Summary Patients under immunosuppressive therapy with tumor necrosis factor alpha (TNF-α) antagonists are vulnerable to various opportunistic infections including leishmaniasis. We present a case ...series of 8 travellers developing cutaneous leishmaniasis whilst on TNF-α antagonist treatment and review the literature on aspects of cutaneous leishmaniasis developing in patients treated with TNF-α antagonists. We make interim recommendations regarding the drug therapy used to maintain remission in travellers with rheumatoid disease travelling to leishmania prone areas. Despite having a medical condition requiring continued rheumatological review the interval to diagnosis appears not to be reduced compared to that described in non-rheumatoid patients. Rheumatologists and family doctors should be aware of the need for post-travel surveillance for leishmaniasis in rheumatoid patients on TNF-alpha antagonist treatment.
We prospectively studied 26 (10 women) patients (age, 37.4 +/- 10.3 years) with different types of refractory focal epilepsy who received topiramate as adjunctive treatment.
Body mass indices (BMI, ...kg/m2) and serum leptin levels (SLL) were investigated at baseline (n = 26) and 9.5 +/- 2.9 (T1; n = 21) and 25.0 +/- 3.5 (T2; n = 18) weeks after initiation of topiramate.
We found significant reductions in BMI (T1, -0.4 +/- 0.7; T2, -1.3 +/- 2.1 kg/m2) but not in SLL, although a tendency for reduced SLL was observed for women. Serum leptin level changes were mostly within the range between fifth and 95th sex-specific BMI-adjusted reference percentiles. Significant inverse correlations were found between baseline values and changes in both BMI (T2; r = -0.76; P < 0.001) and SLL (T2; r = -0.65; P = 0.003). Patients with BMI of 30.0 kg/m2 or greater showed the highest weight loss at T2 (-4.8 +/- 3.2 kg/m2).
Our findings do not provide evidence for a direct causal involvement of leptin in topiramate-related weight loss.
We report the synthesis and photophysical properties of two different photonic devices. The first system describes dinuclear metal complexes with a rigid and linear bridging ligand (PAP) that ...contains an adamantane spacer. We discuss the correlation between the nature of the bridging ligand and the electrochemical as well as photophysical properties of the metal complexes. Two interesting observations can already be pointed out: (i) the lifetime of the intermediate electron-transfer product Ru
III–PAP–Os
II is very long (130 μs); and (ii) for the first time in a dinuclear Ru/Os system, the rate constant of energy transfer from the Ru(II) to the Os(II) unit is faster than the rate of the electron transfer from the Ru(II) to the Os(III) unit. The second system represents a photonic switch which is built up by two subunits, a rhenium complex as the active switching part and an anthracene moiety as detector. We discuss the synthesis, the reversibility of the switch and the energy transfer properties of the new system.
The surface properties of CuInS sub(2) (CIS) thin-film solar cell absorbers are investigated by a combination of electron and soft X-ray spectroscopies. Spatially separated regions of varying colors ...are observed and identified to be dominated by either CuS or Cu sub(2)S surface phases. After their removal by KCN etching, the samples cannot be distinguished by eye and the CIS surface is found to be Cu-deficient in both regions. However, a significantly more pronounced off-stoichiometry in the region initially covered by Cu sub(2)S can be identified. In this region, the resulting surface band gap is also significantly larger than the E sub(g) super(Surf) of the initially CuS-terminated region. Such variations may represent a hidden parameter which, if overlooked, induces irreproducibility and thus prevents systematic optimization efforts. Spatially separated CuInS sub(2) (CIS) surface regions of varying colors are observed and shown to be dominated by either CuS or Cu sub(2)S phases. After removal, the chemical and electronic CIS surface structure still differs. Thus, for a systematic CIS material optimization towards higher-efficiency thin-film solar cells, the Cu sub(2-x)S surface phase composition should be monitored/controlled.
Abstract
The surface properties of CuInS
2
(CIS) thin‐film solar cell absorbers are investigated by a combination of electron and soft X‐ray spectroscopies. Spatially separated regions of varying ...colors are observed and identified to be dominated by either CuS or Cu
2
S surface phases. After their removal by KCN etching, the samples cannot be distinguished by eye and the CIS surface is found to be Cu‐deficient in both regions. However, a significantly more pronounced off‐stoichiometry in the region initially covered by Cu
2
S can be identified. In this region, the resulting surface band gap is also significantly larger than the E
g
Surf
of the initially CuS‐terminated region. Such variations may represent a hidden parameter which, if overlooked, induces irreproducibility and thus prevents systematic optimization efforts.
Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a ZnII‐dependent, membrane‐bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is ...involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((±)‐1, (±)‐43, (±)‐45, and (±)‐46; Table) were designed, based on the X‐ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H‐bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the ZnII ion and two aromatic residues to bind into the hydrophobic S1′ and S2′ pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1–4 and 5–8), with the second one involving a double directed ortho‐metallation of the imidazole platform and a Stille cross‐coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (±)‐1, (±)‐43, (±)‐45, and (±)‐46 all exhibit IC50 values in the single‐digit micromolar activity range (2–4 μM, Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.
Allergy is an immunological disorder of the upper airways, lung, skin, and the gut with a growing prevalence over the last decades in Western countries. Atopy, the genetic predisposition for allergy, ...is strongly dependent on familial inheritance and environmental factors. These observations call for predictive markers of progression from atopy to allergy, a prerequisite to any active intervention in neonates and children (prophylactic interventions/primary prevention) or in adults (immunomodulatory interventions/secondary prevention). In an attempt to identify early biomarkers of the “atopic march” using minimally invasive sampling, CD4+ T cells from 20 adult volunteers (10 healthy and 10 with respiratory allergies) were isolated and quantitatively analyzed and their proteomes were compared in and out of pollen season (± antigen exposure). The proteome study based on high-resolution 2D gel electrophoresis revealed three candidate protein markers that distinguish the CD4+ T cell proteomes of normal from allergic individuals when sampled out of pollen season, namely Talin 1, Nipsnap homologue 3A, and Glutamate-cysteine ligase regulatory protein. Three proteins were found differentially expressed between the CD4+ T cell proteomes of normal and allergic subjects when sampled during pollen season: carbonyl reductase, glutathione S-transferase ω 1, and 2,4-dienoyl-CoA reductase. The results were partly validated by Western blotting.
Dissolution-precipitation phenomena induced by CO sub(2) injection to Altmark Permian sandstone were observed through laboratory experiments carried out under simulated reservoir conditions (125 ...degree C and 50 bars of pressure). The rock sample was collected from the Altmark gas reservoir, which is being considered for enhanced gas recovery. Two sets of experiments were performed with pulverized rock samples in a closed batch reactor with either pure water (run 1) or 3 M aqueous NaCl solution (run 2) and reacted with injected CO sub(2) for 3, 5, and 9 days. The liquid samples were analyzed by inductively coupled plasma optical emission spectroscopy and total reflection X-ray fluorescence, where the latter proved to be a feasible alternative to conventional analytical techniques, especially since only small sample volumes (about 10 mu l) are needed. Chemical analysis for both fluids (water and NaCl brine) indicated a significant dissolution of calcite and anhydrite in the solution, which might be a crucial process during CO sub(2) injection. The brine solution enhanced the dissolution of calcite and anhydrite compared to pure water at the beginning of the reaction. Moreover, the progressive higher Si super(4+)/Al super(3+) molar ratios (in average by a factor of 3) in the brine experiments indicated quartz dissolution. Thermodynamic calculations of mineral saturation indices highlighted the dissolution of the Ca-bearing minerals, which was in agreement with experimental results. Modeling enabled an evaluation of the dissolution processes of minerals in a low-salinity region, yet hindrances to model more saline conditions emphasize the need for further laboratory studies in order to parameterize models for deep aquifer conditions.
Cav1.3 L-type Ca
channels (LTCCs) in cochlear inner hair cells (IHCs) are essential for hearing as they convert sound-induced graded receptor potentials into tonic postsynaptic glutamate release. To ...enable fast and indefatigable presynaptic Ca
signaling, IHC Cav1.3 channels exhibit a negative activation voltage range and uniquely slow inactivation kinetics. Interaction with CaM-like Ca
-binding proteins inhibits Ca
-dependent inactivation, while the mechanisms underlying slow voltage-dependent inactivation (VDI) are not completely understood. Here we studied if the complex formation of Cav1.3 LTCCs with the presynaptic active zone proteins RIM2α and RIM-binding protein 2 (RBP2) can stabilize slow VDI. We detected both RIM2α and RBP isoforms in adult mouse IHCs, where they co-localized with Cav1.3 and synaptic ribbons. Using whole-cell patch-clamp recordings (tsA-201 cells), we assessed their effect on the VDI of the C-terminal full-length Cav1.3 (Cav1.3
) and a short splice variant (Cav1.3
) that lacks the C-terminal RBP2 interaction site. When co-expressed with the auxiliary β3 subunit, RIM2α alone (Cav1.3
) or RIM2α/RBP2 (Cav1.3
) reduced Cav1.3 VDI to a similar extent as observed in IHCs. Membrane-anchored β2 variants (β2a, β2e) that inhibit inactivation on their own allowed no further modulation of inactivation kinetics by RIM2α/RBP2. Moreover, association with RIM2α and/or RBP2 consolidated the negative Cav1.3 voltage operating range by shifting the channel's activation threshold toward more hyperpolarized potentials. Taken together, the association with "slow" β subunits (β2a, β2e) or presynaptic scaffolding proteins such as RIM2α and RBP2 stabilizes physiological gating properties of IHC Cav1.3 LTCCs in a splice variant-dependent manner ensuring proper IHC function.
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