Finding a New \u27Meaning of Meaning\u27

The twofold thesis of this paper is that Putnam is incorrect to accept the existence of narrow content mental states, and that Tyler Burge, in exposing this error, can explain why mental content is not in the hands of the individual. The author studies Burge’s extension of Putnam’s views on mental content, comparing the arguments made in “The Meaning of Meaning” with Burge’s “Individualism and the Mental”. Burge argues that if extension differs on Twin Earth, then so must intension differ—something that Putnam overlooks. Burge’s analysis of the Twin Earth logic and his own counterfactual thought experiment concerning the term arthritis demonstrate that social content always infects mental content, thereby making it impossible for Putnam to say that water can have the same narrow meaning in his Twin Earth example. A corollary to this argument, of course, is Burge’s position that “water” is not an indexical natural kind term

Combined information from Raman spectroscopy and optical coherence tomography for enhanced diagnostic accuracy in tissue discrimination

We thank the UK EPSRC for funding, the CR-UK/EPSRC/MRC/DoH (England) imaging programme, the European Union project FAMOS (FP7 ICT, contract no. 317744) and the European Union project IIIOS (FP7/2007-2013, contract no. 238802). We thank Tayside Tissue Bank for providing us with the tissue samples under request number TR000289. K.D. is a Royal Society-Wolfson Merit Award Holder.Optical spectroscopy and imaging methods have proved to have potential to discriminate between normal and abnormal tissue types through minimally invasive procedures. Raman spectroscopy and Optical Coherence Tomography (OCT) provides chemical and morphological information of tissues respectively, which are complementary to each other. When used individually they might not be able to obtain high enough sensitivity and specificity that is clinically relevant. In this study we combined Raman spectroscopy information with information obtained from OCT to enhance the sensitivity and specificity in discriminating between Colonic Adenocarcinoma from Normal Colon. OCT being an imaging technique, the information from this technique is conventionally analyzed qualitatively. To combine with Raman spectroscopy information, it was essential to quantify the morphological information obtained from OCT. Texture analysis was used to extract information from OCT images, which in-turn was combined with the information obtained from Raman spectroscopy. The sensitivity and specificity of the classifier was estimated using leave one out cross validation (LOOCV) method where support vector machine (SVM) was used for binary classification of the tissues. The sensitivity obtained using Raman spectroscopy and OCT individually was 89% and 78% respectively and the specificity was 77% and 74% respectively. Combining the information derived using the two techniques increased both sensitivity and specificity to 94% demonstrating that combining complementary optical information enhances diagnostic accuracy. These results demonstrate that a multimodal approach using Raman-OCT would be able to enhance the diagnostic accuracy for identifying normal and cancerous tissue types.Publisher PD

Discrimination of bladder cancer cells from normal urothelial cells with high specificity and sensitivity:combined application of atomic force microscopy and modulated Raman spectroscopy

Atomic force microscopy (AFM) and modulated Raman spectroscopy (MRS) were used to discriminate between living normal human urothelial cells (SV-HUC-1) and bladder tumour cells (MGH-U1) with high specificity and sensitivity. MGH-U1 cells were 1.5-fold smaller, 1.7-fold thicker and 1.4-fold rougher than normal SV-HUC-1 cells. The adhesion energy was 2.6-fold higher in the MGH-U1 cells compared to normal SV-HUC-1 cells, which possibly indicates that bladder tumour cells are more deformable than normal cells. The elastic modulus of MGH-U1 cells was 12-fold lower than SV-HUC-1 cells, suggesting a higher elasticity of the bladder cancer cell membranes. The biochemical fingerprints of cancer cells displayed a higher DNA and lipid content, probably due to an increase in the nuclear to cytoplasm ratio. Normal cells were characterized by higher protein contents. AFM studies revealed a decrease in the lateral dimensions and an increase in thickness of cancer cells compared to normal cells; these studies authenticate the observations from MRS. Nanostructural, nanomechanical and biochemical profiles of bladder cells provide qualitative and quantitative markers to differentiate between normal and cancerous cells at the single cellular level. AFM and MRS allow discrimination between adhesion energy, elasticity and Raman spectra of SV-HUC-1 and MGH-U1 cells with high specificity (83, 98 and 95%) and sensitivity (97, 93 and 98%). Such single-cell-level studies could have a pivotal impact on the development of AFM–Raman combined methodologies for cancer profiling and screening with translational significance

Optimization of biotinyl-tyramide-based in situ hybridization for sensitive background-free applications on formalin-fixed, paraffin-embedded tissue specimens

BACKGROUND: Over the past five years in situ hybridization techniques employing tyramide amplification reagents have been developed and promise the potential detection of low/single-copy nucleic acid sequences. However the increased sensitivity that tyramide amplification brings about may also lead to problems of background staining that confound data interpretation. METHODS: In this study those factors enabling background-free biotinyl-tyramide based in situ hybridization assay of formalin-fixed paraffin-embedded tissues have been examined. SiHa, HeLa and CaSki cell lines known to contain HPV integrated into the cell genome, and archival cervical pre-invasive lesions and carcinomas have been successfully assessed using biotinylated HPV and centromeric probes. RESULTS: The single most important factor both for sensitivity and clean background was a tissue unmasking regimen that included treatment with 10 mM sodium citrate pH 6.0 at 95°C followed by digestion with pepsin/0.2 M HCl. Concentrations both of probe and primary streptavidin-peroxidase conjugate and pH of hybridization mix and stringency washes were also critical for sensitivity. Certain probes were more associated with background staining than others. This problem was not related to probe purity or size. In these instances composition of hybridization mix solution was especially critical to avoid background. 3-amino-9-ethylcarbazole was preferred over 3,3'-diaminobenzidene as a chromogen because background was cleaner and the 1–2 copies of HPV16 integrated in SiHa cells were readily demonstrable. HPV detection on metaphase spreads prepared from SiHa cells was only successful when a fluorescent detection method was combined with tyramide reagent. 'Punctate' and 'diffuse' signal patterns were identified amongst tissues consistent with the former representing integration and 'diffuse' representing episomal HPV. Only punctate signals were detected amongst the cell lines and were common amongst high-grade pre-invasive lesions and carcinomas. However it remains to be determined why single/low-copy episomal HPV in basal/parabasal cells of low-grade lesions is not also detectable using tyramide-based techniques and whether every punctate signal represents integration. CONCLUSIONS: A tyramide-based in situ hybridization methodology has been established that enables sensitive, background-free assay of clinical specimens. As punctate signals characterize HPV in high-grade cervical lesions the method may have potential for clinical applications

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

BACKGROUND: Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. METHODS: UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. RESULTS: Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. CONCLUSIONS: UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD

Prolactin

During an oral glucose tolerance test (OGTT) glucose and insulin levels were measured in 26 patients with prolactin-producing pituitary tumours without growth hormone excess. Basal glucose and insulin levels did not differ from the values of an age-matched control group. After glucose load the hyperprolactinaemic patients showed a decrease in glucose tolerance and a hyperinsulinaemia. Bromocriptine (CB 154), which suppressed PRL, improved glucose tolerance and decreased insulin towards normal in a second OGTT. — Human PRL or CB 154 had no significant influence on insulin release due to glucose in the perfused rat pancreas. — These findings suggest a diabetogenic effect of PRL. CB 154 might be a useful drug in improving glucose utilization in hormone-active pituitary tumours

Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-α expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the β-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17β-estradiol (E2) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E2 was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E2 suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E2 inhibition. E2 increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E2 was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GH/JAK/STAT pathway, in which SOCS-2 plays a central mechanistic role

Improving the diagnosis of endometrial hyperplasia using computerized analysis and immunohistochemical biomarkers

Endometrial hyperplasia (EH) is a precursor lesion to endometrial carcinoma (EC). Risks for EC include genetic, hormonal and metabolic factors most notably those associated with obesity: rates are rising and there is concern that cases in pre-menopausal women may remain undetected. Making an accurate distinction between benign and pre-malignant disease is both a challenge for the pathologist and important to the gynecologist who wants to deliver the most appropriate care to meet the needs of the patient. Premalignant change may be recognized by histological changes of endometrial hyperplasia (which may occur with or without atypia) and endometrial intraepithelial neoplasia (EIN). In this study we created a tissue resource of EH samples diagnosed between 2004 and 2009 (n = 125) and used this to address key questions: 1. Are the EIN/WHO2014 diagnostic criteria able to consistently identify premalignant endometrium? 2. Can computer aided image analysis inform identification of EIN? 3. Can we improve diagnosis by incorporating analysis of protein expression using immunohistochemistry. Our findings confirmed the inclusion of EIN in diagnostic criteria resulted in a better agreement between expert pathologists compared with the previous WHO94 criteria used for the original diagnosis of our sample set. A computer model based on assessment of stromal:epithelial ratio appeared most accurate in classification of areas of tissue without EIN. From an extensive panel of putative endometrial protein tissue biomarkers a score based on assessment of HAND2, PTEN, and PAX2 was able to identify four clusters one of which appeared to be more likely to be benign. In summary, our study has highlighted new opportunities to improve diagnosis of pre-malignant disease in endometrium and provide a platform for further research on this important topic

The relationship between 2d knee valgus angle during single leg squat (sls), single leg landing (sll), and forward running

BACKGROUND: Two-dimensional (2D) analysis of knee valgus during common athletic screening tasks such as SLS has been purported to identify individuals who may be at a high-risk of ACL injury. There is limited literature exploring the relationships between joint motion during SLS and other athletic tasks associated with knee joint injuries, in order to evaluate the effectiveness of the SLS to identify athletes with hazardous knee motion in a range of athletic tasks. OBJECTIVE: To assess the relationship between the 2D knee valgus angle among three tasks (SLS, SLL, and Running). DESIGN: A correlational study. SETTING: Undertaken in the Human Performance Laboratory at the University of Salford. PARTICIPANTS: 15 recreational athletes, 7 males and 8 females, were recruited (age 25.25.1 years; height 1.67.38 m; and mass 67.610.93 kg). INTERVENTION: Participants performed a series of SLS, SLL from a 31-cm step, and forward running at percieved maximum speed whilst being videotaped with a 2D digital camera. MAIN OUTCOME MEASUREMENTS: Maximum right knee valgus angle was quantified by measuring the frontal plane projection angle (FPPA) using Quintic Biomechanics v21 software package. RESULTS: A moderate correlation was shown between FPPA during SLS and SLL when the whole participant group was analysed (r=0.35). When split by gender female statistics showed good correlations between the majority of tasks; SLS and SLL (r=0.87), SLS and Run (r=0.59) but weaker between SLL and Run (0.26). CONCLUSIONS: In females the FPPA during SLS correlates with FPPA during SLL and running. This indicates that if a female patient has increased FPPA during SLS they are likely to have increased FPPA across all the tasks. This could potentially reduce the time and tasks required for screening, as only one task would need to be assessed. In males there is little correlation between tasks so the same would not apply in male subjects