A non-toxic concentration of telomerase inhibitor BIBR1532 fails to reduce tert expression in a feeder-free induced pluripotent stem cell model of human motor neurogenesis

Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor

Thermo-optic measurements and their inter-dependencies for delineating cancerous breast biopsy tissue from adjacent normal

The histopathological diagnosis of cancer is the current gold standard to differentiate normal from cancerous tissues. We propose a portable platform prototype to characterize the tissue's thermal and optical properties, and their inter-dependencies to potentially aid the pathologist in making an informed decision. The measurements were performed on 10 samples from five subjects, where the cancerous and adjacent normal were extracted from the same patient. It was observed that thermal conductivity (k) and reduced-scattering-coefficient (μ's) for both the cancerous and normal tissues reduced with the rise in tissue temperature. Comparing cancerous and adjacent normal tissue, the difference in k and μ's (at 940 nm) were statistically significant (p = 7.94e-3), while combining k and μ's achieved the highest statistical significance (6.74e-4). These preliminary results promise and support testing on a large number of samples for rapidly differentiating cancerous from adjacent normal tissues

Epidemiology of Eales Disease in the Central Western India

Objective: To investigate the clinical features and propose a new staging system based on the clinicopathological correlation and formulate new guidelines for management of Eales’ disease in healthy young males. Design: Prospective cohort study. Setting: Vitreo Retinal Department of a tertiary eye care center in Western Central India. Participants: Seventy-four eyes diagnosed with Eales’ disease. Materials and methods: From 2004 to 2010, patients clinically diagnosed with Eales’ disease were enrolled in this study using specific inclusion and exclusion criteria. We examined the patients’ anterior and posterior segments thoroughly. We performed the necessary ocular and systemic investigations. We divided the investigations into three stages: inflammatory, ischemic and complications and the patients were treated accordingly. We treated the patients using medical management, photocoagulation or pars plana vitrectomy. The patients were monitored according to standard schedules and formats. All information was documented using a pre-tested online format and statistical analyses were performed using SPSS ver. 17. A p-value < 0.05 was considered to indicate significance. Outcome measures: Visual acuity. Results: The cohort comprised 74 cases with a mean age of 30 ± 8.73 years. The visual acuity of the presenting cohort was < 3/60 in 64.9% of eyes. The final visual outcome was > 6/12 in 40 eyes (54.1%), 6/60 to 6/18 in 14 eyes (18.9%) and < 1/60 in the remaining 9 eyes at a mean follow-up of 592 days. The visual parameters differed significantly pre-and post-treatment. We evaluated the visual outcome following surgical management. Conclusion: We studied epidemiological facts about anterior and posterior segment findings

Recent advances in biosensing approaches for point-of-care breast cancer diagnostics: challenges and future prospects

Timely and accurate diagnosis of breast cancer is essential for efficient treatment and the best possible survival rates. Biosensors have emerged as a smart diagnostic platform for the detection of biomarkers specific to the onset, recurrence, and therapeutic drug monitoring of breast cancer. There have been exciting recent developments, including significant improvements in the validation, sensitivity, specificity, and integration of sample processing steps to develop point-of-care (POC) integrated micro-total analysis systems for clinical settings. The present review highlights various biosensing modalities (electrical, optical, piezoelectric, mass, and acoustic sensing). It provides deep insights into their design principles, signal amplification strategies, and comparative performance analysis. Finally, this review emphasizes the status of existing integrated micro-total analysis systems (μ-TAS) for personalized breast cancer therapeutics and associated challenges and outlines the approach required to realize their successful translation into clinical settings

Hybrid Spectral-IRDx: Near-IR and Ultrasound Attenuation System for Differentiating Breast Cancer from Adjacent Normal Tissue

OBJECTIVE: While performing surgical excision for breast cancer (lumpectomy), it is important to ensure a clear margin of normal tissue around the cancer to achieve complete resection. The current standard is histopathology; however, it is time-consuming and labour-intensive requiring skilled personnel. METHOD: We describe a Hybrid Spectral-IRDx - a combination of the previously reported Spectral-IRDx tool with multimodal ultrasound and NIR spectroscopy techniques. We show how this portable, cost-effective, minimal-contact tool could provide rapid diagnosis of cancer using formalin-fixed (FF) and deparaffinized (DP) breast biopsy tissues. RESULTS: Using this new tool, measurements were performed on cancerous/fibroadenoma and its adjacent normal tissues from the same patients (N=14). The acoustic attenuation coefficient () and reduced scattering coefficient (s) (at 850, 940, and 1060 nm) for the cancerous/fibroadenoma tissues were reported to be higher compared to adjacent normal tissues, a basis of delineation. Comparing FF cancerous and adjacent normal tissue, the difference in s at 850 nm and 940 nm were statistically significant (p=3.17e-2 and 7.94e-3 respectively). The difference in between the cancerous and adjacent normal tissues for DP and FF tissues were also statistically significant (p=2.85e-2 and 7.94e-3 respectively). Combining multimodal parameters and s (at 940 nm) show highest statistical significance (p=6.72e-4) between FF cancerous/fibroadenoma and adjacent normal tissues. CONCLUSION: We show that Hybrid Spectral-IRDx can accurately delineate between cancerous and adjacent normal breast biopsy tissue. SIGNIFICANCE: The results obtained establish the proof-of-principle and large-scale testing of this multimodal breast cancer diagnostic platform for core biopsy diagnosis

Hippocampal - diencephalic - cingulate networks for memory and emotion: An anatomical guide

This review brings together current knowledge from tract tracing studies to update and reconsider those limbic connections initially highlighted by Papez for their presumed role in emotion. These connections link hippocampal and parahippocampal regions with the mammillary bodies, the anterior thalamic nuclei, and the cingulate gyrus, all structures now strongly implicated in memory functions. An additional goal of this review is to describe the routes taken by the various connections within this network. The original descriptions of these limbic connections saw their interconnecting pathways forming a serial circuit that began and finished in the hippocampal formation. It is now clear that with the exception of the mammillary bodies, these various sites are multiply interconnected with each other, including many reciprocal connections. In addition, these same connections are topographically organised, creating further subsystems. This complex pattern of connectivity helps explain the difficulty of interpreting the functional outcome of damage to any individual site within the network. For these same reasons, Papez’s initial concept of a loop beginning and ending in the hippocampal formation needs to be seen as a much more complex system of hippocampal–diencephalic–cingulate connections. The functions of these multiple interactions might be better viewed as principally providing efferent information from the posterior medial temporal lobe. Both a subcortical diencephalic route (via the fornix) and a cortical cingulate route (via retrosplenial cortex) can be distinguished. These routes provide indirect pathways for hippocampal interactions with prefrontal cortex, with the preponderance of both sets of connections arising from the more posterior hippocampal regions. These multi-stage connections complement the direct hippocampal projections to prefrontal cortex, which principally arise from the anterior hippocampus, thereby creating longitudinal functional differences along the anterior–posterior plane of the hippocampus

Post radiation chylous ascites: a case report

We report a 64 years old gentleman with unresectable right-sided retroperitoneal liposarcoma, who underwent radiotherapy & subsequently developed chylous ascites. He failed conservative management of chylous ascites and this was successfully managed with a peritoneovenous shunt. The pathophysiology and management of post radiational chylous ascites is discussed

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Increased peri-ductal collagen micro-organization may contribute to raised mammographic density

BACKGROUND: High mammographic density is a therapeutically modifiable risk factor for breast cancer. Although mammographic density is correlated with the relative abundance of collagen-rich fibroglandular tissue, the causative mechanisms, associated structural remodelling and mechanical consequences remain poorly defined. In this study we have developed a new collaborative bedside-to-bench workflow to determine the relationship between mammographic density, collagen abundance and alignment, tissue stiffness and the expression of extracellular matrix organising proteins. METHODS: Mammographic density was assessed in 22 post-menopausal women (aged 54–66 y). A radiologist and a pathologist identified and excised regions of elevated non-cancerous X-ray density prior to laboratory characterization. Collagen abundance was determined by both Masson’s trichrome and Picrosirius red staining (which enhances collagen birefringence when viewed under polarised light). The structural specificity of these collagen visualisation methods was determined by comparing the relative birefringence and ultrastructure (visualised by atomic force microscopy) of unaligned collagen I fibrils in reconstituted gels with the highly aligned collagen fibrils in rat tail tendon. Localised collagen fibril organisation and stiffness was also evaluated in tissue sections by atomic force microscopy/spectroscopy and the abundance of key extracellular proteins was assessed using mass spectrometry. RESULTS: Mammographic density was positively correlated with the abundance of aligned periductal fibrils rather than with the abundance of amorphous collagen. Compared with matched tissue resected from the breasts of low mammographic density patients, the highly birefringent tissue in mammographically dense breasts was both significantly stiffer and characterised by large (>80 μm long) fibrillar collagen bundles. Subsequent proteomic analyses not only confirmed the absence of collagen fibrosis in high mammographic density tissue, but additionally identified the up-regulation of periostin and collagen XVI (regulators of collagen fibril structure and architecture) as potential mediators of localised mechanical stiffness. CONCLUSIONS: These preliminary data suggest that remodelling, and hence stiffening, of the existing stromal collagen microarchitecture promotes high mammographic density within the breast. In turn, this aberrant mechanical environment may trigger neoplasia-associated mechanotransduction pathways within the epithelial cell population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0664-2) contains supplementary material, which is available to authorized users