Evaluating hearing performance with cochlear implants within the same patient using daily randomization and imaging-based fitting - The ELEPHANT study.

BACKGROUND: Prospective research in the field of cochlear implants is hampered by methodological issues and small sample sizes. The ELEPHANT study presents an alternative clinical trial design with a daily randomized approach evaluating individualized tonotopical fitting of a cochlear implant (CI). METHODS: A single-blinded, daily-randomized clinical trial will be implemented to evaluate a new imaging-based CI mapping strategy. A minimum of 20 participants will be included from the start of the rehabilitation process with a 1-year follow-up period. Based on a post-operative cone beam CT scan (CBCT), mapping of electrical input will be aligned to natural place-pitch arrangement in the individual cochlea. The CI's frequency allocation table will be adjusted to match the electrical stimulation of frequencies as closely as possible to corresponding acoustic locations in the cochlea. A randomization scheme will be implemented whereby the participant, blinded to the intervention allocation, crosses over between the experimental and standard fitting program on a daily basis, and thus effectively acts as his own control, followed by a period of free choice between both maps to incorporate patient preference. With this new approach the occurrence of a first-order carryover effect and a limited sample size is addressed. DISCUSSION: The experimental fitting strategy is thought to give rise to a steeper learning curve, result in better performance in challenging listening situations, improve sound quality, better complement residual acoustic hearing in the contralateral ear and be preferred by recipients of a CI. Concurrently, the suitability of the novel trial design will be considered in investigating these hypotheses. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03892941. Registered 27 March 2019.

[The diagnostic and therapeutic challenges of bilateral renal oncocytosis : Illustrative case presentations and a review of the literature]. / Die bilaterale renale Onkozytose als diagnostische und therapeutische Herausforderung : Falldarstellung und Literaturreview.

Bilateral oncocytosis along with multiple tumours in both kidneys represents a very rare pathology that is accompanied by diagnostic and therapeutic challenges. We report the case of a 60-year old male patient who underwent computer tomography with incidental detection of multiple bilateral and contrast enhancing renal tumours of different size. Subsequently the patient underwent nephron-sparing tumor resection, first on the right side and 4 weeks later on the left side. The histology of all removed tumors showed evidence of pure oncocytoma. There were no postoperative complications and renal function reached a stable state within 6 months follow-up. The major challenge regarding diagnostic process and therapy of this pathology is to distinguish benign oncocytoma from chromophobe renal cell carcinoma and hybrid tumours, which can all be associated with renal oncocytosis. Because of limitations concerning imaging processes and biopsy, all patients should undergo nephron-sparing surgery as far as possible. On the other hand alternative therapies should - regarding to therapy-associated morbidity and the basically benign prognosis of oncocytoma - be well discussed to obtain informed consent. In this case report different therapy options and the international literature concerning renal oncocytosis will be discussed.

[Electrostimulation for the treatment of a dry mouth feeling]. / Elektrostimulatie voor de behandeling van een drogemondgevoel.

A 67-year-old woman suffered from a burning mouth feeling for 1.5 years and was referred by her dentist to a saliva clinic. At the clinic persistent xerostomia was diagnosed, and Sjögren's syndrome was suspected. After 1 year, a new measurement of the saliva secretion was carried out, which revealed a further decline in saliva secretion rate. The patient was consequently treated with an intra-oral electrostimulating device in order to stimulate the saliva secretion rate and reduce the feeling of a dry mouth. After 2 weeks, the patient experienced a considerable improvement of the subjective oral dryness.

Hypophosphatemic osteomalacia: an unusual clinical presentation of multiple myeloma.

An unusual case of a 75-year-old man is presented who had multiple stress fractures due to adult onset hypophosphatemic osteomalacia, which was the result of Fanconi syndrome, with light chain cast proximal tubulopathy due to multiple myeloma. A 75-year-old man presented with diffuse pain and muscle weakness. He had multiple stress fractures, low serum phosphate, decreased renal tubular reabsorption of phosphate, and normal PTH and FGF23, indicating adult onset hypophosphatemic osteomalacia. Phosphate supplements with calcitriol resulted in clinical recovery and healing of stress fractures. Because of proteinuria, a renal biopsy was performed that revealed Fanconi syndrome with light chain cast proximal tubulopathy and light kappa chains were found in serum and urine. A bone biopsy confirmed the diagnosis of multiple myeloma, and treatment with chemotherapy resulted in cytological and clinical recovery.

Inhibition of bacterial growth and biofilm production by constituents from Hypericum spp.

Biofilm embedded bacterial pathogens such as Staphylococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii are difficult to eradicate and are major sources of bacterial infections. New drugs are needed to combat these pathogens. Hypericum is a plant genus that contains species known to have antimicrobial properties. However, the specific constituents responsible for the antimicrobial properties are not entirely known, nor have most compounds been tested as inhibitors of biofilm development. The investigation presented here tested seven secondary metabolites isolated from the species Hypericum densiflorum, Hypericum ellipticum, Hypericum prolificum, and Hypericum punctatum as inhibitors of bacterial growth and biofilm production. Assays were conducted against Staphylococcus epidermidis, Staphylococcus aureus, clinical methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. Five of the seven compounds demonstrated growth inhibition against the Gram-positive bacteria with minimum inhibitory concentrations (MIC) ranging from 1.95 µg/mL to 7.81 µg/mL. Four of the secondary metabolites inhibited biofilm production by certain Gram-positive strains at sub-MIC concentrations.

The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 µmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 µmol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was <400 µmol/l. BH4 20mg/kg was administered at T = 0 and T = 24. Blood samples were taken at T=0, 8, 16, 24 and 48 h. Responsiveness was defined as ≥ 30% reduction in phenylalanine concentration at ≥ 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a ≥ 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had ≥ 30% phenylalanine decrease not before T = 48. A ≥ 30% decrease was also seen in patients with phenylalanine concentrations <400 µmol/l. CONCLUSION: In the 48-hour BLT, T = 48 seems more informative than T = 24. Sampling at T = 32, and T = 40 may have additional value. BH4 responsiveness can also be predicted with baseline blood phenylalanine <400 µmol/l, when the BLT is positive. Therefore, if these results are confirmed by data on long-term BH4 responsiveness, we advise to first perform a BLT without phenylalanine loading and re-test at higher phenylalanine concentrations when no response is seen. Most likely, the 48-hour BLT is a good indicator for BH4 responsiveness, but comparison with long term responsiveness is necessary.

Nitrogen and phosphorus removal from municipal wastewater effluent using microalgal biofilms.

Microalgal biofilms have so far received little attention as post-treatment for municipal wastewater treatment plants, with the result that the removal capacity of microalgal biofilms in post-treatment systems is unknown. This study investigates the capacity of microalgal biofilms as a post-treatment step for the effluent of municipal wastewater treatment plants. Microalgal biofilms were grown in flow cells with different nutrient loads under continuous lighting of 230 µmol/m(2)/s (PAR photons, 400-700 nm). It was found that the maximum uptake capacity of the microalgal biofilm was reached at loading rates of 1.0 g/m(2)/day nitrogen and 0.13 g/m(2)/day phosphorus. These maximum uptake capacities were the highest loads at which the target effluent values of 2.2 mg/L nitrogen and 0.15 mg/L phosphorus were still achieved. Microalgal biomass analysis revealed an increasing nitrogen and phosphorus content with increasing loading rates until the maximum uptake capacities. The internal nitrogen to phosphorus ratio decreased from 23:1 to 11:1 when increasing the loading rate. This combination of findings demonstrates that microalgal biofilms can be used for removing both nitrogen and phosphorus from municipal wastewater effluent.

Adult issues in phenylketonuria.

Phenylketonuria (PKU) is a classical example of an inherited metabolic disease, in which mental retardation can be prevented successfully by using a diet. However, in adult PKU new problems occur, such as vitamin deficiencies, osteoporosis and the maternal PKU syndrome. The aim of this review article is to provide guidelines for the clinician to understand and manage PKU in adults.

[Clindamycin is unsuitable for the empirical treatment of infections due to pig-related methicillin-resistant Staphylococcus aureus (MRSA)]. / Clindamycine niet geschikt voor empirische behandeling van infecties veroorzaakt door meticillineresistente Staphylococcus aureus (MRSA) afkomstig van varkens.

OBJECTIVE: To determine the antibiotic sensitivity of methicillin-resistant Staphylococcus aureus (MRSA) isolated from persons in contact with pigs. DESIGN: Retrospective. METHOD: The pig-related MRSA collection, built up between January 1st 2003 and November 30th 2006 in the Regional Laboratory for Medical Microbiology and Infection Prevention (RLMMI) of the Jeroen Bosch Hospital, Den Bosch, The Netherlands, was tested for sensitivity to a large number ofantibiotics. RESULTS: A total of 65 isolates were obtained from 53 patients. All (100%) of the pig-related MRSA isolates were sensitive to vancomycin, teicoplanin, nitrofurantoin, rifampicin, linezolid, and quinupristin-dalfopristin. Variable sensitivity was found for erythromycin (40%), clindamycin (48%), cotrimoxazole (48%), aminoglycosides (92%), tetracycline (6%), and quinolones (94%). CONCLUSION: In view of the sensitivities found, clindamycin does not seem suitable for the empirical therapy ofpig-related MRSA-infections. In case of severe infection, therapy should be started either with an intravenous glycopeptide or with oral ciprofloxacin, possibly combined with rifampicin or linezolid.

Absorption and excretion of elderberry (Sambucus nigra L.) anthocyanins in healthy humans.

Pharmacokinetic variables of several dietary anthocyanins (potent natural antioxidants) following consumption of elderberry (Sambucus nigra L.) extract were evaluated in urine and plasma of six healthy volunteers. They were given a single oral dose of either 30 ml (278 mg total anthocyanins) or 200 ml (1852 mg total anthocyanins) of a commercially available elderberry extract. Within 7 h, the fraction of orally administered total anthocyanins (calculated as the sum of cyanidin-3-sambubioside and cyanidin-3-glucoside) excreted unchanged was 0.39% and 0.27% following ingestion of 30 and 200 ml, respectively. The elimination half-life of total anthocyanins was slightly lower following the consumption of 278 mg (1.85 h) than that after the consumption of 1852 mg (2.57 h). The renal clearance (median) of total anthocyanins was 196 and 169 ml/min, respectively. The peak and average systemic exposure to the major elderberry anthocyanidin glycosides in plasma as well as their renal excretion exhibited approximate dose-proportional characteristics within the administered range. The low dose-normalized area under the concentration-time curve (AUC) and the fraction of orally administered anthocyanins recovered unchanged in urine indicate a low bioavailability of these compounds.

Helicobacter pylori antibiotic resistance in a Dutch region: trends over time.

AIM: Most patients treated for H. pylori infection receive empirical therapy based on epidemiological data of antibiotic resistance. However, previous European studies indicate that resistance patterns may be changing. Therefore, the aim of this study was to investigate the prevalence of primary clarithromycin and/or metronidazole resistant H. pylori strains over a six-year period (1997-2002) in a regional hospital. METHODS: All patients visiting Slingeland Hospital in Doetinchem, the Netherlands between 1997 and 2002 with a positive H. pylori culture were included in this study. Susceptibility to metronidazole and clarithromycin was determined by disk diffusion. RESULTS: Of the 1355 patients with an H. pylori positive culture, 1127 did not have a history of H. pylori eradication, 58 did, and for 170 this information was not available. Mean rates of primary resistance to metronidazole and clarithromycin were 14.4% (162/1125) and 1.0% (11/1123), respectively. Primary metronidazole resistance was stable throughout the study period and primary clarithromycin resistance showed a decreasing trend. Patients of foreign descent and from secondary care had a higher chance of harbouring primary metronidazole-resistant H. pylori (adjusted OR (95% CI) 1.75 (1.1 to 2.8), and 1.60 (1.1 to 2.2), respectively). Patients with failed H. pylori eradication had a higher chance of harbouring metronidazole-resistant H. pylori (43 vs 14%, p<0.0001) and clarithromycin-resistantH. pylori (5.3 vs 1.0%, p=0.004) than untreated patients. CONCLUSION: Primary metronidazole resistance is stableat a low level, while primary clarithromycin resistance isvirtually absent in the eastern part of the Netherlands.Therefore, triple therapy with a proton pump inhibitor,clarithromycin and amoxicillin can remain the empiricaltreatment of choice in the Netherlands.

Bioavailability of anthocyanidin-3-glycosides following consumption of elderberry extract and blackcurrant juice.

Pharmacokinetic parameters and the bioavailability of several dietary anthocyanins following consumption of blackcurrant juice and elderberry extract were compared exploratorily in 6 healthy volunteers. They were given a single oral dose of either 137 ml of blackcurrant juice (144.8 mg total anthocyanins) or 30 ml of elderberry extract (147.3 mg total anthocyanins). Within 7 hours, the urinary excretion of total anthocyanins (i.e. the sum of all assayed anthocyanidin glycosides) was 0.04% and 0.37% of the administered dose following blackcurrant juice and elderberry extract ingestion, respectively. Pharmacokinetic parameters based on non-compartmental methods for plasma and urine concentrations exhibited higher variability in urinary excretion after ingestion of elderberry extract. Anthocyanin absorption was significantly greater following the intake of elderberry extract than after the intake of blackcurrant juice as shown by the 5.3- and 6.2-fold higher estimates of dose-normalized Cmax and AUC(0-tZ) of total anthocyanins, respectively. The geometric means of t(1/2) were not significantly different following elderberry extract (1.74 h) and blackcurrant juice ingestion (1.73 h, p > 0.05). The urinary excretion rate of intact anthocyanins was fast, appeared to be monoexponential for both blackcurrant juice and elderberry extract. However, in order to evaluate the contribution of anthocyanins to the health-protecting effects of blackcurrant juice and elderberry extract it will be necessary to perform further studies on the unchanged glycosides and their in vivo metabolites in human plasma and urine.

Java-based graphical user interface for the MRUI quantitation package.

This article describes the Java-based version of the magnetic resonance user interface (MRUI) quantitation package. This package allows MR spectroscopists to easily perform time-domain analysis of in vivo MR spectroscopy data. We show that the Java programming language is very well suited for developing highly interactive graphical software applications such as the MRUI software. We have also established that MR quantitation algorithms, programmed in other languages, can easily be embedded into the Java-based MRUI by using the Java native interface (JNI). This new graphical user interface (GUI) has been conceived for the processing of large data sets and uses prior knowledge data-bases to make interactive quantitation algorithms more userfriendly.

Bioactive anthocyanins detected in human urine after ingestion of blackcurrant juice.

Anthocyanins are a group of very efficient bioactive compounds that are widely distributed in plant food. Several fruits (blackcurrant, blackberry, red grape) and some vegetables (eggplant, onion, red radish) are rich sources of these natural pigments. Extracts of some of them are used as food colorants as well as components of pharmaceutical preparations and functional foods. Anthocyanins, through their ability to inhibit radical reactions, are considered to exert several protective effects in the human body. Until now there has been only a small amount of data available on their capability, in intact or metabolized form, to reach the systemic circulation of humans. The present study was designed to determine the potential bioavailability in humans of the most important anthocyanins of blackcurrants: delphinidine-3-glucoside, delphinidine-3-rutinoside, cyanidine-3-glucoside, and cyanidine-3-rutinoside. Urinary samples from 4 healthy volunteers (2 women and 2 men) were collected before (baseline) and over a period of 5 hours with intervals of 30 minutes after the ingestion of 200 mL of blackcurrant juice (containing 153 mg of anthocyanins). Using high-performance liquid chromatography (HPLC), it was possible to quantify the 4 main anthocyanins of blackcurrants, excreted unchanged in the urine (0.020-0.050% of the oral doses). We present data on the bioavailability in humans of blackcurrant anthocyanins, which are dietary antioxidants with possible biological effects.

Age dependence of human gastrocnemius Mg2+: fitting 31P-NMR spectra using quantum mechanics-based prior knowledge.

The age dependence of human gastrocnemius Mg2+ concentration is demonstrated. To quantitate Mg2+ concentration, an original and accurate fitting algorithm using quantum mechanics-based prior knowledge is detailed. In a group of 28 volunteers (14 females) in the age range 5-80 years, pH, PCr/ATP and Pi/ATP values in the gastrocnemius were 7.02 +/- 0.02 pH, 4.16 +/- 0.33 and 0.13 +/- 0.02, respectively and independent of age and sex. By contrast, intracellular Mg2+ concentration (mM) decreased linearly (p < 0.05) with age (Mg2+ = 0.7803 +/- 0.0247-0.0027 +/- 0.0005 * age). No difference was found between sexes. From these results, it follows that care must be taken when comparing muscle Mg2+ data from subjects of different age. The hypothesis can be put forward that during aging insufficient intake and/or increased depletion of Mg2+ (e.g., intestinal hypoabsorption or urinary leakage) may affect the musculoskeletal system.

Effect of folic acid and betaine on fasting and postmethionine-loading plasma homocysteine and methionine levels in chronic haemodialysis patients.

OBJECTIVES: To study fasting and postmethionine-loading (increment and decrement) plasma homocysteine levels in end-stage renal disease (ESRD) patients in relation to B-vitamin status and after folic acid treatment without or with betaine. DESIGN: Plasma total homocysteine (tHcy) and methionine levels were measured in chronic haemodialysis patients after an overnight fast, and 6 and 24 h after an oral methionine load (0.1 g kg-1). The patients were subsequently randomized to treatment with folic acid 5 mg daily with or without betaine 4 g daily, and the loading test was repeated after 12 weeks. The patients were then re-randomized to treatment with 1 or 5 mg folic acid daily for 40 weeks, after which a third loading test was performed. SETTING: Haemodialysis unit of university hospital and centre for haemodialysis. SUBJECTS: Twenty-nine consecutive maintenance (> 3 months) haemodialysis patients, not on folic acid supplementation, 26 of whom completed the study. RESULTS: At baseline, the mean fasting, the 6 h postload and the 6 h postload increment plasma tHcy levels were increased as compared with those in healthy controls (46.8 +/- 6.9 (SEM), 92.8 +/- 9.1 and 46.0 +/- 4.2 mumol L-1, respectively) and correlated with serum folate (r = -0.42, P = 0.02; r = -0.61, P = 0.001 and r = -0.54, P = 0.003, respectively), but not with vitamin B6 or vitamin B12. At week 12, these variables had all decreased significantly. Betaine did not have additional homocysteine-lowering effects. At week 52, fasting and postload tHcy levels did not differ significantly between patients on 1 or 5 mg folic acid daily. Plasma tHcy half-life and plasma methionine levels after methionine loading were not altered by folic acid treatment. CONCLUSIONS: In chronic haemodialysis patients, fasting as well as postmethionine-loading plasma tHcy levels depend on folate status and decrease after folic acid therapy. Increased postload homocysteine levels in these patients therefore do not necessarily indicate an impaired transsulphuration capacity only; alternatively, folate may indirectly influence transsulphuration. The elucidation of the complex pathogenesis of hyperhomocysteinaemia in chronic renal failure requires further investigation.

Amorpha-4,11-diene synthase catalyses the first probable step in artemisinin biosynthesis.

The endoperoxide sesquiterpene lactone artemisinin and its derivatives are a promising new group of drugs against malaria. Artemisinin is a constituent of the annual herb Artemisia annua L. So far only the later steps in artemisinin biosynthesis--from artemisinic acid--have been elucidated and the expected olefinic sesquiterpene intermediate has never been demonstrated. In pentane extracts of A. annua leaves we detected a sesquiterpene with the mass spectrum of amorpha-4,11-diene. Synthesis of amorpha-4,11-diene from artemisinic acid confirmed the identity. In addition we identified several sesquiterpene synthases of which one of the major activities catalysed the formation of amorpha-4,11-diene from farnesyl diphosphate. This enzyme was partially purified and shows the typical characteristics of sesquiterpene synthases, such as a broad pH optimum around 6.5-7.0, a molecular mass of 56 kDa, and a K(m) of 0.6 microM. The structure and configuration of amorpha-4,11-diene, its low content in A. annua and the high activity of amorpha-4,11-diene synthase all support that amorpha-4,11-diene is the likely olefinic sesquiterpene intermediate in the biosynthesis of artemisinin.

Fish oil and glycemic control in diabetes. A meta-analysis.

OBJECTIVE: Hypertriglyceridemia is associated with cardiovascular disease in diabetes. Fibrates effectively lower, but do not always normalize, serum triglyceride levels. Fish oil supplements may then be added to lower serum triglyceride levels. Doubt remains whether the net effect of fish oil intake on glycemic control is beneficial in diabetes. We therefore performed a meta-analysis from published clinical trials. RESEARCH DESIGN AND METHODS: Data sources were Medline (Cologne, Germany), Excerpta Medica, Current Contents, review articles, and published reference lists. Publications of 26 trials were selected, and all trials included more than five diabetes (IDDM and NIDDM) patients and addressed the effects of fish oil (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) on serum lipids and glucose tolerance. We (C.E.F., M.J.F.M.J.) extracted data independently based on predetermined criteria. Studies were classified according to design. RESULTS: All studies combined showed a decrease in mean triglyceride concentrations in association with fish oil: -0.60 mmol/l (95% CI, -0.84 to -0.33, P < 0.01) and a slight but significant increase in serum LDL cholesterol: 0.18 mmol/l (95% CI, 0.04-0.32, P = 0.01), with both findings most prominent in NIDDM. No significant changes in HbA1c percentages occurred in diabetic subjects treated with fish oil. Fasting blood glucose levels were increased with borderline significance in NIDDM subjects (0.43 mmol/l [95% CI, 0.00-0.87], P = 0.06) and were significantly lower in IDDM subjects (-1.86 mmol/l [95% CI, -3.1 to -0.61], P < 0.05). Significant dose-response effects of EPA (g/day) on HbA1c and triglycerides and of DHA (g/day) on fasting blood glucose levels, HbA1c, and triglycerides were demonstrated only in NIDDM subjects. CONCLUSIONS: The use of fish oil has no adverse affects on HbA1c in diabetic subjects and lowers triglyceride levels effectively by almost 30%. However, this may be accompanied by a slight increase in LDL cholesterol concentration. Fish oil may be useful in treating dyslipidemia in diabetes.