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In a patient with a bacterial nephritis and renal stones an incidental finding of a complicated renal cyst on the opposite side wasmade on CT scan. In contrast to the CT findings, on ultrasound examination the lesion appeared to be a solid mass. The injection of ultrasound contrast material confirmed this by showing an enhancement of the whole lesion. Finally, the histological finding after nephrectomy results in a renal cell carcinoma pT1a. In this situation contrast enhanced ultrasound seems to be more sensitive than CT scan in detecting the perfusion of a renal mass. [ABSTRACT FROM AUTHOR]

What we believe to be a new type of transparent photon sieve is presented with application for presbyopia correction. Inspired by blazed gratings, we propose to design an intracorneal implant with slanted holes. The slopes introduce a new degree of freedom, breaking the symmetry of energy distribution along the optical axis and allowing to balance the energy between near and far vision. This new implant design is presented together with the simulation, manufacturing and validation methods. The first experimental results obtained with an implant manufactured in a biocompatible material are presented confirming the potential of the approach.

Nicotine substitution is a mainstay component in smoking cessation schemes. Current products including patches are poorly effective mainly because they do not give smokers the same pharmacokinetic profile of nicotine as cigarette consumption. This work evaluates a new computer operated delivery system for time controlled pulsatile transdermal administration of nicotine in a phase I clinical trial with twelve heavy smoking male volunteers. The device was affixed to the ventral side of the leading lower arm of the subjects and was programmed to deliver two pulses of drug within 16h with three delivery rates in a consecutive dose escalation study. Tolerability of the three increasing doses of nicotine was established. Plasma concentration of nicotine exhibited two peaks and one trough and reached therapeutically effective levels that behaved linearly with the drug load concentration of the device. In vivo input rate, delivered amount and elimination kinetics were deduced by pharmacokinetic modeling to analyze device performance. Timing, dose and duration of delivery were controlled by system operation parameters. Hence, feasibility of controlled pulsatile delivery of nicotine at predetermined intervals was demonstrated. After additional optimization, preprogrammed or on demand administration to meet individualized and circadian replacement needs should improve smoking cessation efficacy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: More than 95% of the body carnitine is located in skeletal muscle, where it is essential for energy metabolism. Vegetarians ingest less carnitine and carnitine precursors and have lower plasma carnitine concentrations than omnivores. Principle aims of the current study were to assess the plasma and skeletal muscle carnitine content and physical performance of male vegetarians and matched omnivores under basal conditions and after L-carnitine supplementation., Results: Sixteen vegetarians and eight omnivores participated in this interventional study with oral supplementation of 2 g L-carnitine for 12 weeks. Before carnitine supplementation, vegetarians had a 10% lower plasma carnitine concentration, but maintained skeletal muscle carnitine stores compared to omnivores. Skeletal muscle phosphocreatine, ATP, glycogen and lactate contents were also not different from omnivores. Maximal oxygen uptake (VO2max) and workload (P max) per bodyweight (bicycle spiroergometry) were not significantly different between vegetarians and omnivores. Sub-maximal exercise (75% VO2max for 1 h) revealed no significant differences between vegetarians and omnivores (respiratory exchange ratio, blood lactate and muscle metabolites). Supplementation with L-carnitine significantly increased the total plasma carnitine concentration (24% in omnivores, 31% in vegetarians) and the muscle carnitine content in vegetarians (13%). Despite this increase, P max and VO2max as well as muscle phosphocreatine, lactate and glycogen were not significantly affected by carnitine administration., Conclusions: Vegetarians have lower plasma carnitine concentrations, but maintained muscle carnitine stores compared to omnivores. Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.

Purpose: The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone., Methods: The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg)., Results: Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo., Conclusions: Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.

Laparoscopic adjustable gastric banding (LAGB) has been considered by many as the treatment of choice for morbid obesity because of its simplicity and encouraging early results. The aim of this prospective study was to critically assess the effects, complications, and outcome after LAGB in the long-term, based on a 12-year experience. Between June 1998 and June 2009, all patients with implantation of a LAGB have been enrolled in a prospective clinical trial. Results were recorded and classified, with special regard to long-term complications, re-operation rate, and graft survival. LAGB was performed in 167 patients (120 female, 47 male) with a mean age of 40.1 +/- 5.2 years. Operative mortality was 0%, overall 1.2% (not band-related). Overall patient follow-up was 94.0%. Mean excess weight loss (EWL) after 1, 2, 5, 8, and 10 years was 31.1 +/- 7.5% (p < 0.005), 44.2 +/- 6.5% (p < 0.001), 50.3 +/- 6.9% (p < 0.001), 51.7 +/- 6.3% (p < 0.001), and 48.8 +/- 6.0% (p < 0.001), respectively. The non-responder rate (EWL < 30%) after 2, 5, 8, and 10 years was 24.5%, 18.3%, 12.5%, and 16.6%, respectively. The early complication rate (<30 days) was 7.8% (13/167), with 10 minor and three major complications. Late complications (>30 days) occurred in 40.1% (67/167), of whom seven were minor and 60 were major complications (three band infections, two band migrations, 11 band leakages, two slippings/pouch dilatations, two band intolerances, and 40 esophageal dilatations). The overall re-operation rate was 20.4% (34/167). The graft survival of the implanted band after 2, 5, 8, 10, and 12 years was 98.8%, 94.0%, 86.8%, 85.0%, and 85.0%, respectively. The failure rate of the procedure after 2, 5, 8, and 10 years was 25.7%, 24.3%, 25.7%, and 31.6%, respectively. In the present long-term high-participation follow-up study, LAGB is a safe and effective surgical treatment for morbid obesity. However, the high complication, re-operation, and long-term failure rates lead to the conclusion that LAGB should be performed in selected cases only, until reliable criteria for patients at low risk for long-term complications are developed.

We report on a patient with Pneumocystis jirovecii pneumonia who developed fever, rash, eosinophilia and hepatitis 10 days after initiation of a therapy with sulfamethoxazole and trimethoprim. A DRESS syndrome was diagnosed and the therapy was changed successfully to pyrimethamine and dapsone. We describe the clinical picture, causative drugs, pathogenesis, differential diagnoses and therapy of this life-threatening disease to acquaint the general practitioner with it.

Clopidogrel hydrogen sulfate is an antiplatelet agent administered, alone or in combination with acetyl salicylic acid, approved in the prevention of cardiovascular events based on large-scale clinical trials. The new salt formulations clopidogrel where approved based on pharmacokinetic measurements of the inactive prodrug on few healthy volunteers, without any other medication. Clopidogrel hydrogen sulfate has a wide variability in platelet response and the pharmacokinetic of the active metabolite is not dose-linear. Ideally, new clopidogrel salts should be tested for therapeutic equivalence in the target patient population. Should this not be feasible, consistent bioequivalence data should be obtained for the active metabolite, using a properly validated and standardized test method.

We report a case of severe intoxication with extended-release verapamil. In addition to cardiovascular toxicities with hypotension, atrioventricular block and bradycardia, the patient suffered from grand-mal seizure and pulmonary edema 13 and 48 hours respectively, after ingestion of 4.8 g of extended-release verapamil. Adverse reactions after intoxications with extended-release tablets appear delayed with prolonged manifestation of symptoms. Early and repetitive administration of activated charcoal and antegrade whole bowel lavage are crucial, even in primary asymptomatic patients.

Aim: Described are the clinical and, especially, the contrast-enhanced ultrasonographic presentation and recovery of four cases of fascioliasis occurring between December 2008 and February 2009., Materials and Methods: A detailed history, clinical examination and laboratory investigation were followed by contrast-enhanced ultrasonography of the liver and serological evidence for the presence of antibodies. A final contrast-enhanced ultrasound was performed 6 weeks after treatment with triclabendazole., Results: The patients displayed a variety of symptoms ranging from vasospastic myocardial infarction diagnosed via coronary angiography and a first-time occurrence of migraine as a result of hypereosinophilia to fever with weight loss and tumor-like liver lesions. The contrast-enhanced ultrasonographic hepatic changes in fascioliasis are characterized by segmental arterial hyperemia with emphasis on the liver periphery and subcapsular canalicular sparing corresponding to parenchymal necrosis and hemorrhage. In the later phases areas with inflammatory changes were unmasked due to phlebitis of the small portal vessels and granulomatous parenchymal changes. All four patients were successfully treated with triclabendazole without experiencing any serious side effects., Conclusion: Contrast-enhanced ultrasonography is well suited for the diagnosis and monitoring of hepatic fascioliasis., (Georg Thieme Verlag KG Stuttgart . New York.)

Macitentan (ACT-064992) is an orally active endothelin receptor antagonist. We first compared the in vitro dissolution characteristics of uncoated and film-coated tablets with hard gelatin capsules containing 10mg ACT-064992. Subsequently, we compared the oral pharmacokinetics of ACT-064992 and its active metabolite ACT-132577 of the coated tablet and the gelatin capsule formulation in 11 male volunteers. The dissolution profile showed a rapid disintegration of all formulations with >90% dissolution of ACT-064992 within 45 min. The pharmacokinetics of ACT-064992 and its metabolite ACT-132577 were comparable for the two formulations. ACT-064992 revealed a slow absorption (median t(max) 8h) and a terminal half-life of approximately 13 h. Bioequivalence criteria were met for AUC(0-t) and AUC(0-infinity). Mean C(max) was 19% lower after ingestion of the tablet compared to capsules with its lower 90% confidence limit below the accepted bioequivalence range. The pharmacokinetics of the metabolite ACT-132577, characterized by a t(max) of approximately 48 h and a terminal half-life of approximately 45 h, was not different between the two formulations. We conclude that the absorption profile of the tablet differs from the capsule in peak but not in total exposure, which is not expected to be of clinical significance.

We present a case of massive overdose with the atypical antipsychotic quetiapine in a 34-year-old woman (body weight 65 kg). At admission, approximately 2 to 4 hours after ingestion of approximately 24 g of quetiapine, the patient was comatose (Glasgow Coma Scale score 5), requiring orotracheal intubation and transfer to the intensive care unit. Because of myoclonic jerks and generalized seizures, benzodiazepines were administered. In addition to transient mild hypotension after intubation, the main cardiovascular manifestation was sinus tachycardia. The QT interval was normal, and the QTc interval (Bazett's correction) was maximally prolonged to 620 ms. However, no malignant arrhythmias were observed. The patient recovered within 2 days but remained agitated and aggressive, for which she was transferred to the psychiatric clinic. The pharmacokinetics of quetiapine in such a large overdose could not be described by simple first-order kinetics. The initially observed rapid decline of the plasma concentrations of quetiapine could be simulated by first-order kinetics (half life = 4.1 hr) and can most probably be explained by rapid distribution into tissues. The final elimination of the drug from the body occurred after approximately 34 hours at much slower rate, most probably reflecting redistribution from tissues into blood and consecutive hepatic clearance of the drug.

A 55-year-old male patient was hospitalized with severe nausea, vomiting and icterus. Laboratory testing showed hepatocellular damage. After exhaustive testing, the exclusion diagnosis of a toxic hepatitis was reached. There was a strong temporal correlation with the ingestion of Hong Hua 29, a preparation from Traditional Chinese Medicine (TCM). This medication had been started twelve days prior to the first appearance of symptoms. The existing drug regimen included gabapentin (Neurontin), esomeprazole (Nexium) and prednisone (Prednison Streuli) for the therapy of an acute sensory and motor neuropathy of unknown aetiology. After cessation of Hong Hua 29, gabapentin and esomeprazole, transaminase levels started to declined and normalized within three months. According to the Swissmedic criteria of imputability, a causal correlation between the observed symptoms and the administration of Hong Hua 29 is possible.

We describe a 44-year-old male patient with human immunodeficiency virus (HIV) infection and pulmonary arterial hypertension who was treated with several protease inhibitors and with sildenafil. In order to guide treatment with sildenafil, the pharmacokinetics and dynamics of sildenafil were monitored at various time points. In comparison with healthy subjects, the maximal concentration in plasma (Cmax), area under the curve (AUC), and elimination half-life of sildenafil were approximately doubled in the patient. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 hours, the pulmonary arterial hypertension and physical performance of the patient improved significantly. We conclude that the elimination of sildenafil is impaired in patients treated with protease inhibitors, but to a lesser extent than predicted from single-dose studies reported in the literature. Patients treated concomitantly with protease inhibitors and sildenafil need close monitoring of plasma levels, pharmacodynamics, and toxicity of sildenafil in order to be treated optimally.

The authors present a patient with refractory epilepsy who was treated with very high doses (up to 4 mg/min) of intravenous midazolam, phenytoin, carbamazepine, and other antiepileptics. Because it was known from the literature that the half-life of midazolam can increase at high dosage, the kinetics of midazolam (MDZ), 1'-hydroxymidazolam, and 4-hydroxymidazolam were assessed at steady state (dosage 1 mg/min) and after stopping treatment. Total body clearance of MDZ (33 L/kg) and intrinsic hepatic clearance (19 mL/min/kg) at steady state were both five to 10 times higher than after normal therapeutic doses, demonstrating hepatic cytochrome (CYP) 3A induction. Despite the high body clearance, the half-life of MDZ was in the range of 24 hours, approximately 10 times higher than after normal therapeutic doses. The volume of distribution at steady state was 33 L/kg, approximately 50 times higher than after normal therapeutic doses. The free fraction of MDZ was 58% at steady state, much higher than the 3% to 6% at normal therapeutic doses. The kinetics of intravenous MDZ is strongly dependent on its dose and on hepatic CYP3A activity. Even in patients with hepatic CYP3A induction, the half-life of MDZ increases with high doses as a result of a rise in its volume of distribution, which is a consequence of an increase in the free fraction of MDZ.

Serum carbohydrate antigen 19-9 (CA 19-9) has been identified as biochemical marker for biliary tract cancer (BTC). The purpose of this study was to evaluate its value as a treatment response marker and its value as a prognostic parameter in patients with unresectable BTC. We analyzed 70 patients with BTC treated with chemotherapy. CA 19-9 levels before and after two treatment courses were analyzed with respect to their effect on treatment response. Patients were categorized into two subgroups according to biliary stenting: patients without endoscopic intervention or biliary drainage (non-stent subgroup) and patients with endoluminal stenting (stent subgroup). Pretreatment CA 19-9 levels were prognostic with respect to overall survival for the entire study population. Patients with CA 19-9 levels above the median of 300 units/mL had a nearly 3-fold risk for early death (hazard ratio, 2.92; 95% confidence interval, 1.51-5.64; adjusted P = 0.002) as compared with patients with CA 19-9 levels

In an 81-year-old patient with a history of long-standing stable chronic renal failure a diagnosis of multiple myeloma was made. After an initial chemotherapy, a therapy with intravenous pamidronate, 90 mg monthly, was initiated. After four years of well tolerated therapy, pamidronate was stopped and zoledronate, 4 mg intravenously every four weeks, was started. After approximately one year, an elevated plasma creatinine was noted for the'first time, progressing to end stage renal failure within the next months. At admission, besides end-stage renal failure, severe asymptomatic hypocalcemia was noted. Renal biopsy findings included severe tubulointerstitial damage compatible with drug-induced tubular injury. Prerenal and postrenal failure could be excluded as well as myeloma kidney. The diagnosis of zoledronate-associated end-stage renal failure was made and treatment with hemodialysis was started. Hypocalcemia was treated with calcium and vitamin D3 supplements. After two years of follow up, the patient still required hemodialysis.

Background: The possible role of alcohol in the development of hepatotoxicity associated with therapeutic doses of paracetamol (acetaminophen) is currently debated., Case Report: We describe 2 patients who were regular consumers of alcohol and who developed liver failure within 3-5 days after hospitalization and stopping alcohol consumption while being treated with 4 g paracetamol/day. A paracetamol serum level obtained in one of these patients was not in the toxic range. Possible risk factors for the development of hepatotoxicity in patients treated with therapeutic doses of paracetamol are discussed., Conclusion: In patients with risk factors, e.g. regular consumption of alcohol, liver failure is possible when therapeutic doses are ingested. We propose that the paracetamol dose should not exceed 2 g/day in such patients and that their liver function should be monitored closely while being treated with paracetamol., ((c) 2007 S. Karger AG, Basel)

Purpose: To prospectively determine reproducibility of magnetic resonance (MR) angiography and MR spectroscopy of deoxymyoglobin in assessment of collateral vessels and tissue perfusion in patients with critical limb ischemia (CLI) and to follow changes in patients undergoing intramuscular vascular endothelial growth factor (pVEGF)-C gene therapy, percutaneous transluminal angioplasty, supervised exercise training, or no therapy., Materials and Methods: Study and gene therapy protocols were approved, and all patients gave written informed consent. To determine repeatability and reproducibility, seven patients underwent MR angiography and five underwent MR spectroscopy. The techniques were used to judge disease progress in 12 other patients with or without therapy: MR angiography to help determine change in visualization of collateral vessels and MR spectroscopy to help assess change in perfusion at proximal and distal calf levels. MR angiographic results were subjectively analyzed by three blinded readers. Intraobserver variability was expressed as 95% confidence interval (CI) (n=7); interobserver variability, as kappa statistic (n=15). Reexamination variability of MR spectroscopy was given as 95% CI for subsequent recovery times, and correlation with disease extent was calculated with Kendall taub rank correlation. Fisher-Yates test was used to correlate changes with pressure measurements and clinical course., Results: Intraobserver and interobserver concordance was sensitive for detection of collateral vessels. Intraobserver agreement was 85.7% (95% CI: 42.1%, 99.6%). Interobserver agreement was high for small collateral vessels (kappa=0.74, P <.001) and fair for large collateral vessels (kappa=0.36, P=.002). MR spectroscopy was reproducible (95% CI: +/-26 seconds for proximal, +/-21 seconds for distal) and showed a correlation with disease extent (proximal calf, taub=0.84, P <.001; distal calf, taub=0.68, P=.04). Small collateral vessels increased over time (P=.04) but did not correlate with pressure measurements and clinical course. Recovery time correlated with clinical course (proximal calf, P=.03; distal calf, P=.005)., Conclusion: MR angiography and MR spectroscopy of deoxymyoglobin can help document changes in visualization of collateral vessels and tissue perfusion in patients with CLI.

Background: Aim was to analyze the association between local infection and amputation rate in patients with chronic critical limb ischemia (CLI) with or without successful revascularization., Patients and Methods: We performed a retrospective analysis of 56 consecutive patients with 57 critically ischemic legs seen at the University Hospital Bern. Patients with CLI were selected if ischemic lesions and follow-up of more than 2 months were documented. Infection was suggested when 2 of the following criterion were present: temperature > 37 degrees C, C-reactive protein > 50 mg/L, leukocytes > 10 x 10(3)/microliter ("2 of 3" criterion), or a putrid secretion was documented ("secretion" criterion)., Results: In patients with successful revascularization (n = 39), there was a significant shift from 10.3% major to 33.3% minor amputations (Chi Square p value = 0.014) as compared to patients without or with failed revascularization (n = 18) with 44.4% and 11.1% (Chi Square p value = 0.008), respectively. An infection was suggested in 22 of 53 limbs (41.5%) according to the "2 of 3" criterion, and 30 of 57 limbs (52.6%) satisfying the "secretion" criterion. Both criteria, were significantly more common in patients undergoing amputation as compared to patients without amputation (p = 0.001). Multiple lesions were more common in patients with major amputations (p = 0.026)., Conclusion: Successful revascularization effectively reduces major amputations and leads to healing of ischemic ulcers. Secondary foot infections are frequent. Infections are associated with a significantly higher rate of minor and major amputations, also in patients with successful revascularization, and should be treated adequately as well as in time with antibiotics.