Assessment of the quality of anti-tuberculosis medicines in Almaty, Kazakhstan, 2014.

SETTING: In 2009, the World Health Organization (WHO) conducted a survey of the quality of four anti-tuberculosis drugs in the former Soviet Union countries. Kazakhstan had the highest proportion of substandard drugs. OBJECTIVE: To assess the quality of anti-tuberculosis drugs used in Kazakhstan in 2014. DESIGN: Fourteen anti-tuberculosis drugs from the Almaty Interdistrict TB Dispensary were randomly selected and screened for quality using Global Pharma Health Fund Minilab™ testing. First, the product and packaging were physically inspected to determine whether tablets/capsules were intact (i.e., whether they contained the full amount of the drug, and whether the packaging was genuine). Second, the tablets/capsules were dissolved in water to test whether they could be adequately absorbed by the body. Finally, semi-quantitive analyses were undertaken using thin-layer chromatography to verify the presence and concentration of the active pharmaceutical ingredient and to detect impurities. RESULTS: We discovered no counterfeit medicines. However, 163 (19%) of the 854 anti-tuberculosis drugs sampled failed at least one of the three tests. These samples were found among 24/50 (48%) batches of 14 anti-tuberculosis drugs. CONCLUSION: Our study identified a high proportion of poor-quality first- and second-line anti-tuberculosis drugs. Use of these medicines may lead to treatment failure and the development of drug resistance. Confirmatory testing should be performed to determine if they should be removed from the market.

Limited influence of Si on the preservation of Fe mineral-encrusted microbial cells during experimental diagenesis.

The reconstruction of the history of microbial life since its emergence on early Earth is impaired by the difficulty to prove the biogenicity of putative microfossils in the rock record. While most of the oldest rocks on Earth have been exposed to different grades of diagenetic alterations, little is known about how the remains of micro-organisms evolve when exposed to pressure (P) and temperature (T) conditions typical of diagenesis. Using spectroscopy and microscopy, we compared morphological, mineralogical, and chemical biosignatures exhibited by Fe mineral-encrusted cells of the bacterium Acidovorax sp. BoFeN1 after long-term incubation under ambient conditions and after experimental diagenesis. We also evaluated the effects of Si on the preservation of microbial cells during the whole process. At ambient conditions, Si affected the morphology but not the identity (goethite) of Fe minerals that formed around cells. Fe-encrusted cells were morphologically well preserved after 1 week at 250 °C-140 MPa and after 16 weeks at 170 °C-120 MPa in the presence or in the absence of Si. Some goethite transformed to hematite and magnetite at 250 °C-140 MPa, but in the presence of Si more goethite was preserved. Proteins-the most abundant cellular components-were preserved over several months at ambient conditions but disappeared after incubations at high temperature and pressure conditions, both in the presence and in the absence of Si. Other organic compounds, such as lipids and extracellular polysaccharides seemed well preserved after exposure to diagenetic conditions. This study provides insights about the composition and potential preservation of microfossils that could have formed in Fe- and Si-rich Precambrian oceans.

ScatterJ: An ImageJ plugin for the evaluation of analytical microscopy datasets.

We present ScatterJ, an ImageJ plugin that allows for extracting qualitative as well as quantitative information from analytical microscopy datasets. A large variety of analytical microscopy methods are used to obtain spatially resolved chemical information. The resulting datasets are often large and complex, and can contain information that is not obvious or directly accessible. ScatterJ extends and complements existing methods to extract information on correlation and colocalization from pairs of species-specific or element-specific maps. We demonstrate the possibilities to extract information using example datasets from biogeochemical studies, although the plugin is not restricted to this type of research. The information that we could extract from our existing data helped to further our understanding of biogeochemical processes such as mineral formation or heavy metal sorption. ScatterJ can be used for a variety of different two-dimensional (2D) and three-dimensional (3D) datasets such as energy-dispersive X-ray spectroscopy maps, 3D confocal laser scanning microscopy maps, and 2D scanning transmission X-ray microscopy maps.

Tailored care for somatoform vertigo/dizziness: study protocol for a randomised controlled trial evaluating integrative group psychotherapy.

UNLABELLED: Vertigo/dizziness (VD) ranks high in lifetime prevalence and clinical relevance. Nearly half of the complex VD disorders presenting at specialised units for vertigo or otoneurological disorders are not fully explained by an identifiable medical illness, but instead are related to anxiety, depressive, or somatoform disorders. Although there is some evidence that psychotherapy may be effective for these patients, therapeutic options remain unsatisfactory. This report describes the objectives, design and methods of a randomised, controlled clinical trial, evaluating the efficacy of manualised, multimodal group psychotherapy, based on integrative psychotherapy (IPT) and tailored to subgroups of mental disorders in medically unexplained VD. This psychotherapeutic approach will be compared to self-help groups (n = 172; n = 86 per study arm). Improvements with regard to handicap due to VD at 12 months follow-up will serve as primary outcome. Additionally, measures of generic quality of life, severity of vertigo, depression, anxiety, somatisation as well as Head Impulse Test and Computerized Static Posturography will be applied. We will also analyse the cost-effectiveness of this trial. The study aims to improve treatment of this therapeutically underserved population who are often severely impaired in their working and daily lives. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02320851. TRIAL STATUS: This is an on-going study; recruitment for the study is about to start.

Multiple ionization and fragmentation dynamics of molecular iodine studied in IR-XUV pump-probe experiments.

The ionization and fragmentation dynamics of iodine molecules (I(2)) are traced using very intense (∼10(14) W cm(-2)) ultra-short (∼60 fs) light pulses with 87 eV photons of the Free-electron LASer at Hamburg (FLASH) in combination with a synchronized femtosecond optical laser. Within a pump-probe scheme the IR pulse initiates a molecular fragmentation and then, after an adjustable time delay, the system is exposed to an intense FEL pulse. This way we follow the creation of highly-charged molecular fragments as a function of time, and probe the dynamics of multi-photon absorption during the transition from a molecule to individual atoms.

Optimizing the performance of the entropic splitter for particle separation.

Recently, it has been shown that entropy can be used to sort Brownian particles according to their size. In particular, a combination of a static and a time-dependent force applied on differently sized particles which are confined in an asymmetric periodic structure can be used to separate them efficiently, by forcing them to move in opposite directions. In this paper, we investigate the optimization of the performance of the "entropic splitter." Specifically, the splitting mechanism and how it depends on the geometry of the channel, and the frequency and strength of the periodic forcing is analyzed. Using numerical simulations, we demonstrate that a very efficient and fast separation with a practically 100% purity can be achieved by a proper optimization of the control variables. The results of this work could be useful for a more efficient separation of dispersed phases such as DNA fragments or colloids dependent on their size.

Electron rearrangement dynamics in dissociating I(2)

The charge rearrangement in dissociating I_{2}^{n+} molecules is measured as a function of the internuclear distance R using extreme ultraviolet pulses delivered by the free-electron laser in Hamburg. Within an extreme ultraviolet pump-probe scheme, the first pulse initiates dissociation by multiply ionizing I_{2}, and the delayed probe pulse further ionizes one of the two fragments at a given time, thus triggering charge rearrangement at a well-defined R. The electron transfer between the fragments is monitored by analyzing the delay-dependent ion kinetic energies and charge states. The experimental results are in very good agreement with predictions of the classical over-the-barrier model demonstrating its validity in a thus far unexplored quasimolecular regime relevant for free-electron laser, plasma, and chemistry applications.

3-D analysis of bacterial cell-(iron)mineral aggregates formed during Fe(II) oxidation by the nitrate-reducing Acidovorax sp. strain BoFeN1 using complementary microscopy tomography approaches.

The formation of cell-(iron)mineral aggregates as a consequence of bacterial iron oxidation is an environmentally widespread process with a number of implications for processes such as sorption and coprecipitation of contaminants and nutrients. Whereas the overall appearance of such aggregates is easily accessible using 2-D microscopy techniques, the 3-D and internal structure remain obscure. In this study, we examined the 3-D structure of cell-(iron)mineral aggregates formed during Fe(II) oxidation by the nitrate-reducing Acidovorax sp. strain BoFeN1 using a combination of advanced 3-D microscopy techniques. We obtained 3-D structural and chemical information on different cellular encrustation patterns at high spatial resolution (4-200 nm, depending on the method): more specifically, (1) cells free of iron minerals, (2) periplasm filled with iron minerals, (3) spike- or platelet-shaped iron mineral structures, (4) bulky structures on the cell surface, (5) extracellular iron mineral shell structures, (6) cells with iron mineral filled cytoplasm, and (7) agglomerations of extracellular globular structures. In addition to structural information, chemical nanotomography suggests a dominant role of extracellular polymeric substances (EPS) in controlling the formation of cell-(iron)mineral aggregates. Furthermore, samples in their hydrated state showed cell-(iron)mineral aggregates in pristine conditions free of preparation (i.e., drying/dehydration) artifacts. All these results were obtained using 3-D microscopy techniques such as focused ion beam (FIB)/scanning electron microscopy (SEM) tomography, transmission electron microscopy (TEM) tomography, scanning transmission (soft) X-ray microscopy (STXM) tomography, and confocal laser scanning microscopy (CLSM). It turned out that, due to the various different contrast mechanisms of the individual approaches, and due to the required sample preparation steps, only the combination of these techniques was able to provide a comprehensive understanding of structure and composition of the various Fe-precipitates and their association with bacterial cells and EPS.

Brownian motion in confined geometries.

In a great number of technologically and biologically relevant cases, transport of micro- or nanosized objects is governed by both omnipresent thermal fluctuations and confining walls or constrictions limiting the available phase space. The present Topical Issue covers the most recent applications and theoretical findings devoted to studies of Brownian motion under confinement of channel-like geometries.

Time-resolved measurement of interatomic coulombic decay in Ne2.

The lifetime of interatomic Coulombic decay (ICD) [L. S. Cederbaum et al., Phys. Rev. Lett. 79, 4778 (1997)] in Ne2 is determined via an extreme ultraviolet pump-probe experiment at the Free-Electron Laser in Hamburg. The pump pulse creates a 2s inner-shell vacancy in one of the two Ne atoms, whereupon the ionized dimer undergoes ICD resulting in a repulsive Ne+(2p(-1))-Ne+(2p(-1)) state, which is probed with a second pulse, removing a further electron. The yield of coincident Ne+-Ne2+ pairs is recorded as a function of the pump-probe delay, allowing us to deduce the ICD lifetime of the Ne2(+)(2s(-1)) state to be (150±50) fs, in agreement with quantum calculations.

Experimental and computational analysis of the secretome of the hyperthermophilic archaeon Pyrococcus furiosus.

Although Pyrococcus furiosus is one of the best studied hyperthermophilic archaea, to date no experimental investigation of the extent of protein secretion has been performed. We describe experimental verification of the extracellular proteome of P. furiosus grown on starch. LC-MS/MS-based analysis of culture supernatants led to the identification of 58 proteins. Fifteen of these proteins had a putative N-terminal signal peptide (SP), tagging the proteins for translocation across the membrane. The detected proteins with predicted SPs and known function were almost exclusively involved in important extracellular functions, like substrate degradation or transport. Most of the 43 proteins without predicted N-terminal signal sequences are known to have intracellular functions, mainly (70 %) related to intracellular metabolism. In silico analyses indicated that the genome of P. furiosus encodes 145 proteins with N-terminal SPs, including 21 putative lipoproteins and 17 with a class III peptide. From these we identified 15 (10 %; 7 SPI, 3 SPIII and 5 lipoproteins) under the specific growth conditions of this study. The putative lipoprotein signal peptides have a unique sequence motif, distinct from the motifs in bacteria and other archaeal orders.

Hydrodynamically enforced entropic trapping of Brownian particles.

We study the transport of Brownian particles through a corrugated channel caused by a force field containing curl-free (scalar potential) and divergence-free (vector potential) parts. We develop a generalized Fick-Jacobs approach leading to an effective one-dimensional description involving the potential of mean force. As an application, the interplay of a pressure-driven flow and an oppositely oriented constant bias is considered. We show that for certain parameters, the particle diffusion is significantly suppressed via the property of hydrodynamically enforced entropic particle trapping.

Brownian transport in corrugated channels with inertia.

Transport of suspended Brownian particles dc driven along corrugated narrow channels is numerically investigated in the regime of finite damping. We show that inertial corrections cannot be neglected as long as the width of the channel bottlenecks is smaller than an appropriate particle diffusion length, which depends on the the channel corrugation and the drive intensity. With such a diffusion length being inversely proportional to the damping constant, transport through sufficiently narrow obstructions turns out to be always sensitive to the viscosity of the suspension fluid. The inertia corrections to the transport quantifiers, mobility, and diffusivity markedly differ for smoothly and sharply corrugated channels.

Driven Brownian transport through arrays of symmetric obstacles.

We numerically investigate the transport of a suspended overdamped Brownian particle which is driven through a two-dimensional rectangular array of circular obstacles with finite radius. Two limiting cases are considered in detail, namely, when the constant drive is parallel to the principal or the diagonal array axes. This corresponds to studying the Brownian transport in periodic channels with reflecting walls of different topologies. The mobility and diffusivity of the transported particles in such channels are determined as functions of the drive and the array geometric parameters. Prominent transport features, like negative differential mobilities, excess diffusion peaks, and unconventional asymptotic behaviors, are explained in terms of two distinct lengths, the size of single obstacles (trapping length), and the lattice constant of the array (local correlation length). Local correlation effects are further analyzed by continuously rotating the drive between the two limiting orientations.

Entropic splitter for particle separation.

We present a particle separation mechanism which induces the motion of particles of different sizes in opposite directions. The mechanism is based on the combined action of a driving force and an entropic rectification of the Brownian fluctuations caused by the asymmetric form of the channel along which particles proceed. The entropic splitting effect shown could be controlled upon variation of the geometrical parameters of the channel and could be implemented in narrow channels and microfluidic devices.

The Munich Diagnostic and Predictor Study of Dizziness: objectives, design, and methods.

This report describes the objectives, design, and methods of the Munich Diagnostic and Predictor Study of Dizziness, a prospective study investigating diagnostic subgroups, correlates, and predictors of dizziness that is not sufficiently explained medically but clearly related to a psychiatric disorder. All patients presenting at the Integrated Centre for Research and Treatment of Vertigo, Balance and Ocular Motor Disorders at the University Hospital Großhadern in Munich, Germany, are investigated during their first-time visit. The study consists of a baseline and two follow-up assessment points at 6 and 12 months. At the baseline assessment point, all participants complete self-rated questionnaires concerning dizziness, depression, anxiety, dissociative and traumatic experiences, somatization, body sensations and perception, cognitions, attachment, personality, quality of life and experiences with the health care system. Additionally, a structured clinical interview is conducted to assess mental disorders. Then, the neurologists complete questionnaires regarding the subjective doctor-patient relationship and to document the somatic diagnoses and results. The follow-up measurements consist of self-rated questionnaires. This study aims to improve the diagnosis and treatment of patients who suffer from dizziness related to a psychiatric disorder and who are often severely impaired in their working and daily lives.

[Prospective, randomised study of the Bauer and ALMI approaches concerning MRI findings and muscle-specific blood parameters]. / Prospektive, randomisierte Studie zwischen Bauer- und ALMI-Zugang unter Berücksichtigung von MRI-Befunden und muskelspezifischen Blutparametern.

PURPOSE: The purpose of the present study was to evaluate the MRI of the hip musculature as well as specific blood parameters on comparison of the Bauer approach with the minimally invasive ALMI approach. MATERIAL AND METHODS: We compared two patient groups after total hip replacement, which were operated either via the Bauer or the ALMI approach. All 47 patients had the same cementless hip design. All surgeries were performed by two experienced hip surgeons with experience of more than 1200 ALMI approaches. The patient groups did not differ concerning age, sex or side which was operated on. All MRI were performed in a standardised technique with a Philips Outlook Proview (0.23 Tesla). Patients were scanned preoperatively, within 2 weeks after surgery and at time of follow-up 14 months after surgery. The evaluation of the MRI findings was performed by two independent and blinded examiners. In order to document the muscle damage we documented myoglobin (the day before surgery, 6 hours postoperatively and at the first postop. day) und troponin (6 hours postoperatively). RESULTS: Preoperatively the male patients showed a significantly larger diameter of the gluteus medius muscle. We also could demonstrate in many patients a fatty degeneration even before surgery. At time of follow-up there was no significant difference between the two patient populations concerning the fatty degeneration. There was also no significant difference concerning the muscle atrophy. Muscle oedema, that was present before surgery, however, was no longer present at the time of follow-up. Two patients even preoperatively showed a lesion of the gluteus medius tendon. The range of the postoperative myoglobin level was high (118-5411 µg/L), in the ALMI group the standard deviation was 1445 µg/L, in the Bauer group it was 738 µg/L. There was no significant difference between both groups. Similar findings were documented for the troponin levels. CONCLUSION AND CLINICAL RELEVANCE: Even before THR many patients show significant degeneration in the hip muscles. Muscle oedema that was present before surgery had disappeared at the time of follow-up. The fatty degeneration was still present at the time of follow-up. There was no difference concerning the muscle atrophy between the ALMI and the Bauer groups.

Entropic particle transport: higher-order corrections to the Fick-Jacobs diffusion equation.

Transport of point-size Brownian particles under the influence of a constant and uniform force field through a planar three-dimensional channel with smoothly varying, axis-symmetric periodic side walls is investigated. Here we employ an asymptotic analysis in the ratio between the difference of the widest and the most narrow constriction divided through the period length of the channel geometry. We demonstrate that the leading-order term is equivalent to the Fick-Jacobs approximation. By use of the higher-order corrections to the probability density we show that in the diffusion-dominated regime the average transport velocity is obtained as the product of the zeroth-order Fick-Jacobs result and the expectation value of the spatially dependent diffusion coefficient D(x), which substitutes the constant diffusion coefficient in the common Fick-Jacobs equation. The analytic findings are corroborated with the precise numerical results of a finite element calculation of the Smoluchowski diffusive particle dynamics occurring in a reflection symmetric sinusoidal-shaped channel.

Human neutrophil peptides sputum levels in symptomatic smokers and COPD patients.

BACKGROUND AND OBJECTIVES: Human Neutrophil Peptides (HNP) are major neutrophils' products which may contribute to the airway inflammation and lung remodelling during chronic obstructive pulmonary disease (COPD). We aimed to assess whether HNP sputum concentrations could be used as indicators of airway inflammation and progression towards pulmonary functional impairment, and correlate with the degree of airways obstruction. MATERIALS AND METHODS: We measured, by ELISA tests, HNP concentrations from 37 symptomatic smokers and 34 COPD patients. All participants underwent pulmonary function tests. Sputum samples were collected at the enrolment, and 6 months after smoking cessation. Differences between groups and correlation coefficients between variables were determined using non parametric tests. RESULTS: Sputum HNP concentrations were higher in COPD patients as compared to symptomatic smokers (14 +/- 1.5 microg/ml vs 1.6 +/- 0.4 microg/ml; p < 0.0001). Among COPD patients HNP concentrations were higher in individuals with severe obstruction than in patients with mild to moderate COPD (19.9 +/- 2.3 microg/ml vs 10.3 +/- 0.8 microg/ml, p = 0.003). A negative correlation was observed between HNP levels and FEV1 (rho = -0.38, p = 0.02), and FEV1/FVC (rho = -0.42, p = 0.01). No differences were found in HNP levels before and after 6 months of smoking withdrawal (1.1 microg/ml +/- 0.3 vs 1.1 microg/ml +/- 0.3 for symptomatic smokers, p = 0.9, and 14.4 microg/ml +/- 1 vs 16 microg/ml +/- 1.1 for COPD, p = 0.6). DISCUSSION: Sputum levels of HNP may represent a marker of severity of functional impairment in COPD. Our data support the hypothesis that HNP may have a role in smoking- and COPD-related lung inflammation.

Psychotherapy in dizziness: a systematic review.

BACKGROUND: About 30-50% of complex dizziness disorders are organically not sufficiently explained or related to a psychiatric disorder. Of patients with such dizziness disorders, 80% are severely impaired by dizziness in their daily and working lives; nevertheless, they are often not diagnosed or treated adequately. OBJECTIVES: This review aims to give a systematic overview of psychotherapeutic approaches and their efficacy regarding the treatment of dizziness that is medically not sufficiently explained or related to a psychiatric disorder. METHODS: A systematic literature search was conducted in Medline, PSYNDEX and PsycINFO. Included in this systematic review were (randomised) controlled trials ((R)CTs) concerning psychotherapy in patients with dizziness, medically not sufficiently explained or associated with a psychiatric disorder. If possible, Hedges' g was used to express the effect sizes (ES) of the treatment. Heterogeneity was assessed using the Q statistic. In addition, the quality of the studies was rated. RESULTS: Three (R)CTs were included. All studies used cognitive-behavioural treatment methods in combination with relaxation techniques or vestibular rehabilitation. All studies suggested that psychotherapy may provide improvement. The mean ES in the treatment groups was 0.46 (95% CI 0.05 to 0.88) for dizziness related outcome, 0.10 (-0.44 to 0.64) for anxiety and 0.17 (-0.24 to 0.58) for depression whereas in the control groups the mean dizziness related ES was -0.04 (-0.44 to 0.37), anxiety related ES was -0.03 (-0.43 to 0.38) and depression related ES was -0.02 (-0.42 to 0.38). The quality of the studies was average. Sample sizes were small, however, and there was a lack of long term studies. CONCLUSION: This systematic review provides some preliminary evidence that psychotherapy may be effective in patients with dizziness that is medically not sufficiently explained or due to a psychiatric disorder. The results should be replicated in larger samples and follow-up RCTs.