Summary
The p35 knockout (p35−/−) mouse is an animal model of temporal lobe epilepsy that recapitulates key neuroanatomic abnormalities—granule cell dispersion and mossy fiber sprouting—observed in ...the hippocampal formation of humans, as well as spontaneous seizure activity. It is a useful model in which to study the relationship between the abnormal neuronal structure and seizure activity to further our understanding of cortical dysplasia in epileptogenesis. Our previous work using this mouse model characterized the anatomic features of the dentate granule cells and the functional implications of these abnormalities on increased recurrent excitation. These data also suggested that there might be compromised inhibition in this animal model. We pursued this possibility, focusing our investigation on inhibitory circuitry. In preliminary investigations using neuroanatomic tools (immunocytochemistry, camera lucida reconstructions of individually labeled interneurons, and electron microscopy) combined with intracellular electrophysiology, we observed no significant reduction in the number of symmetric versus asymmetric synaptic contacts on dentate granule cell somata, and no statistically significant changes in evoked early or late inhibition. Although there were some abnormalities in the morphology/distribution of inhibitory interneurons (as well as a larger population of dentate granule cells) of the dentate gyrus, overall inhibition in the p35 knockout mouse appeared to be largely intact.
One of the major changes in the revised (2018) FIGO-staging system is the addition of stage IIIC to the previously used 2009 system. We evaluated the prognostic value of positive pelvic and/or ...para-aortic lymph nodes in patients with cervical cancer.
A nationwide retrospective cohort study was performed by analyzing data from the Netherlands Cancer Registry. All patients newly diagnosed with stage IB-IVA between 2005 and 2018 were identified. Three-year, 5-year and 15-year overall survival (OS) rates were estimated with the Kaplan-Meier method.
Of the included 6082 patients, 1740 patients (29%) had pelvic and/or para-aortic lymph node metastases. For patients with FIGO 2009 stage IB-IB1-IIA-IIA1 and stage IB2-IIA2-IIB with pelvic and/or para-aortic lymph node metastases the OS was significantly different (p < 0.001 and p = 0.009), with a 5-year OS of 77% and 67%, compared with 92% and 74% for women without lymph node metastases. For FIGO 2009 stage IIIA-IIIB-IVA with and without lymph node metastases, survival rates are not significantly different (p = 0.064). For FIGO 2018 stage IIIC the 3y-OS, 5y-OS and 15-year OS are 72%, 65% and 59% respectively. Survival rates of IIIC diagnosed based on imaging (IIICr) are significantly impaired compared to stage IIIC diagnosed based on pathology (IIICp) (p < 0.001).
Patients with FIGO 2009 stage IB–IIB cervical cancer with pelvic and/or para-aortic lymph node metastases have significantly impaired survival compared to patients without metastases. Survival rates of patients with FIGO 2009 stage IIIA–IVA are not affected by lymph node metastases.
•Survival rates of FIGO 2009 stage IB–IIB are significantly affected by lymph node metastases•Survival rates of FIGO 2009 stage IIIA–IVA are not affected by lymph node metastases•Survival rates of IIICr are significantly more impaired compared to stage IIICp.
Summary
Objective
Aberrations in brain development may lead to dysplastic structures such as periventricular nodules. Although these abnormal collections of neurons are often associated with ...difficult‐to‐control seizure activity, there is little consensus regarding the epileptogenicity of the nodules themselves. Because one common treatment option is surgical resection of suspected epileptic nodules, it is important to determine whether these structures in fact give rise, or essentially contribute, to epileptic activities.
Methods
To study the excitability of aberrant nodules, we have examined c‐fos activation in organotypic hippocampal slice cultures generated from an animal model of periventricular nodular heterotopia created by treating pregnant rats with methylazoxymethanol acetate. Using this preparation, we have also attempted to assess tissue excitability when the nodule is surgically removed from the culture. We then compared c‐fos activation in this in vitro preparation to c‐fos activation generated in an intact rat treated with kainic acid.
Results
Quantitative analysis of c‐fos activation failed to show enhanced nodule excitability compared to neocortex or CA1 hippocampus. However, when we compared cultures with and without a nodule, presence of a nodule did affect the excitability of CA1 and cortex, at least as reflected in c‐fos labeling. Surgical removal of the nodule did not result in a consistent decrease in excitability as reflected in the c‐fos biomarker.
Significance
Our results from the organotypic culture were generally consistent with our observations on excitability in the intact rat—as seen not only with c‐fos but also in previous electrophysiologic studies. At least in this model, the nodule does not appear to be responsible for enhanced excitability (or, presumably, seizure initiation). Excitability is different in tissue that contains a nodule, suggesting altered network function, perhaps reflecting the abnormal developmental pattern that gave rise to the nodule.
Summary
p53 plays an essential role in mediating apoptotic responses to cellular stress, especially DNA damage. In a kainic acid (KA)–induced seizure model in mice, hippocampal CA1 pyramidal cells ...undergo delayed neuronal death at day 3–4 following systemic KA administration. We previously demonstrated that CA1 neurons in p53−/− animals are protected from such apoptotic neuronal loss. However, extensive morphological damage associated with DNA strand breaks in CA1 neurons was found in a fraction of p53−/− animals at earlier time points (8 h to 2 days). No comparable acute damage was observed in wild‐type animals. Stereological counting confirmed that there was no significant loss of CA1 pyramidal cells in p53−/− animals at 7 days post‐KA injection. These results suggest that seizure‐induced DNA strand breaks are accumulated to a greater extent but do not lead to apoptosis in the absence of p53. In wild‐type animals, therefore, p53 appears to stimulate DNA repair and also mediate apoptosis in CA1 neurons in this excitotoxicity model. These results also reflect remarkable plasticity of neurons in recovery from injury.
The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the ...premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence, were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of FMRpolyG, and deficits in motor function.
We report on the construction of a light pulser monitoring system for the electromagnetic lead tungstate (PbWO4) calorimeter of the future P¯ANDA experiment at FAIR. The system consists of a high ...intensity LED source, an optical fibre distribution system, and a novel and compact continuous light attenuation mechanism based on LCDs allowing operation inside the magnetic field of the P¯ANDA detector. The physics objectives of the P¯ANDA experiment require a highly sophisticated electromagnetic calorimeter covering an energy range spanning more than three orders of magnitude. In order to perform precision measurements with this electromagnetic calorimeter based on lead tungstate crystals in the high-luminosity environment of the P¯ANDA experiment, a frequent monitoring of radiation induced transmittance losses in the crystals on a level of 0.5% is required. This precision can be achieved on a day-by-day basis between regular π0/η invariant mass calibrations, performed at least once a day.
The lateral brightness achievable with high-power GaAs-based laser diodes having long and broad waveguides is commonly regarded to be limited by the onset of higher-order lateral modes. For the study ...of the lateral-mode competition two complementary simulation tools are applied, representing different classes of approximations. The first tool bases on a completely incoherent superposition of mode intensities and disregards longitudinal effects like spatial hole burning, whereas the second tool relies on a simplified carrier transport and current flow. Both tools yield agreeing power-current characteristics that fit the data measured for 5-23 µm wide ridges. Also, a similarly good qualitative conformance of the near and far fields is found. However, the threshold of individual modes, the partition of power between them at a given current, and details of the near and far fields show differences. These differences are the consequence of a high sensitivity of the mode competition to details of the models and of the device structure. Nevertheless, it can be concluded concordantly that the brightness rises with increasing ridge width irrespective of the onset of more and more lateral modes. The lateral brightness 2 W mm−1mrad−1 at 10 MW cm−2 power density on the front facet of the investigated laser with widest ridge (23 µm) is comparable with best values known from much wider broad-area lasers. In addition, we show that one of the simulation tools is able to predict beam steering and coherent beam coupling without introducing any phenomenological coupling coefficient or asymmetries.
Broad-area diode lasers with increased brightness and efficiency are presented, which are fabricated using an enhanced self-aligned lateral structure by means of a two-step epitaxial growth process ...with an intermediate etching step. In this structure, current-blocking layers in the device edges ensure current confinement under the central stripe, which can limit the detrimental effects of current spreading and lateral carrier accumulation on beam quality. It also minimizes losses at stripe edges, thus lowering the lasing threshold and increasing conversion efficiency, while maintaining high polarization purity. In the first realization of this structure, the current block is integrated within an extreme-triple-asymmetric epitaxial design with a thin p-doped side, meaning that the distance between the current block and the active zone can be minimized without added process complexity. Using this configuration, enhanced self-aligned structure devices with 90 µm stripe width and 4 mm resonator length show up to 20% lower threshold current, 21% narrower beam waist, and slightly higher (1.03×) peak efficiency in comparison to reference devices with the same dimensions, while slope, divergence angle and polarization purity remain almost unchanged. These results correspond to an increase in brightness by up to 25%, and measurement results of devices with varying stripe widths follow the same trend.
Diabet. Med. 28, 1123–1130 (2011)
Aims The UK National Health Service in England pays for inpatients using a formula (‘tariff’). The appropriateness of the tariff for people with diabetes is ...unknown. We have compared the tariff paid and costs for inpatients with/without diabetes and tested the concept of a ‘diabetes‐attributable hospitalization cost’.
Methods This was a cross‐sectional, retrospective 12‐month audit in a single teaching hospital assessing mortality, bed days per annum and ‘diabetes‐attributable hospitalization cost’ (i.e. the proportion of costs for all patients with diabetes in excess of that paid for comparable patients without diabetes).
Results There were 64 829 inpatient admissions, with 4864 of those coded as having diabetes; 12.9% was estimated to be the number of patients having diabetes but not coded. People with diabetes occupied 13.9% of all bed days and were 18.1% (1.3–37.8%) more likely to die (age adjusted). The mean bed days per annum were greatest among those with (vs. without) diabetes (men 10.9 ± 17.0 vs. 6.3 ± 12.8; women 11.4 ± 19.4 vs. 5.9 ± 11.6; P < 0.001). The greatest excess admission rates were among those aged 25–64 years. The annual mean tariff was greater for those with diabetes (5380 ± 8740) than those without diabetes (3706 ± 6221) (P < 0.001). The overall cost was even higher among those with diabetes: 5835 ± 11 246 vs. 3567 ± 7238 (P < 0.001). The diabetes‐attributable hospitalization cost was 46.5% (9 125 085). An HbA1c > 10.0% (> 86 mmol/mol) was associated with excess hospitalization.
Conclusions Those with diabetes cost more and are more likely to die when inpatients. The tariff paid for diabetes is high, but in this centre less than the actual costs. Approaches known to reduce hospitalization are urgently required.
PDF
