The mammalian protein ZnT3 resides on synaptic vesicle membranes of zinc-containing neurons, suggesting its possible role in vesicular zinc transport. We show here that histochemically reactive zinc, ...corresponding to the zinc found within synaptic vesicles, was undetectable in the brains of mice with targeted disruption of the ZnT3 gene. Total zinc levels in the hippocampus and cortex of these mice were reduced by about 20%. The ultrastructure of mossy fiber boutons, which normally store the highest levels of vesicular zinc, was unaffected. Mice with one normal ZnT3 allele had reduced levels of ZnT3 protein on synaptic vesicle membranes and had intermediate amounts of vesicular zinc. These results demonstrate that ZnT3 is required for transport of zinc into synaptic vesicles and suggest that vesicular zinc concentration is determined by the abundance of ZnT3.
National and international guidelines recommend empiric first-line treatments of individuals infected with Helicobacter pylori without prior antimicrobial susceptibility testing. For this reason, ...knowledge of primary resistance to first-line antibiotics such as clarithromycin is essential. We assessed the primary resistance of H. pylori in Germany to key antibiotics by molecular genetic methods and evaluated risk factors for the development of resistance.
Gastric tissue samples of 1851 yet treatment-naïve H. pylori-positive patients were examined with real-time PCR or PCR and Sanger sequencing for mutations conferring resistance to clarithromycin, levofloxacin and tetracycline. Clinical and epidemiological data were documented and univariable and multivariable logistic regression analyses were conducted.
Overall primary resistances were 11.3% (210/1851) to clarithromycin, and 13.4% (201/1497) to levofloxacin; resistance to tetracycline (2.5%, 38/1497) was as low as combined resistance to clarithromycin/levofloxacin (2.6%, 39/1497). Female sex and prior antimicrobial therapies owing to unrelated bacterial infections were risk factors for clarithromycin resistance (adjusted OR (aOR) 2.3, 95% CI 1.6–3.4; and 2.6, 95% CI 1.5–4.5, respectively); older age was associated with levofloxacin resistance (aOR for those ≥65 years compared with those 18–35 years: 6.6, 95% CI 3.1–14.2).
Clarithromycin might still be recommended in first-line eradication therapies in yet untreated patients, but as nearly every tenth patient may carry clarithromycin-resistant H. pylori it may be advisable to rule out resistance ahead of treatment by carrying out susceptibility testing or prescribing an alternative therapy.
Correct identification of patients with lymph node metastasis from cervical cancer prior to treatment is of great importance, because it allows more tailored therapy. Patients may be spared ...unnecessary surgery or extended field radiotherapy if the nodal status can be predicted correctly. This review captures the existing knowledge on the identification of lymph node metastases in cervical cancer. The risk of nodal metastases increases per 2009 FIGO stage, with incidences in the pelvic region ranging from 2% (stage IA2) to 14–36% (IB), 38–51% (IIA) and 47% (IIB); and in the para-aortic region ranging from 2 to 5% (stage IB), 10–20% (IIA), 9% (IIB), 13–30% (III) and 50% (IV). In addition, age, tumor size, lymph vascular space invasion, parametrial invasion, depth of stromal invasion, histological type, and histological grade are reported to be independent prognostic factors for the risk of nodal metastases. Furthermore, biomarkers can contribute to predict a patient’s nodal status, of which the squamous cell carcinoma antigen (SCC-Ag) is currently the most widely used in squamous cell cervical cancer. Still, pre-treatment lymph node assessment is primarily performed by imaging, of which diffusion-weighted magnetic resonance imaging has the highest sensitivity and 2-deoxy-2-
18
Ffluoro-D-glucose positron emission computed tomography the highest specificity. Imaging results can be combined with clinical parameters in nomograms to increase the accuracy of predicting positives nodes. Despite all the progress regarding pre-treatment prediction of lymph node metastases in cervical cancer in recent years, prediction rates are not robust enough to safely abandon surgical staging of the pelvic or para-aortic region yet.
To investigate and compare overall survival (OS), disease-free survival (DFS) and toxicity of women who underwent either chemoradiotherapy with or without prior lymph node debulking or upfront ...chemotherapy followed by radiotherapy and hyperthermia (triple therapy) for locally advanced cervical cancer (LACC) to identify a potential role for triple therapy.
Women with histologically proven LACC and with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2 and IIA2 to IVA were included. Cox regression analyses were used for calculating hazard ratios and to adjust for confounding variables. A multivariable logistic regression analysis was used to examine the influence of covariates on toxicity.
A total of 370 patients were included of whom 58% (
= 213) received chemoradiotherapy (CRT), 18% (
= 66) received node-debulking followed by chemoradiotherapy (LND-CRT) and 25% (
= 91) received triple therapy (TT). Five-year OS was comparable between the three treatment groups, with 53% (95% confidence interval 46-59%) in the CRT group, 45% (33-56%) in the LND-CRT group and 53% (40-64%) in the TT group (
= 0.472). In the adjusted analysis, 5-year OS and DFS were comparable between the three treatment groups. No chemotherapy-related differences in toxicity were observed.
This study suggests that the toxicity and survival of TT is similar to CRT or LND-CRT.
Modern treatment guidelines for women with advanced cervical cancer recommend staging using 2-deoxy-2-
Ffluoro-D-glucose positron emission computed tomography (
FFDG-PET/CT). However, the risk of ...false-positive nodes and therapy-related adverse events requires caution in treatment planning. Using data from the Netherlands Cancer Registry (NCR), we estimated the impact of
FFDG-PET/CT on treatment management in women with locally advanced cervical cancer, i.e., on nodal boosting, field extension, and/or debulking in cases of suspected lymph nodes.
Women diagnosed between 2009 and 2017, who received chemoradiotherapy for International Federation of Gynaecology and Obstetrics (2009) stage IB2, IIA2-IVB cervical cancer with an
FFDG-positive node, were retrospectively selected from the NCR database. Patients with pathological nodal examination before treatment were excluded. The frequency of nodal boosting, extended-field radiotherapy, and debulking procedures applied to patients with
FFDG-positive lymph nodes was evaluated.
Among the 434 eligible patients with
FFDG-positive nodes, 380 (88%) received interventions targeting these lymph nodes: 84% of these 380 patients received nodal boosting, 78% extended-field radiotherapy, and 12% debulking surgery.
FFDG-positive nodes in patients receiving these treatments were more likely to be classified as suspicious than inconclusive (
= 0.009), located in the para-aortic region (
< 0.001), and larger (
< 0.001) than in patients who did not receive these treatments.
While existing guidelines advocate
FFDG-PET/CT-guided treatment planning for the management of advanced cervical cancer, this study highlights that not all cases of
FFDG-positive nodes received an intervention, possibly due to the risk of false-positive results. Improvement of nodal staging may reduce suboptimal treatment planning.
Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that is the result of a CGG trinucleotide repeat expansion in the range of 55-200 in the 5` UTR of the
FMR1
gene. ...To better understand the progression of this disorder, a knock-in (CGG KI) mouse was developed by substituting the mouse CGG8 trinucleotide repeat with an expanded CGG98 repeat from human origin. It has been shown that this mouse shows deficits on the water maze at 52 weeks of age. In the present study, this CGG KI mouse model of FXTAS was tested on behavioral tasks that emphasize spatial information processing. The results demonstrate that at 12 and 24 weeks of age, CGG KI mice were unable to detect a change in the distance between two objects (metric task), but showed intact detection of a transposition of the objects (topological task). At 48 weeks of age, CGG KI mice were unable to detect either change in object location. These data indicate that hippocampal-dependent impairments in spatial processing may occur prior to parietal cortex-dependent impairments in FXTAS.
Electrons and holes injected into a semiconductor heterostructure containing quantum wells are captured with a finite time. We show theoretically that this very fact can cause a considerable excess ...contribution to the series resistivity and this is one of the main limiting factors to higher efficiency for GaAs based high-power lasers. The theory combines a standard microscopic-based model for the capture-escape processes in the quantum well with a drift-diffusion description of current flow outside the quantum well. Simulations of five GaAs-based devices differing in their Al-content reveal the root-cause of the unexpected and until now unexplained increase of the series resistance with decreasing heat sink temperature measured recently. The finite capture time results in resistances in excess of the bulk layer resistances (decreasing with increasing temperature) from 1 mΩ up to 30 mΩ in good agreement with the experiment.
The rapid advancement of
9
Be
+
ion-based quantum computing is creating a high demand for scalable and specialized laser sources. For this purpose, laser radiation at 313 nm is necessary which is ...generated by frequency doubling of 626 nm laser emission. Laser sources in this spectral region lack simplicity and need to be miniaturized. We carry out a systematic improvement of room temperature semiconductor laser structures emitting at 626 nm. They are based on a GaInP single quantum well embedded in AlGaInP grown on GaAs. We first investigate the structure theoretically and determine its limits and optima. We select the three most promising quantum well combinations, which are grown by metal-organic vapor-phase epitaxy. Furthermore, we fabricate broad-area lasers with dimensions of 1600
μ
m
×
100
μ
m. All structures show laser operation around 626 nm. We are able to achieve a threshold current density of 721 A/cm
2
, a slope of 0.384 mW/mA and total maximum output power of 708 mW under pulsed excitation. Based on these results, we believe that quantum computing focusing on beryllium ions will highly benefit from these results.
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