[Validation of the Dutch Glasgow Anti- psychotic Side-Effect Scale for Clozapine]. / Glasgow Antipsychotica Bijwerkingen Schaal voor Clozapine; validatie van de Nederlandstalige versie.

BACKGROUND: To monitor the unique side effect pattern of clozapine, the Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C) was developed in English and validated. This questionnaire was previously translated to Dutch, and revised, but not yet validated. AIM: The current study concerns the validation of the second revision of the GASS-C-NL-R2 for the Dutch language. METHOD: Two Spearman correlation tests were conducted to compare GASS-C-NL-R2 with the Dutch version of the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) at two time p´oints. There was one week between these two time points. The test-retest reliability was determined using a Spearman correlation test and Cronbach's alpha on the GASS-C-NL-R2 between the two time points. In addition, a factor analysis was performed. RESULTS: Spearman's correlation coefficient between the GASS-C-NL-R2 and the LUNSERS was 0.830 (p < 0.001, n = 72) at the first time point and 0.684 (p < 0.001, n = 50) at the second time point. GASS-C-NL-R2 also had a strong test-retest reliability: Spearman's correlation coefficient was 0.680 (p < 0.001; n = 46), and Cronbach's alpha was 0.847, n = 78. Factor analysis showed that all questions were relevant. CONCLUSION: The current study shows that GASS-C-NL-R2 is a valid and reliable questionnaire to monitor side effects related to clozapine with a relatively high prevalence. Future studies should focus on the practical utility of GASS-C-NL-R2 with a larger sample size.

Influence functions for a hysteretic deformable mirror with a high-density 2D array of actuators.

We present modeling and analysis of a hysteretic deformable mirror where the facesheet interacts with a continuous layer of piezoelectric material that can be actuated distributively by a matrix of electrodes through multiplexing. Moreover, a method to calculate the actuator influence functions is described considering the particular arrangement of electrodes. The results are presented in a semi-analytical model to describe the facesheet's deformation caused by a high-density array of actuators, and validated in a simulation. The proposed modeling of an interconnection layout of electrodes is used to determine the optimal pressures the actuators must exert to achieve a desired surface deformation.

Local control and toxicity after stereotactic radiotherapy in brain metastases patients and the impact of novel systemic treatments.

BACKGROUND AND PURPOSE: Treatment modalities for patients with brain metastases consist of surgery, radiotherapy, and systemic treatments such as immunotherapy and targeted therapy. Although much is known about local control of brain metastases after radiotherapy and surgery alone, more understanding is needed of the additional effect of new systemic treatments. Our study presents real-world data about the combined effects of different local and systemic treatment strategies on local response of irradiated brain metastases. MATERIALS AND METHODS: We performed a retrospective consecutive cohort study of patients that presented with brain metastases in our institution between June 2018 and May 2020, reporting the impact of radiotherapy alone versus radiotherapy combined with systemic treatment on local control of irradiated brain metastases and toxicity. Chemotherapy and targeted therapy were temporarily discontinued around irradiation. RESULTS: 262 consecutively treated patients were included in the study. Median time to local failure of irradiated brain metastases was 18 months (IQR 9-34), median overall survival was 20 months (IQR 10-36). 211 (81 %) patients received systemic treatment. Patients with breast cancer had a worse local control (HR 2.3, 95 % CI 1.0-5.0, p = 0.038), as did patients without any systemic treatment (HR 2.1, 95 % CI 1.1-4.3, p = 0.034). Symptomatic radiation necrosis occurred in 36 (14 %) patients. A diameter > 2.5 cm was associated with a higher risk of radiation necrosis. No association was found between systemic treatment in combination with local radiotherapy and symptomatic radiation necrosis. CONCLUSION: Patients who received any form of systemic treatment had better local control after stereotactic radiosurgery for brain metastases. We did not find an association between systemic treatment and the incidence of radiation necrosis.

Prevalence of anemia and its impact on mortality and hospitalization rate in predialysis patients.

BACKGROUND/AIM: Anemia is associated with increased mortality and morbidity in both early and very late stages of chronic kidney disease (CKD). The aim of this study was to assess whether anemia is a risk factor for mortality or hospitalization in CKD stage 4-5 predialysis patients not yet on dialysis. METHODS: Incident predialysis patients were included between 1999 and 2001 and followed until January 2008 or death. Anemia was defined as mean hemoglobin (Hb) < or =11 g/dl in the 3 months before the start of predialysis. Associations were assessed by Cox regression, linear and logistic regression analysis. RESULTS: A total of 472 patients were included (median follow-up time 12 months, 11% died, 79% started dialysis). Mean Hb was 11.2 g/dl (minimum 7.6, maximum 16.9). Forty-eight percent of patients had anemia at the start of predialysis care. The adjusted mortality risk (hazard ratio, 95% confidence interval) for anemic compared to nonanemic patients was 1.92 (1.04, 3.52). Anemia tended to be related to all-cause but not to non-dialysis-related hospitalization risk. CONCLUSION: At the start of predialysis care, 48% of patients had anemia. Anemia as defined in guideline targets is not associated with an increase in hospitalizations not related to renal replacement therapy, but is likely an important risk factor for mortality in predialysis patients.

A diagnostic tool for self-poisoned patients: Analysis of gastric content and lavage fluids.

Approximately 500 patients per year are admitted to the emergency department (ED) of the Erasmus University Medical Center presenting with intoxications with medication. For adequate treatment, it is sometimes important to know which drugs in which quantities were ingested. This can require laboratory analysis of blood or urine samples; however, these samples do not provide information about the possible effects that can still be expected. We performed toxicological screening on the gastric content of three patients admitted to our ED in January and February 2018. These patients underwent gastric lavage or received a gastric tube as part of routine care. The gastric fluid was analysed via UPLC-MS/MS using the Waters method for toxicological screening. In all three patients, we successfully determined drugs in the gastric content. In two patients, we identified more different drugs in the gastric content than in blood plasma. In the other patient, admitted approximately six hours after a severe autointoxication with the betablocker metoprolol, we found significant amounts of metoprolol in the gastric content acquired by gastric lavage. We therefore believe that analysis of gastric content after an intoxication can have multiple applications; for example, it may provide information about symptoms of intoxication that can be expected, it may aid patient care and may provide insight in the toxicokinetics of different drugs. In conclusion, we demonstrate that toxicological screening and quantification of drug levels in gastric content is possible and has potential as an adjunct in patient care, but limitations need to be addressed before implementation in clinical practice.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

Different effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on sterol synthesis in various human cell types.

The three vastatins examined, lovastatin, simvastatin and pravastatin, are equally strong inhibitors of the sterol synthesis in human hepatocytes in culture with IC50-values of 4.1, 8.0 and 2.0 nM, respectively. However, in the human extrahepatic cells: umbilical vascular endothelial cells, retinal pigment epithelial cells, cornea fibroblasts and granulosa cells, pravastatin was much less inhibiting the sterol synthesis than lovastatin or simvastatin. It was observed as well that longer incubation with the vastatins resulted in higher IC50-values. In order to show that the feedback regulation mechanism for 3-hydroxy-3-methylglutaryl-coenzyme A reductase was involved in this phenomena mRNA levels were measured in human vascular endothelial cells after incubation with the vastatins for 3.5 h and for 20 h. Indeed, lovastatin and simvastatin gave rise to higher levels of HMG-CoA reductase mRNA after 20 h than after 3.5 h of incubation. The differences observed in different human cell types can be explained by supposing that pravastatin is transported into the human hepatocyte via a liver-specific transporter. This was supported by the results of uptake experiments with 14C-labelled pravastatin and 14C-labelled simvastatin into human hepatocytes compared to that into human umbilical endothelial cells (as an example of an extrahepatic cell type). [14C]-Simvastatin was associated with both cell types, whereas [14C]-pravastatin was hardly associated with human endothelial cells, but to a similar extent as [14C]-simvastatin with human hepatocytes.

Measurement of left ventricular wall stress.

Forces in the myocardial wall can be measured in several ways or calculated using certain simplifying assumptions. In this study we investigated the reliability of two measurement methods, one of which was introduced by Feigl et al (1967), whereas the other method was developed in our laboratory. Both methods were tested in actively contracting skeletal muscle and beating hearts of open-chest dogs by comparing the force transferred from the muscle to the transducer under various circumstances. It appeared that changes in muscle length, be it through initial length changes or through shortening during contractions, had a great influence on the transfer of force to the transducer, for both methods, in both preparations. In the heart a decrease in internal left ventricular diameter of 15% resulted in a 50% reduction of force transferred to the transducer, independent of whether the length took place as a change in filling or as a change in ejection volume. In skeletal muscle the length-dependent effects during shortening were larger and those resulting from initial length changes were more variable than in beating hearts. That the effects of muscle length changes are of such magnitude means that, if no other errors exist, they alone would invalidate that until principally different methods of measuring wall stress in the myocardium are discovered, attempts at accurate calculation of myocardial wall stress are a better approach than wall stress measurements.

Further characterization of an antigenic site of HIV-1 gp120 recognized by virus neutralizing human monoclonal antibodies.

OBJECTIVE: The aim of this study is to characterize antigenic sites on HIV-1 gp120 which may be important for the development of active and passive immunization strategies against HIV-1 infection. DESIGN: Two HIV-1-seropositive individuals were selected from the Amsterdam cohort and Epstein-Barr virus (EBV)-transformed B cells were generated from their peripheral blood mononuclear cells, which produce HIV-1-specific human monoclonal antibodies (HuMAb). METHODS: HuMAb were generated and selected based on their reactivities with native gp120. Reactivity with HIV-1 strains from phylogenetically different subfamilies was determined by immunostaining and virus neutralization assays. Specificity for the CD4-binding site was tested by an inhibition enzyme-linked immunosorbent assay and amino acids (aa) involved in the binding of the HuMAb were identified with a set of gp120 molecules with single aa substitutions. RESULTS: Three HuMAb (GP13, GP44, GP68) were generated, all recognizing a conserved conformation dependent epitope within, or topographically near, the CD4-binding site of gp120. HuMAb GP13 and GP68 neutralized a broad range of HIV-1 strains from phylogenetically different subfamilies, whereas HuMAb GP44 exhibited a more restricted pattern of neutralizing activity. The patterns of gp120 aa involved in their binding were unique for each of these HuMAb. CONCLUSIONS: The pattern of reactivities of these three HIV-1-neutralizing HuMAb developed in these studies is similar to, but distinct from other human and rodent MAb that recognize this antigenic site of HIV-1 gp120.

Angiotensin converting enzyme inhibition improves diagnostic procedures for renovascular hypertension in dogs.

In renovascular hypertension adaptive mechanisms in the poststenotic kidney are a probable cause of the 20 to 25% false-negative findings during rapid sequence urography or [123I]o-iodohippurate renography. We blocked the renin-angiotensin system in an effort to increase the yield of these diagnostic procedures. Chronically instrumented, salt-depleted conscious dogs were used in which a light (n = 5), moderate (n = 4), or severe (n = 2) renal artery stenosis was induced. Before stenosis 10 of the dogs showed no left-right differences with either diagnostic procedure, and angiotensin converting enzyme (ACE) inhibition did not change this result. Two to 3 weeks after induction of a renal artery stenosis, all dogs showed signs of renovascular hypertension. However, only 50% of the renograms and 22% of the urograms showed differences between the two kidneys indicative of the presence of stenosis. After ACE inhibition, all previously negative test results became positive (abnormal) and previously existing left-right differences became more evidence. Electromagnetically measured renal blood flow on the stenotic side did not change during ACE inhibition (146 +/- 13 vs 145 +/- 21 ml/min), whereas contralateral blood flow showed a distinct increase (207 +/- 18 vs 282 +/- 20 ml/min, p less than 0.01). In conclusion, ACE inhibition markedly improves the sensitivity of rapid sequence urography and hippurate renography in the diagnosis of renovascular hypertension in the two-kidney, one clip Goldblatt hypertensive dog. The effects of ACE inhibition on the handling of the different tracers do not appear to be related to its effects on renal blood flow or systemic blood pressure.

Reflex epilepsy evoked by decision making.

A patient had seizures while playing chess or cards or when filling out complex forms, doing complex mathematical problems, and during certain parts of the neuropsychological testing. Seizures were myoclonic and accompanied and electroencephalographic dysrhythmia of the atypical spike and wave type. Evoked seizures were not related to visual, tactile, or auditory stimuli or clues. In chess, seizures occurred when he was on the defense and threatened. Simple decision making or physiologic stress did not evoke seizures nor did nonsequential decision making under verbal pressure. Evoking factors were complex decision making in a sequential fashion and with an element of stress or concern regarding the outcome of the decision making. Stimulus was usually nonverbal. Three major factors--decision complexity, sequential factor, and related stress or concern--may have some reciprocal relationships.

Angiotensin-converting enzyme inhibition-induced changes in hippurate renography and renal function in renovascular hypertension.

UNLABELLED: We studied the mechanism of angiotensin-converting enzyme (ACE) inhibition-induced changes in hippurate renography of the poststenotic kidney. METHODS: Ten male mongrel dogs, six with unilateral and four with bilateral renal artery stenosis, were equipped with renal artery blood flow probes and catheters in the aorta, atrium and both renal veins. RESULTS: Enalaprilat (10 mg intravenously) in conscious dogs with renal artery stenoses produced changes in all stenotic (n = 11) but not in nonstenotic kidney 123I-hippurate renograms (n = 6). Renographic changes correlated significantly with initiation of intrarenal 131I-hippurate retention, a decrease in mean arterial pressure (MAP), renal extraction of 131I-hippurate and 125I-iothalamate (r = 0.68, r = 0.62, r = 0.84, r = 0.83, respectively) but not with renal blood flow changes (r = 0.34). Furthermore, renal uptake of 131I-hippurate and 125I-iothalamate decreased in stenotic kidneys with a grade II renogram (-52 +/- 11% and -79 +/- 6%, respectively). Iodine-125-hippurate autoradiograms of stenotic kidneys during ACE inhibition showed tracer retention mainly in the proximal tubular cells. Results during osmotic diuresis supported our findings. CONCLUSION: Angiotensin-converting enzyme inhibition-induced hippurate retention curves of poststenotic kidneys appear to result from a sequence of events. A decrease in MAP combined with efferent vasodilation leads to a decrease in intraglomerular capillary pressure. This decrease in pressure causes a decrease in glomerular filtration rate and proximal tubular urine flow. This decrease in turn hampers tubular hippurate transit and transport across the luminal membrane, leading to intrarenal hippurate retention and, in more severe cases, decreased renal hippurate uptake.

Different analogues of farnesyl pyrophosphate inhibit squalene synthase and protein:farnesyltransferase to different extents.

The inhibitory potency of farnesyl pyrophosphate analogues was investigated on two farnesyl pyrophosphate-consuming enzymes: squalene synthase, a secondary regulation site in the cholesterol synthesis pathway, and protein:farnesyl transferase, which plays a role in the function of Ras-proteins. For the transferase determination a rapid in vitro assay, using Sepharose-bound Ras-peptides, was developed. The distinct farnesyl pyrophosphate analogues showed a different order of potency in the inhibition of these two enzymes. Using the farnesyl transferase assay with pre-p21Ha-ras as substrate the same result was obtained. The difference observed in the in vitro assays was also reflected in the inhibition of cholesterol synthesis, protein prenylation in general and Ha-ras farnesylation in Rat-1.H-ras13 cells, a rat fibroblast cell line that overproduces human p21Ha-ras. This work shows that farnesyl pyrophosphate analogues can be developed for specific inhibition of different processes such as cholesterol synthesis and protein prenylation.

The mechanism and diagnostic value of angiotensin I converting enzyme inhibition renography.

The effect of angiotensin converting enzyme (ACE) inhibition on the sensitivity of radionuclide renography in the diagnosis of a unilateral renal artery stenosis was tested both in a conscious dog model and in the human situation. ACE inhibition (10 mg enalaprilic acid, intravenously) markedly improved the sensitivity of [123I]hippuran renography in 10 renovascular hypertensive dogs with a mild to moderate unilateral renal artery stenosis from 50 to 100%. This improved sensitivity was due to an ACE-inhibition-induced delayed tracer handling at the stenotic side without an appreciable change in the renographic curve at the contralateral side. A similar phenomenon was observed in 15 hypertensive patients with an angiographically proved unilateral renal artery stenosis. Both [123I]hippuran and 99mTc-diethylenetriaminepentaacetic acid (DTPA) handling was delayed on the stenotic side after oral enalapril treatment. However, only a moderate increase in sensitivity was observed comparing control renograms to ACE-inhibition renograms: from 87 to 93% for hippuran, and from 60 to 86% for DTPA. Eight of these 15 patients underwent either surgery or angioplasty resulting in a successful correction of the stenosis. Hypertension was more or less cured in five patients. Each of these patients had shown an ACE-inhibition-induced change in the renogram at the stenotic side, suggesting that such a response may predict the curability of the hypertension. However, of the three patients that showed no blood pressure change upon successful revascularization, two showed a positive ACE-inhibition renogram. In conclusion, in an ideal setting as obtained in animal experiments, ACE inhibition improves the sensitivity of renographic studies to 100%. However, its value in the clinical setting needs more standardization.

Differences in erythrocyte sodium transport between human plasma and artificial medium: the role and character of sodium efflux and influx stimulating plasma factors.

The main objective of this study was to further characterize the plasma factor(s) which stimulate sodium efflux from erythrocytes, which we reported previously. Dialysis of plasma against an artificial medium using membranes with varying molecular mass cut-off points revealed relative molecular mass(es) of the factor(s) of 100-1000 Da. The factor(s) could be absorbed on Dowex at pH 1.5 and Amberlite at pH 11.0, indicating 'Zwitterionic' character. They are hydrophilic and resistant to acid hydrolysis. These characteristics and direct measurements of contents made amino acids likely candidates for the efflux stimulating properties of the factor(s). Indeed, plasma amino acids added to artificial medium could abolish the sodium efflux difference between plasma and the artificial medium. The efflux stimulating effect of amino acids appeared not to be the result of sodium influx stimulation. A coincident finding was that plasma also contains dialyzable sodium influx stimulating factor(s) which are not amino acids.

Human plasma contains low molecular weight factors which stimulate active sodium transport in erythrocytes.

The aim of this study was to establish whether differences in sodium efflux rate constants (ke) in human erythrocytes occur when artificial media are compared with plasma. Using a 22Na tracer method, a mean total ke of 0.49 +/- 0.10 h-1 and significantly (p less than 0.05) lower ke values in Hanks' solution (0.43 +/- 0.08 h-1) and Basic Salt Solution (0.37 +/- 0.07 h-1) were observed. Exhaustive dialysis of plasma against Hanks' solution over a membrane with relative molecular mass cut-off of 1000 Da resulted in a decrease of the plasma total ke value to that measured in Hanks' solution. After equilibrium dialysis of plasma against Hanks' solution a decrease of total ke was found in plasma and an increase of the ke in Hanks' solution was measured. The data suggest the presence of an excess of dialyzable, active sodium transport stimulating plasma factor(s) with relative molecular mass below 1000 Da.

GC-MS determination of ratios of stable-isotope labelled to natural urea using [13C15N2]urea for studying urea kinetics in serum and as a means to validate routine methods for the quantitative assay of urea in dialysate.

A GC-MS determination of urea in serum or spent dialysate is described, using 13C15N2-labelled urea and assaying the area ratio of labelled to natural urea by mass fragmentographic monitoring of fragments m/e 153 and 156, after its eventual conversion into the trimethylsilylether-derivative of 2-hydroxypyrimidine. The procedure can be successfully applied in the follow-up of the disappearance of labelled urea in serum after intravenous injection in man, enabling kinetic parameters of urea to be established, e.g. for purposes of studying the effectiveness of dialysis procedures. Furthermore the method can be used for validation of routine methods for measuring urea in other fluids, in particular dialysate. Examples are given of both applications of the GC-MS method described.

Nephrotic syndrome preceding Hodgkin's disease by 42 months.

A 52-year-old man developed minimal change nephrotic syndrome which responded only partially to prednisolone. The addition of cyclophosphamide resulted in a complete remission. During a second episode of nephrotic syndrome prednisolone and cyclophosphamide only gave a partial remission. During a third episode, 42 months after the initial presentation, Hodgkin's disease clinical stage IA was diagnosed. Mantle field radiation therapy was given after which proteinuria gradually decreased to zero in the course of 17 months. The patient has remained free of disease until now (15 months).

Phosphate binders do not reduce bioavailability of oral cefuroxime-axetil in patients on peritoneal dialysis treatment.

Cefuroxime is a second-generation cephalosporin that can be used for the treatment of peritoneal dialysis-related peritonitis. Cefuroxime-axetil is an orally available pro-drug of cefuroxime. The effect of concomitant use of a phosphate binder on the bioavailability of cefuroxime-axetil was studied in 7 continuous ambulatory peritoneal dialysis (CAPD) patients who had not recently suffered from peritonitis. On two occasions, we measured cefuroxime levels in plasma, peritoneal effluent, and urine for 24 h after the ingestion of 1 g of cefuroxime-axetil: once together with a phosphate binder (+PB) and once without (-PB). Peak plasma concentrations (Cmax) were +PB: 22.7 mg/L (15.3-32.6) (median and range) and -PB: 23.2 mg/L (18.9-27.4). The area under the curve (AUC) of the plasma levels was +PB: 364 mg h/L (247-530) and -PB: 368 mg h/L (296-438). The plasma elimination half-life (t1/2) was +PB: 13.9 h (11.5-14.6) and -PB: 13.8 h (12.2-15.4). Cefuroxime concentrations in the peritoneal effluent from the first exchange were 1.9 mg/L (0.5-6.2) (+PB) and 3.4 mg/L (2.1-4.7) (-PB). In the peritoneal effluent from the second up to the last exchange, the cefuroxime levels were stable at +PB: 5.0 mg/L (2.0-8.8) and -PB: 5.3 mg/L (1.8-7.5). The total amount of cefuroxime excreted into peritoneal effluent and urine was +PB: 82 mg (30-124), -PB: 100 mg (36-129). So Cmax, AUC, t1/2 and the total amount of excreted cefuroxime were not different. Therefore, the bioavailability of cefuroxime-axetil is not reduced by the use of a phosphate binder.

[Dialysis an the elderly]. / Dialyse bij ouderen.

In the Netherlands, only one third of the patients of 65 years or older with terminal renal failure are currently admitted to dialysis treatment. Dialysis in older patients frequently leads to adequate survival and good subjective quality of life. In other words, age as such is not a contraindication to dialysis. Haemodialysis and peritoneal dialysis have about the same clinical results in older patients, as is the case in younger age groups; the choice depends on patient-linked factors and on the patient's preference. It is to be expected that in a number of years the majority of dialysis patients will be aged 65 years or older.