Backreflection diagnostics for ultra-intense laser plasma experiments based on frequency resolved optical gating.

We report on the development and implementation of a time resolved backscatter diagnostics for high power laser plasma experiments at the petawatt-class laser facility PHELIX. Pulses that are backscattered or reflected from overcritical plasmas are characterized spectrally and temporally resolved using a specially designed second harmonic generation frequency resolved optical gating system. The diagnostics meets the requirements made by typical experiments, i.e., a spectral bandwidth of more than 30nm with sub-nanometer resolution and a temporal window of 10ps with 50fs temporal resolution. The diagnostics is permanently installed at the PHELIX target area and can be used to study effects such as laser-hole boring or relativistic self-phase-modulation which are important features of laser-driven particle acceleration experiments.

Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug.

INTRODUCTION: Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using lorazepam as model drug. METHODS: Three different formulation strategies were explored to improve the solubility. Firstly, water-soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12months. RESULTS: An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12months at 4°C, with lorazepam content remaining >95%. Related substances increased during the study period but remained below 2%. In-use stability was proven up to 4weeks. CONCLUSION: An organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding.

A randomised, controlled, double-blind trial of ultrasound-guided phrenic nerve block to prevent shoulder pain after thoracic surgery.

Moderate to severe ipsilateral shoulder pain is a common complaint following thoracic surgery. In this prospective, parallel-group study at Odense University Hospital, 76 patients (aged > 18 years) scheduled for lobectomy or pneumonectomy were randomised 1:1 using a computer-generated list to receive an ultrasound-guided supraclavicular phrenic nerve block with 10 ml ropivacaine or 10 ml saline (placebo) immediately following surgery. A nerve catheter was subsequently inserted and treatment continued for 3 days. The study drug was pharmaceutically pre-packed in sequentially numbered identical vials assuring that all participants, healthcare providers and data collectors were blinded. The primary outcome was the incidence of unilateral shoulder pain within the first 6 h after surgery. Pain was evaluated using a numeric rating scale. Nine of 38 patients in the ropivacaine group and 26 of 38 patients in the placebo group experienced shoulder pain during the first 6 h after surgery (absolute risk reduction 44% (95% CI 22-67%), relative risk reduction 65% (95% CI 41-80%); p = 0.00009). No major complications, including respiratory compromise or nerve injury, were observed. We conclude that ultrasound-guided supraclavicular phrenic nerve block is an effective technique for reducing the incidence of ipsilateral shoulder pain after thoracic surgery.

Congenital Chloride Diarrhea: Diagnosis by Easy-Accessible Chloride Measurement in Feces.

Background. Congenital chloride diarrhea (CCD) is an autosomal recessive disorder caused by mutations in the genes encoding the intestinal Cl(-)/HCO3 (-) exchanger and is clinically characterized by watery, profound diarrhea, electrolyte disturbances, and metabolic alkalosis. The CCD diagnosis is based on the clinical symptoms and measurement of high chloride concentration in feces (>90 mmol/L) and is confirmed by DNA testing. Untreated CCD is lethal, while long-term clinical outcome improves when treated correctly. Case Presentation. A 27-year-old woman had an emergency caesarian due to pain and discomfort in gestational week 36 + 4. The newborn boy had abdominal distension and yellow fluid per rectum. Therapy with intravenous glucose and sodium chloride decreased his stool frequency and improved his clinical condition. A suspicion of congenital chloride diarrhea was strongly supported using blood gas analyzer to measure an increased chloride concentration in the feces; the diagnosis was confirmed by DNA testing. Discussion. Measurement of chloride in feces using an ordinary blood gas analyzer can serve as a preliminary analysis when congenital chloride diarrhea is suspected. This measurement can be easily performed with a watery feces composition. An easy-accessible chloride measurement available will facilitate the diagnostics and support the initial treatment if CCD is suspected.

[Patient safety in Sweden]. / Patientensicherheitsarbeit in Schweden.

This article describes the patient safety work in Sweden and the cooperation between the Nordic countries in the area of patient safety. It depicts the national infrastructure, methods and partners in patient safety work as well as the development in key areas. Since 2000, the interest in patient safety and quality issues has significantly increased. A national study (2009) showed that more than 100,000 patients (8.6 %) experienced preventable harm in hospitals. Since 2007, all Swedish counties and regions work on the "National commitment for increased patient safety" to systematically minimize adverse events in the healthcare system. Also, a national strategy for patient safety has been proposed based on a new law regulating the responsibility for patient safety (2011) and a zero vision in terms of preventable harm and adverse events. The Nordic collaboration in this field currently focuses on the development of indicators and quality measurement with respect to nosocomial infections, harm in inpatient somatic care, patient safety culture, hospital mortality and polypharmacy in the elderly. The Nordic collaboration is driven by the development, exchange and documentation of experiences and evidence on patient safety indicators. The work presented in this article is only a part of the Swedish and the Nordic efforts related to patient safety and provides an interesting insight into how this work can be carried out.

Development and validation of a paediatric oral formulation of clonidine hydrochloride.

Many drugs are unavailable in suitable paediatric dosage forms. We describe the development and validation of a stable paediatric oral formulation of clonidine hydrochloride 50 µg/ml, allowing individualised paediatric dosing and easy administration. Stability of the extemporaneously compounded formulation of clonidine hydrochloride was assessed using a validated HPLC method. Clonidine hydrochloride was stable in the buffered aqueous solution at room temperature for up to 9 months. The described formulation is chemically stable for at least 9 months when stored in brown 100 ml PET bottles at room temperature, enabling adequate oral treatment in paediatric patients.

Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.

AIMS: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. METHODS: [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. RESULTS: Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. CONCLUSIONS: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.

Long-term treatment with empagliflozin, a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.

Empagliflozin is a potent, selective sodium glucose co-transporter-2 inhibitor that is in development for the treatment of type 2 diabetes. This series of studies was conducted to assess the in vivo pharmacological effects of single or multiple doses of empagliflozin in Zucker diabetic fatty rats. Single doses of empagliflozin resulted in dose-dependent increases in urinary glucose excretion and reductions in blood glucose levels. After multiple doses (5 weeks), fasting blood glucose levels were reduced by 26 and 39% with 1 and 3 mg/kg empagliflozin, respectively, relative to vehicle. After 5 weeks, HbA1c levels were reduced (from a baseline of 7.9%) by 0.3 and 1.1% with 1 and 3 mg/kg empagliflozin, respectively, versus an increase of 1.1% with vehicle. Hyperinsulinaemic-euglycaemic clamp indicated improved insulin sensitivity with empagliflozin after multiple doses versus vehicle. These findings support the development of empagliflozin for the treatment of type 2 diabetes.

Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8mnd : implications to delayed myelination and oligodendrocyte maturation.

AIMS: CLN8 deficiency underlies one of a group of devastating childhood neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The function of the CLN8 protein is currently unknown, but a role in lipid metabolism has been proposed. In human CLN8 diseased brains, alterations in lipid composition have been detected. To further investigate the connection of CLN8 to lipid metabolism, we characterized the lipid composition of early symptomatic Cln8-deficient mouse (Cln8(mnd)) brains. METHODS: For lipid profiling, Cln8(mnd) cerebral cortical tissue was analysed by liquid chromatography/mass spectrometry. Galactolipid synthesis was measured through enzyme activity and real-time mRNA expression analyses. Based on the findings, myelination and white matter integrity were studied by immunohistochemistry, stereological methods, electron microscopy and magnetic resonance imaging. The development of myelin-forming oligodendrocytes was also studied in vitro. RESULTS: Sphingolipid profiling showed a selective reduction in myelin-enriched galactolipids. The mRNA expression and activity of UDP-galactose:ceramide galactosyltransferase (CGT), the key enzyme in the galactolipid synthesis, was reduced in the Cln8(mnd) brain. Expression of oligodendrocyte markers suggests a maturation defect. The amount of myelin was reduced in 1-month-old Cln8(mnd) mice, but reached normal levels by 5 months of age. The level of Cln8 gene expression followed the developmental pattern of myelin formation and was high in primary oligodendrocytes. CONCLUSIONS: Taken together, these observations suggest that galactolipid deficiency and delayed myelin maturation characterize the early CLN8 disease pathogenesis through a maturation defect of oligodendrocytes.

Symptoms, prostate volume, and urodynamic findings in elderly male volunteers without and with LUTS and in patients with LUTS suggestive of benign prostatic hyperplasia.

OBJECTIVES: To estimate the differences in symptoms, prostate volume, and urodynamic variables of symptom-free elderly volunteers, volunteers with lower urinary tract symptoms (LUTS), and urologic patients with LUTS suggestive of benign prostatic hyperplasia. METHODS: The study included 14 male volunteers without LUTS, 17 male volunteers with LUTS, and 565 urologic patients with LUTS who met the criteria of the International Consensus Committee on Benign Prostatic Hyperplasia. They were older than 50 years, they voided more than 150 mL during free uroflowmetry, their residual volume and prostate volume were estimated, and their American Urological Association symptom scores were collected. All men were also evaluated by urodynamic studies. RESULTS: The prostate volume, residual volume, urethral resistance factor, and symptom scores were significantly lower and the maximal free flow rate and effective capacity significantly higher in the symptom-free volunteers than in the volunteers and patients with LUTS. Except for prostate volume, the variables in volunteers with LUTS closely approximated those of the patients with LUTS. The volunteers with LUTS had a smaller prostate volume than did the patients with LUTS. Nevertheless, the maximal free flow rate, symptoms, degree of obstruction, and prevalence of residual volume did not differ between the two groups. Men with an unstable bladder were present in all groups. CONCLUSIONS: Symptom-free volunteers had smaller prostate volumes, less residual volume, lower symptom scores, a lower urethral resistance factor, a higher maximal free flow rate, and a higher effective capacity than those with LUTS. Except for a smaller prostate volume, the findings in the volunteers with LUTS closely approximated those of the urologic patients with LUTS.

Interactions between prostate volume, filling cystometric estimated parameters, and data from pressure-flow studies in 565 men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

The aim of this study was to establish the characteristics and to investigate the interactions between prostate volume, degree of obstruction, bladder contractility, the prevalence of residual volume, bladder compliance, bladder capacities, and the prevalence of instability in a large, well-defined group of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). The 565 consecutive men included in this study met the criteria of the International Consensus Committee on BPH and voided more than 150 mL during uroflowmetry. Their residual urine volume and prostate size were estimated, and filling cystometry and pressure-flow studies were performed. Fifty-three percent of the men appeared to have obstruction. We found a positive correlation between prostate volume and Schäfer's obstruction grade, except that mean prostate volume decreased at Schäfer's grades 5 and 6. Significant negative correlations existed between Schäfer's grade and cystometric bladder capacity and effective capacity. Bladder outlet obstruction results in incomplete emptying. Of all men, 26% had a significant residual volume ( > 20% of cystometric capacity). Thirty-nine percent did not have residual volume. Of the 565 men, 46% had an unstable bladder. In particular, patients with an unstable bladder in the sitting and lying positions have a significantly higher Schäfer's grade and contractility grade and a significantly lower cystometric and effective bladder capacity compared with patients without instability. Patients with a residual volume or instability were significantly older. We conclude that in men with LUTS suggestive of BPH, abnormalities of bladder and bladder outlet function vary greatly and have complex mutual interactions.

One 24-hour frequency-volume chart in a woman with objective urinary motor urge incontinence is sufficient.

OBJECTIVES: To determine whether one 24-hour frequency-volume (FV) chart in a woman with objective urinary motor urge incontinence is sufficient to gain insight into her voiding habits. METHODS: Retrospectively, women 18 years old and older with urodynamically confirmed urinary motor urge incontinence without neurologic disease or other urologic pathologic findings, who correctly completed two or three 24-hour FV charts during normal daily life, were studied. For each patient, we compared the voiding parameters (mean voided volume, diuria, nocturia, minimum and maximum voided volumes, and total voided volume) and fluid intake calculated from the first FV chart with the same data calculated from all the FV charts. RESULTS: Ninety-eight adult women were recruited. A marked dropout occurred, and 60 patients remained to be evaluated (mean age 54.5 +/- 15.5 years). The calculated voiding parameters agreed with those in published reports. Strong associations existed between all voiding parameters and fluid intake calculated from the first FV chart and those calculated from all FV charts (P <0.001 for all parameters). Compared with the well-known variability, the differences between the voiding parameters calculated from the first FV chart and those from all charts were small. These results agreed with studies in other patient groups (benign prostatic hyperplasia and interstitial cystitis) that analyzed the use of only one 24-hour FV chart. CONCLUSIONS: The use of only one 24-hour FV chart completed during normal daily life by a woman with objective urinary motor urge incontinence is sufficient to gain insight into her voiding habits.

Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker (fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body adiposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the major fat depots but also to fat deposition throughout the body. Adipocyte sizing profiles, fat pad histology, and DNA content show that Pio treatment increased the number of small adipocytes because of both the appearance of new adipocytes and the shrinkage and/or disappearance of existing mature adipocytes. The remodeling was time dependent, with new small adipocytes appearing in clusters throughout the fat pad, and accompanied by a three- to fourfold increase in citrate synthase and fatty acid synthase activity. The appearance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutaneous. This differential depot effect resulted in a redistribution of the fat mass in the abdominal region such that there was an increase in the visceral:subcutaneous ratio, as confirmed by MRI analysis. Although the increased adiposity is paradoxical to an improvement in insulin sensitivity, the quantitative increase of adipose mass should be viewed in context of the qualitative changes in adipose tissue, including the remodeling of adipocytes to a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ultimately improving insulin sensitivity and the metabolic state.

Prevalence and bothersomeness of lower urinary tract symptoms in benign prostatic hyperplasia and their impact on well-being.

PURPOSE: We established the prevalence and bothersomeness of symptoms and their impact on well-being in a large group of strictly selected men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Included in our study were 475 consecutive men who met the criteria of the International Consensus Committee on BPH and voided more than 150 ml. during uroflowmetry. International Prostate Symptom Scores and quality of life score were determined. We included the 7 bothersomeness questions of the Symptom Problem Index and the 4 of the BPH Impact Index of the American Urological Association Measurement Committee. These questions refer to the degree of bothersomeness caused by urinary problems and how they affect various health domains. RESULTS: The symptoms with the highest prevalence based on mean scores were weak urinary stream, frequency and urgency. Urgency, nocturia and hesitancy were the most bothersome symptoms. Patients were only discouraged from performing normal daily activity when the symptom index exceeded 20. Incomplete emptying and frequency bothersomeness correlated strongly, and weak urinary stream and hesitancy bothersomeness correlated weakly with all health and quality of life domains. CONCLUSIONS: Weak urinary stream, frequency and urgency were the most prevalent symptoms, while urgency, nocturia and hesitancy were the most bothersome symptoms. In contrast to weak urinary stream and hesitancy, the bothersomeness of incomplete emptying and frequency was strongly associated with well-being.

The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice.

This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.

[Malignant melanoma of the ciliary body. A diagnostic problem]. / Das maligne Melanom des Ziliarkörpers. Ein diagnostisches Problem.

BACKGROUND: Ciliary body melanoma is often diagnosed too late and therefore has a poor prognosis. The circular infiltration of the iridocorneal angle by malignant cells can lead to secondary glaucoma, often misdiagnosed as pigmentary glaucoma. MATERIAL AND METHODS: In a 40-year-old patient the diagnosis "atypical pigmentary glaucoma" was made due to elevated intraocular pressure and pigmentation of the iridocorneal angle; no changes were present in the iris. In a second case pronounced pigmentation of the chamber angle and secondary glaucoma led to the clinical diagnosis of a ring melanoma and resulted in enucleation of the globe. RESULTS: In the first case, increasing pigmentation of the chamber angle over 4 weeks led to the presumed diagnosis of a ring melanoma. Histopathological evaluation confirmed the diagnosis of a ring melanoma of the ciliary body. In the second case histology revealed retinal detachment with intraocular bleeding without intraocular melanoma. The pigmentation in the lower part of the chamber angle was due to hemosiderosis. CONCLUSION: Diagnosis of ciliary body melanomas may be difficult in some cases due to its similarity to other eye diseases. The differential diagnosis of malignant melanoma of the ciliary body should be considered in cases of unilateral pigmentary glaucoma.

Symptoms and quality of life versus age, prostate volume, and urodynamic parameters in 565 strictly selected men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

OBJECTIVES: To investigate the associations of symptoms and quality of life with age, prostate volume, and urodynamic parameters in a large group of strictly selected men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: The 565 consecutive men met all the criteria of the International Consensus Committee on benign prostatic hyperplasia and voided more than 150 mL during uroflowmetry. The residual volumes and prostate sizes were estimated. The International Prostate Symptom Score (IPSS) and quality-of-life score were collected and urodynamic evaluations performed. RESULTS: The prostate volume and obstruction grade were not, but low detrusor contractility and low bladder capacity were, significantly associated with symptoms. Except for nocturia, older men presented with lower voiding scores on the IPSS. The presence of a residual urine volume hardly influenced patients' symptoms and quality of life. Men with an unstable bladder scored higher on frequency, urgency, and nocturia on the IPSS, but the symptom index and quality-of-life score were not affected by the presence of an unstable bladder. Because of the high variability and subjective interpretation of symptoms and because urodynamic parameters may have opposite implications than symptoms and vice versa, associations were still weak. CONCLUSIONS: Except for nocturia, older men had lower voiding scores on the IPSS. Prostate volume and obstruction grade were not, but low detrusor contractility and low capacities were, associated with the symptom index. The presence of an unstable bladder and/or residual volume was hardly associated with the symptom index or quality-of-life score. Although we used a large group of strictly selected men, the associations were still weak.

The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter.

Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation. No deficiency in fucosyltransferase activities or in the activities of enzymes involved in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced. To identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabditis elegans, encoding multi-spanning transmembrane proteins with homology to known nucleotide sugar transporters, and transfected them into fibroblasts from an LAD II patient. One of these clones re-established expression of fucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fucosylated glycoconjugates. Both proteins were localized to the Golgi. The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region. Overexpression of this mutant protein in cells from a patient with LAD II did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein. Thus, we have identified the first putative GDP-fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II.