Drinking behaviour and alcohol-related harm amongst older adults: analysis of existing UK datasets.

Older adults experience age-related physiological changes that increase sensitivity and decrease tolerance to alcohol and there are a number of age-related harms such as falls, social isolation and elder abuse, which are compounded by alcohol misuse. Despite this unique vulnerability and the fact that the number of older adults is increasing, the literature on drinking behaviour and alcohol-related harm in older adults is sparse. This article describes a secondary analysis of UK data to address this knowledge gap

Current measures of metabolic heterogeneity within cervical cancer do not predict disease outcome

<p>Abstract</p> <p>Background</p> <p>A previous study evaluated the intra-tumoral heterogeneity observed in the uptake of F-18 fluorodeoxyglucose (FDG) in pre-treatment positron emission tomography (PET) scans of cancers of the uterine cervix as an indicator of disease outcome. This was done via a novel statistic which ostensibly measured the spatial variations in intra-tumoral metabolic activity. In this work, we argue that statistic is intrinsically <it>non</it>-spatial, and that the apparent delineation between unsuccessfully- and successfully-treated patient groups via that statistic is spurious.</p> <p>Methods</p> <p>We first offer a straightforward mathematical demonstration of our argument. Next, we recapitulate an assiduous re-analysis of the originally published data which was derived from FDG-PET imagery. Finally, we present the results of a principal component analysis of FDG-PET images similar to those previously analyzed.</p> <p>Results</p> <p>We find that the previously published measure of intra-tumoral heterogeneity is intrinsically non-spatial, and actually is only a surrogate for tumor volume. We also find that an optimized linear combination of more canonical heterogeneity quantifiers does not predict disease outcome.</p> <p>Conclusions</p> <p>Current measures of intra-tumoral metabolic activity are not predictive of disease outcome as has been claimed previously. The implications of this finding are: clinical categorization of patients based upon these statistics is invalid; more sophisticated, and perhaps innately-geometric, quantifications of metabolic activity are required for predicting disease outcome.</p

Oxford Phase 3 unicompartmental knee arthroplasty: medium-term results of a minimally invasive surgical procedure

PURPOSE: In the last decade, a major increase in the use of and interest in unicompartmental knee arthroplasty (UKA) has developed. The Oxford Phase 3 UKA is implanted with a minimally invasive technique using newly developed instruments. The objective of this prospective study was to evaluate the outcome of UKA in patients with medial osteoarthritis of the knee in a high-volume unit. METHODS: Two-hundred and forty-four UKAs were performed with a minimally invasive approach. The median age was 72 (43-91) years. The median follow-up was 4.2 years (range 1-10.4 years). Fourteen patients died, and nine were considered to be lost to follow-up, but all had a well-functioning prosthesis in situ until their last follow-up. Pain, function and health-related quality of life were evaluated pre- and postoperatively using patient- and assessor-based outcome scores, as well as radiographic evidence. RESULTS: The mean Knee Society knee and function scores, WOMAC-scores, Oxford-score and VAS pain and satisfaction all improved. Nine knees required revision. Eleven patients required an additional arthroscopic procedure due to persisting pain secondary to intra-articular pathology, and four patients required manipulation under anaesthesia because of limited range of motion. The 7-year cumulative survival rate of the arthroplasty was 94.4%. A low incidence (21%) of a radiolucent line beneath the tibial component was observed at 5 years of follow-up. CONCLUSION: This study showed a high survival rate of the Oxford Phase 3 UKA. Patient satisfaction and functional performance were also very high. Major complication rate was low; in addition, the incidence of radiolucency under the tibial component, when compared to present literature, was low. When strict indication criteria are followed, excellent, durable, and in our opinion reliable, results can be expected for this procedur

The emergent rhizosphere: imaging the development of the porous architecture at the root-soil interface

The rhizosphere is the zone of soil infuenced by a plant root and is critical for plant health and nutrient acquisition. All below ground resources must pass through this dynamic zone prior to their capture by plant roots. However, researching the undisturbed rhizosphere has proved very challenging. Here we compare the temporal changes to the intact rhizosphere pore structure during the emergence of a developing root system in diferent soils. High resolution X-ray Computed Tomography (CT) was used to quantify the impact of root development on soil structural change, at scales relevant to individual micro-pores and aggregates (µm). A comparison of micro-scale structural evolution in homogenously packed soils highlighted the impacts of a penetrating root system in changing the surrounding porous architecture and morphology. Results indicate the structural zone of infuence of a root can be more localised than previously reported (µm scale rather than mm scale). With time, growing roots signifcantly alter the soil physical environment in their immediate vicinity through reducing root-soil contact and crucially increasing porosity at the root-soil interface and not the converse as has often been postulated. This ‘rhizosphere pore structure’ and its impact on associated dynamics are discussed

Requirement of Male-Specific Dosage Compensation in Drosophila Females—Implications of Early X Chromosome Gene Expression

Dosage compensation equates between the sexes the gene dose of sex chromosomes that carry substantially different gene content. In Drosophila, the single male X chromosome is hypertranscribed by approximately two-fold to effect this correction. The key genes are male lethal and appear not to be required in females, or affect their viability. Here, we show these male lethals do in fact have a role in females, and they participate in the very process which will eventually shut down their function—female determination. We find the male dosage compensation complex is required for upregulating transcription of the sex determination master switch, Sex-lethal, an X-linked gene which is specifically activated in females in response to their two X chromosomes. The levels of some X-linked genes are also affected, and some of these genes are used in the process of counting the number of X chromosomes early in development. Our data suggest that before the female state is set, the ground state is male and female X chromosome expression is elevated. Females thus utilize the male dosage compensation process to amplify the signal which determines their fate

Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor

PPS, a Large Multidomain Protein, Functions with Sex-Lethal to Regulate Alternative Splicing in Drosophila

Alternative splicing controls the expression of many genes, including the Drosophila sex determination gene Sex-lethal (Sxl). Sxl expression is controlled via a negative regulatory mechanism where inclusion of the translation-terminating male exon is blocked in females. Previous studies have shown that the mechanism leading to exon skipping is autoregulatory and requires the SXL protein to antagonize exon inclusion by interacting with core spliceosomal proteins, including the U1 snRNP protein Sans-fille (SNF). In studies begun by screening for proteins that interact with SNF, we identified PPS, a previously uncharacterized protein, as a novel component of the machinery required for Sxl male exon skipping. PPS encodes a large protein with four signature motifs, PHD, BRK, TFS2M, and SPOC, typically found in proteins involved in transcription. We demonstrate that PPS has a direct role in Sxl male exon skipping by showing first that loss of function mutations have phenotypes indicative of Sxl misregulation and second that the PPS protein forms a complex with SXL and the unspliced Sxl RNA. In addition, we mapped the recruitment of PPS, SXL, and SNF along the Sxl gene using chromatin immunoprecipitation (ChIP), which revealed that, like many other splicing factors, these proteins bind their RNA targets while in close proximity to the DNA. Interestingly, while SNF and SXL are specifically recruited to their predicted binding sites, PPS has a distinct pattern of accumulation along the Sxl gene, associating with a region that includes, but is not limited to, the SxlPm promoter. Together, these data indicate that PPS is different from other splicing factors involved in male-exon skipping and suggest, for the first time, a functional link between transcription and SXL–mediated alternative splicing. Loss of zygotic PPS function, however, is lethal to both sexes, indicating that its role may be of broad significance

Use of S-100B to Evaluate Therapy Effects during Bevacizumab Induction Treatment in AJCC Stage III Melanoma

To investigate the feasibility of using bevacizumab to improve the survival of American Joint Committee on Cancer (AJCC) stage III melanoma patients, we investigated how a single bevacizumab treatment affected nodal disease and a panel of biomarkers in clinically fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT)-staged, stage III melanoma patients, prior to therapeutic lymph node dissection (TLND). Four weeks before TLND, nine patients (median age 50, range 28.8-62.1 years; two male, seven female) with palpable lymph node metastases received 7.5 mg/kg bevacizumab. Before and after this treatment, all patients were assessed by measurements of the maximum standardized uptake value (SUVmax) by FDG-PET scan, and serum S-100B and lactate dehydrogenase (LDH). After TLND, the dissection specimen was analyzed for number of removed lymph nodes, number of metastatic lymph nodes, and tumor necrosis. Median follow-up was 15.5 (2.2-32.9) months. Histopathological analysis revealed tumor necrosis in six patients, of whom five had an S-100B decline and one had an unchanged S-100B level after bevacizumab. The other three patients showed an S-100B increase and no necrosis. Tumor necrosis was correlated with S-100B decrease (P = 0.048). No association was found between necrosis and the markers SUVmax and LDH. No wound healing disturbances were encountered. Tumor necrosis in dissection specimens was associated with declining S-100B levels, while elevated S-100B was only found in cases with no necrosis. Bevacizumab might be useful in treating AJCC stage III melanoma patients prior to TLND, and S100-B appears to be a useful marker for assessment of treatment effects