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Atom probe tomography (APT) is used to quantify atomic-scale elemental and isotopic compositional variations within a very small volume of material (typically <0.01 µm3). The small analytical volume ideally contains specific compositional or microstructural targets that can be placed within the context of the previously characterized surface in order to facilitate a correct interpretation of APT data. In this regard, careful targeting and preparation are paramount to ensure that the desired target, which is often smaller than 100 nm, is optimally located within the APT specimen. Needle-shaped specimens required for atom probe analysis are commonly prepared using a focused ion beam scanning electron microscope (FIB-SEM). Here, we utilize FIB-SEM-based time-of-flight secondary ion mass spectrometry (ToF-SIMS) to illustrate a novel approach to targeting <100 nm compositional and isotopic variations that can be used for targeting regions of interest for subsequent lift-out and APT analysis. We present a new method for high-spatial resolution targeting of small features that involves using FIB-SEM-based electron deposition of platinum “buttons” prior to standard lift-out and sharpening procedures for atom probe specimen manufacture. In combination, FIB-ToF-SIMS analysis and application of the “button” method ensure that even the smallest APT targets can be successfully captured in extracted needles.
The early and effective detection of neurocognitive disorders poses a key diagnostic challenge. We examined performance on common cognitive bedside tests according to differing delirium syndromal status and clinical (motor) subtypes in hospitalized elderly medical inpatients.
A battery of nine bedside cognitive tests was performed on elderly medical inpatients with DSM-IV delirium, subsyndromal delirium (SSD), and no delirium (ND). Patients with delirium were compared according to clinical (motor) subtypes.
A total of 198 patients (mean age 79.14 ± 8.26) were assessed with full syndromal delirium (FSD: n = 110), SSD (n = 45), and ND (n = 43). Delirium status was not associated with differences in terms of gender distribution, age, or overall medication use. Dementia burden increased with greater delirium status. Overall, the ability to meaningfully engage with the tests varied from 59% for the Vigilance B test to 85% for Spatial Span Forward test and was lowest in patients with FSD, where engagement ranged from 32% for the Vigilance B test to 77% for the Spatial Span Forwards test. The ND group was distinguished from SSD group for the Months of the year backwards, Vigilance B, global VSP, Clock Drawing test, and Interlocking Pentagons test. The SSD group was distinguished from the FSD group by Vigilance A, Spatial Span Forward, and Spatial Span Backwards. Regarding differences among motor subtypes in terms of percentage engagement and performance, the No subtype group had higher ratings across all tests. Delirious patients with no subtype had significantly lower scores on the DRS-R98 than for the other three subtype categories.
Simple bedside tests of attention, vigilance, and visuospatial ability are useful in distinguishing neurocognitive disorders, including SSD from other presentations.
Resistance training (RT) and increased dietary protein are recommended to attenuate age-related muscle loss in the elderly. This study examined the effect of a lean red meat protein-enriched diet combined with progressive resistance training (RT+Meat) on health-related quality of life (HR-QoL) in elderly women. In this 4-month cluster randomised controlled trial, 100 women aged 60–90 years (mean 73 years) from self-care retirement villages participated in RT twice a week and were allocated either 160 g/d (cooked) lean red meat consumed across 2 meals/d, 6 d/week or ≥1 serving/d (25–30 g) carbohydrates (control group, CRT). HR-QoL (SF-36 Health Survey questionnaire), lower limb maximum muscle strength and lean tissue mass (LTM) (dual-energy X-ray absorptiometry) were assessed at baseline and 4 months. In all, ninety-one women (91 %) completed the study (RT+Meat (n 48); CRT (n 43)). Mean protein intake was greater in RT+Meat than CRT throughout the study (1·3 (sd 0·3) v. 1·1 (sd 0·3) g/kg per d, P<0·05). Exercise compliance (74 %) was not different between groups. After 4 months there was a significant net benefit in the RT+Meat compared with CRT group for overall HR-QoL and the physical component summary (PCS) score (P<0·01), but there were no changes in either group in the mental component summary (MCS) score. Changes in lower limb muscle strength, but not LTM, were positively associated with changes in overall HR-QoL (muscle strength, β: 2·2 (95 % CI 0·1, 4·3), P<0·05). In conclusion, a combination of RT and increased dietary protein led to greater net benefits in overall HR-QoL in elderly women compared with RT alone, which was because of greater improvements in PCS rather than MCS.
In an intensive livestock production, a shorter suckling period allows more piglets to be born. However, this practice leads to a number of disorders including nutrient malabsorption, resulting in diarrhoea, malnutrition and dehydration. A number of strategies have been proposed to overcome weaning problems. Artificial sweeteners, routinely included in piglets' diet, were thought to enhance feed palatability. However, it is shown in rodent models that when included in the diet, they enhance the expression of Na+/glucose co-transporter (SGLT1) and the capacity of the gut to absorb glucose. Here, we show that supplementation of piglets' feed with a combination of artificial sweeteners saccharin and neohesperidin dihydrochalcone enhances the expression of SGLT1 and intestinal glucose transport function. Artificial sweeteners are known to act on the intestinal sweet taste receptor T1R2/T1R3 and its partner G-protein, gustducin, to activate pathways leading to SGLT1 up-regulation. Here, we demonstrate that T1R2, T1R3 and gustducin are expressed together in the enteroendocrine cells of piglet intestine. Furthermore, gut hormones secreted by the endocrine cells in response to dietary carbohydrates, glucagon-like peptides (GLP)-1, GLP-2 and glucose-dependent insulinotrophic peptide (GIP), are co-expressed with type 1 G-protein-coupled receptors (T1R) and gustducin, indicating that L- and K-enteroendocrine cells express these taste elements. In a fewer endocrine cells, T1R are also co-expressed with serotonin. Lactisole, an inhibitor of human T1R3, had no inhibitory effect on sweetener-induced SGLT1 up-regulation in piglet intestine. A better understanding of the mechanism(s) involved in sweetener up-regulation of SGLT1 will allow the identification of nutritional targets with implications for the prevention of weaning-related malabsorption.
Traditional anti-cancer drugs preferentially kill rapidly growing tumour cells rather than normal cells. However, most of these drugs have no preferential selection towards cancer cells and are taken up by the whole body, resulting in significant adverse side effects. Therapeutic molecules that could specifically inhibit undesirable phenotypes are an attractive way of eliminating cancer cells. There is a widespread effort to develop inhibitors against signal transduction molecules that play a key role in the proliferative, migratory and invasive properties of a cancer cell. Grb7 is an adaptor-type signalling protein that is recruited via its Src-homology 2 (SH2) domain to a variety of tyrosine kinases. Grb7 is overexpressed in breast, oesophageal and gastric cancers, and may contribute to the invasive potential of cancer cells. Molecular interactions involving Grb7 therefore provide attractive targets for therapeutic intervention.
Abstract: Retrospective analysis of detailed patient and tumour factors associated with a complete response to combination inductive chemotherapy with CDDP-5FU (96 or 120 hour continuous infusion) was performed using data from 147 patients with a previously untreated squamous cell carcinoma of the oral cavity, oropharynx or pharyngo-larynx following completion of two (29 patients) or three (118 patients) cycles. Adverse reactions to chemotherapy were documented for all 164 patients included in the study. Eight drug-related deaths occurred due to: acute myocardial infarction (five patients), peptic ulcer disease (two patients) and severe neutropenia with sepsis (one patient). Severe non-lethal complications included marrow depletion (14 patients), peptic ulcer (two patients), thrombophlebitis (seven patients), angina pectoris (two patients), stroke (one patient), pulmonary oedema (one patient) and convulsions (one patient). Six patients refused further treatment because of untoward side effects and tumoral progression was observed in three cases. Separate response rates for the primary site and nodes were determined and analysis of respective predictive factors of response was performed. Complete response was obtained in 31 per cent at the primary site versus 18 per cent for the nodes (p<0.05). The combined (primary site + nodes) overall complete response rate was 22 per cent. Among 11 factors studied (age, sex, performance status, primary site, tumour differentiation, initial resectability, 5FU dosage per cycle, number of cycles, T, N and TN stages), only performance status, N stage, resectability and number of cycles were associated with a combined complete response. Multivariate analysis showed performance status, N stage, TN stage and resectability to be significant predictive factors of a combined complete response. Optimum use of inductive chemotherapy will ultimately rely upon a better knowledge of predictive factors in order to avoid drug-related complications in patients not expected to respond.
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