/L, respectively. Inter-assay variability was 35.0 and 4.8% at 6.2 and 130.4 mumol/L, respectively. The median salivary creatinine concentrations was 8.5 mumol/L (range 6-18 mumol/L) in healthy subjects (n = 23), and 84 mumol/L (range 18-591 mumol/L) in patients with renal disease (n = 25). Salivary and serum creatinine concentrations were not related in healthy subjects, however, a significant relationship was found in the patients (r = 0.784, P < 0.001). Using salivary creatinine concentration of 16.8 mumol/L as a cut off value, all patients would have been detected with one false positive result (sensitivity 100%, specificity 95.7%, efficiency 97.7%). Thus, salivary creatinine estimations may be used to identify subjects with serum creatinine concentrations above 120 mumol/L.

Effect of low protein concentration on serum sodium measurement: pseudohypernatraemia and pseudonormonatraemia!

BACKGROUND: The effect of high concentrations of protein or lipid on the measurement of plasma sodium by indirect ion selective electrode (ISE) causing pseudohyponatraemia and pseudonormonatraemia is well described. The effect of a low total protein concentration, however, has not been described. METHODS: In order to examine this, over a 2-week period the total protein concentration was measured on all samples received for urea and electrolyte measurement. All samples with a low (<50 g/L) or a high (> 80 g/L) total protein concentration had sodium measured by both direct and indirect ISE. RESULTS: There were approximately equal numbers of samples with a protein concentration less than 50 g/L (1.3%) as samples with a protein concentration greater than 80 g/L (1.3%). The frequency of erroneous sodium results owing to the use of an indirect ISE was less in hypoproteinaemic (2%) than in hyperproteinaemic (20%) samples.