Crystal sedimentation and stone formation

Mechanisms of crystal collision being the first step of aggregation (AGN) were analyzed for calcium oxalate monohydrate (COM) directly produced in urine. COM was produced by oxalate titration in urine of seven healthy men, in solutions of urinary macromolecules and in buffered distilled water (control). Crystal formation and sedimentation were followed by a spectrophotometer and analyzed by scanning electron microscopy. Viscosity of urine was measured at 37°C. From results, sedimentation rate (vS), particle diffusion (D) and incidences of collision of particles in suspension by sedimentation (IS) and by diffusion (ID) were calculated. Calculations were related to average volume and urinary transit time of renal collecting ducts (CD) and of renal pelvis. vS was in urine 0.026 ± 0.012, in UMS 0.022 ± 0.01 and in control 0.091 ± 0.02 cm min−1 (mean ± SD). For urine, a D of 9.53 ± 0.97 μm within 1 min can be calculated. At maximal crystal concentration, IS was only 0.12 and ID was 0.48 min−1 cm−3 which, even at an unrealistic permanent and maximal crystalluria, would only correspond to less than one crystal collision/week/CD, whereas to the same tubular wall being in horizontal position 1.3 crystals/min and to a renal stone 624 crystals/cm2 min could drop by sedimentation. Sedimentation to renal tubular or pelvic wall, where crystals can accumulate and meet with a tissue calcification or a stone, is probably essential for stone formation. Since vS mainly depends on particle size, reducing urinary supersaturation and crystal growth by dietary oxalate restriction seems to be an important measure to prevent aggregation

The axial charge of the nucleon on the lattice and in chiral perturbation theory

We present recent Monte Carlo data for the axial charge of the nucleon obtained by the QCDSF-UKQCD collaboration for N_f=2 dynamical quarks. We compare them with formulae from chiral perturbation theory in finite and infinite volume and find a remarkably consistent picture.Comment: 6 pages, 3 figures, talk presented at Lattice2005 (weak matrix elements), needs PoS.cl

Quality of life and other psychological factors in patients with tooth wear

Aim: To investigate the relationship between generic and condition-specific (CS) quality of life, general psychological wellbeing and personality in patients with tooth wear. / Materials and methods: Ethical approval was granted (REC:10/H0709/21). Patients aged 18-70 years with tooth wear completed the Oral Impact on Daily Performance (OIDP) quality of life questionnaire, the NEO-FFI Personality questionnaire and the General Health Questionnaire-12 (GHQ). Tooth wear was measured with the Basic Erosive Wear Examination (BEWE). / Results: In total, 102 subjects were recruited. Increased BEWE scores were correlated with older age and worse generic and CS-related quality of life. Increased neuroticism was correlated with increased: generic and CS OIDP scores; generic and CS eating scores; CS smiling scores; and CS carrying out major work scores. Increased GHQ scores were positively correlated with increased: generic and CS OIDP scores; generic and CS eating scores; CS speaking scores; generic and CS cleaning scores; generic relaxing scores; generic and CS smiling scores; and generic emotional state scores (p <0.05). Multivariable linear regression analyses showed that increased neuroticism and decreased GHQ both had an independent effect on generic and CS OIDP scores when adjusted for tooth wear severity (p <0.05). / Conclusion: Quality of life perception is complex and was not only affected by worsening levels of tooth wear

New drug, new problem: do hip fracture patients taking NOACs experience delayed surgery, longer hospital stay, or poorer outcomes?

INTRODUCTION: Neck of femur fractures are common in the comorbid, often anticoagulated, elderly. Non-vitamin K antagonist oral anticoagulants (NOACs) may affect patient outcomes. We aimed to evaluate whether hip fracture patients admitted on warfarin or NOAC therapy were at risk of operative delay, prolonged length of stay, or increased mortality. METHODS: We collected data for 845 patients admitted to our centre between October 2014 and December 2016. Multivariable linear regression analysis was performed to test the association between warfarin and NOAC therapy on time to surgery and length of stay. Variables in the regression model were age, sex, admission AMTS, pre-fracture mobility, ASA score, fracture type, and operation type. Fisher's exact test was used to evaluate whether warfarin or NOAC therapy delayed surgery beyond 36 or 48 hours, or decreased 30-day, 6-month, or 12-month survival. RESULTS: Time to surgery was delayed in anticoagulated patients (p = 0.028). NOAC therapy was independently associated with increased time to surgery beyond 36 hours (p = 0.001), although not beyond 48 hours (p = 0.355), whereas warfarin therapy was not associated with either. Anticoagulation did not increase length of stay (p = 0.331). Warfarin therapy significantly reduced 30-day survival (p = 0.007), but NOAC therapy did not (p = 0.244). Neither warfarin nor NOAC therapy affected further survival. CONCLUSIONS: NOAC therapy delays time to surgery beyond the NHS England 'Best Practice Tariff' in hip fracture patients. We aim to prospectively investigate long-term outcomes. Without a NOAC antidote, policy must change to ensure time-appropriate surgery for patients on NOACs. Preoperative involvement of the haematology team is essential.non

SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease has two types, the cardiac form and the digestive form; some patients have symptoms of both. How the parasite causes digestive disease is poorly understood. It is known that damage to the gut’s nervous system is an important factor, but it has been unclear exactly where and when this damage occurs during the course of an infection and also why only a subset of infected people suffer from this outcome. We studied infections in mice and found certain combinations of strains of parasites and mice that exhibited symptoms similar to human digestive Chagas patients, including a problem with peristalsis that localised specifically to the colon. Using parasites that were genetically engineered to emit both bioluminescent and fluorescent light, we tracked infections over time and were able to analyse rare infected cells deep within the muscle tissue of the wall of the colon. We found evidence of damaged neurons in the same location as these infection foci over 6 months after initial infection. Our results show that digestive Chagas disease probably develops as a result of chronic infection and inflammation, which potentially changes approaches to treatment

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Quality of diabetes care in breast, colorectal, and prostate cancer

This is the final version. Available on open access from Springer via the DOI in this recordPURPOSE: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls. METHODS: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer. RESULTS: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review. CONCLUSIONS: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution

Infections with Trypanosoma cruzi are usually lifelong despite generating a strong adaptive immune response. Identifying the sites of parasite persistence is therefore crucial to understanding how T. cruzi avoids immune-mediated destruction. However, this is a major technical challenge, because the parasite burden during chronic infections is extremely low. Here, we describe an integrated approach involving comprehensive tissue processing, ex vivo imaging, and confocal microscopy, which allowed us to visualize infected host cells in murine tissue with exquisite sensitivity. Using bioluminescence-guided tissue sampling, with a detection level of 200 parasites, which we term mega-nests. In contrast, during the acute stage, when the total parasite burden is considerably higher and many cells are infected, nests containing >50 parasites are rarely found. In C3H/HeN mice, but not BALB/c mice, we identified skeletal muscle as a major site of persistence during the chronic stage, with most parasites being found in large mega-nests within the muscle fibers. Finally, we report that parasites are also frequently found in the skin during chronic murine infections, often in multiple infection foci. In addition to being a site of parasite persistence, this anatomical reservoir could play an important role in insect-mediated transmission and have implications for drug development.IMPORTANCETrypanosoma cruzi causes Chagas disease, the most important parasitic infection in Latin America. Major pathologies include severe damage to the heart and digestive tract, although symptoms do not usually appear until decades after infection. Research has been hampered by the complex nature of the disease and technical difficulties in locating the extremely low number of parasites. Here, using highly sensitive imaging technology, we reveal the sites of parasite persistence during chronic-stage infections of experimental mice at single-cell resolution. We show that parasites are frequently located in smooth muscle cells in the circular muscle layer of the colon and that skeletal muscle cells and the skin can also be important reservoirs. This information provides a framework for investigating how the parasite is able to survive as a lifelong infection, despite a vigorous immune response. It also informs drug development strategies by identifying tissue sites that must be accessed to achieve a curative outcome