The Redox Activity of Protein Disulfide Isomerase Inhibits ALS Phenotypes in Cellular and Zebrafish Models.

Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases of amyotrophic lateral sclerosis (ALS), and 20% of familial ALS cases are due to mutations in superoxide dismutase 1 (SOD1). Redox regulation is critical to maintain cellular homeostasis, although how this relates to ALS is unclear. Here, we demonstrate that the redox function of protein disulfide isomerase (PDI) is protective against protein misfolding, cytoplasmic mislocalization of TDP-43, ER stress, ER-Golgi transport dysfunction, and apoptosis in neuronal cells expressing mutant TDP-43 or SOD1, and motor impairment in zebrafish expressing mutant SOD1. Moreover, previously described PDI mutants present in patients with ALS (D292N, R300H) lack redox activity and were not protective against ALS phenotypes. Hence, these findings implicate the redox activity of PDI centrally in ALS, linking it to multiple cellular processes. They also imply that therapeutics based on PDI's redox activity will be beneficial in ALS.

A simple reminder system improves venous thromboembolism prophylaxis rates and reduces thrombotic events for hospitalized patients1.

BACKGROUND: Compliance with venous thromboembolism (VTE) prophylaxis is poor. OBJECTIVES: We sought to determine whether a simple electronic reminder applicable to all hospitalized patients would increase prophylaxis rates and reduce VTE rates. METHODS: An electronic reminder was added to the electronic medical record admission note used by all services in our hospital. Prophylaxis, VTE and bleeding rates before and after implementation were compared. Data were analyzed with sas version 9.1. RESULTS: Among all adult medical and surgical patients admitted to our hospital during the time periods studied, 42.8% (1236/2888) before and 60.0% (1410/2350) after the reminder was added received appropriate prophylaxis as per American College of Chest Physicians (ACCP) guidelines (P < 0.001). The difference reached significance for both medical (51.0% vs. 68.9%; P < 0.001) and surgical (48.0% vs. 61.0%; P < 0.001) services. Fewer patients were diagnosed with VTE after our reminder was added (1.1% vs. 0.3%; P = 0.001), and there was a trend towards fewer bleeds (1.1% vs. 0.6%; P = 0.09). The presence of the reminder was an independent predictor for prophylaxis being given (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.70-2.18; P < 0.001), and was independently associated with a decreased risk for VTE (OR 0.30, 95% CI 0.14-0.64; P = 0.003) after adjustment for other VTE risk factors. CONCLUSION: Adding an electronic reminder to the admission note improved prophylaxis rates and reduced VTE rates across services. The system is easily reproducible and applicable to other facilities. The improvement obtained was modest, so additional measures will probably be needed to optimize prophylaxis rates.

Induction of oxidative stress in the red macroalga Gracilaria tenuistipitata by pollutant metals.

Heavy metals are environmental pollutants that have the potential to induce severe stress-reactions in organisms on land as well as in the sea. We have studied effects of short term sublethal concentrations of copper (Cu2+) and cadmium (Cd2+) on the reactive oxygen metabolism of the marine red macroalga Gracilaria tenuistipitata. Additions of either 0.2 ppm Cu2+ or 1 ppm Cd2+ caused decreased growth (approximately 60%), increased oxidation of lipids and increased oxidative damage to proteins as shown by increased content of protein carbonyl groups. Together this strongly suggests an induction of oxidative stress. Cu2+ caused more oxidative damage than Cd2+. As a response to the increased oxidative stress, addition of Cu2+ induced the activities of catalase, ascorbate peroxidase, and superoxide dismutase. In contrast, Cd2+ only caused increased catalase activity. Ten-fold lower concentrations of the metals did not cause an increase in enzyme activity. Both heavy metals also increased the content of the antioxidants beta-carotene and lutein. The results show that Cd2+ and, to a larger extent, Cu2+ induce oxidative stress in short-term experiments and the seaweed responds by increasing the activity of the reactive oxygen metabolism.

Wheelchair coasting downhill is a reliable work task.

OBJECTIVE: To measure test-retest reliability of physiological responses during submaximal wheelchair downhill and horizontal treadmill ergometry. DESIGN: A test-retest design was used on a convenience sample. Four male and three female non-wheelchair users, (22-43 years of age) propelled or coasted in a wheelchair under steady-state conditions. Four minute work bouts were performed at 1, 2, 3, and 4 km/hr. (0.62, 1.24, 1.86 and 2.5 mph, respectively) at 0 degrees, -2 degrees, and -4 degrees. Subjects were studied twice under each of the 12 conditions. Six tests were performed daily, with testing occurring over four days. Dependent variables included oxygen consumption, minute ventilation and heart. Intraclass correlation coefficients were determined for each set of paired tests. RESULTS: Intraclass correlation coefficients were high for absolute VO_{2}(R=0.84-0.99), V_{E} (R=0.86-0.98) and HR (R=0.95-1.0) over the range of 4 speeds and 3 inclinations studied. On average, % differences from test 1 to test 2 were less than 3%. CONCLUSION: At the treadmill speeds and inclinations (positive and negative) studied in this investigation, untrained wheelchair users responded in a physiologically reliable manner.

Elemental anomalies at the cretaceous-tertiary boundary, woodside creek, new zealand.

Iridium and 26 other elements were determined in shale from the Cretaceous-Tertiary boundary at the locus classicus (for iridium anomalies) at Woodside Creek, New Zealand. Iridium, gold, copper, cobalt, chromium, nickel, arsenic, molybdenum, and iron were enriched in the basal 2 millimeters of the 8-millimeter shale parting as compared with the rest of the stratigraphic column. No other shale partings in the column had anomalous concentrations of any element when the data were expressed on a carbonate-free basis. The boundary material showed striking compositional similarities with the Stevns Klint Danish boundary shale. Elemental concentrations were in general much higher in the New Zealand material than in nonboundary shales from elsewhere in the world. The high concentration of iridium (153 nanograms per gram) in the basal layer of the boundary, together with the enrichment of other siderophile elements supports the idea of an extraterrestrial source for much of the material. The iridium/gold ratio of 2.1 is also in accordance with such a source. The iridium content of the basal layer is higher than for any other marine boundary shale obtained on land. The integrated iridium value is 187 nanograms per square centimeter of boundary surface.

Estrogen regimen of women with endometrial carcinoma. A retrospective case-control study at Radiumhemmet.

In order to detect a possible association between exogeneous estrogens and endometrial cancer under Swedish circumstances, the previous use of estrogens among 622 cases of endometrial cancer 1974-77 has been compared with that of the average female population, represented by a randomly selected sample of 1 866 contemporaries to the cancer cases. Among women aged 50-69 years, 6-36 months of use of 'natural' and/or to a much lesser extent 'synthetic' estrogens was equally common in the two groups. However, starting in 1976, 3-6 years of use became increasingly more common among cancer cases. Taking 1974-77 together, cancer cases had been on such a long-term regimen more than 5 times as commonly as controls. Additional progestagen treatment was equally rare in the two groups. Tumors of estrogen users were of a significantly lower grade than those of non-users of the same age. While it cannot be concluded at this stage that estrogens are cocarcinogenic, the evident possibility motivates a somewhat cautious, restrictive approach to prescription. Progestagens could be added sequentially, though it is not yet verified that they abolish the association between endometrial cancer and estrogens that is now recognized by many investigators.

PIP: In order to detect a possible association between exogenous estrogens and endometrial cancer under Swedish circumstances, the previous use of estrogens among 622 cases of endometrial cancer, 1974-77, was compared with that of the average female population, represented by a randomly selected sample of 1866 contemporaries to the cancer cases. Among women aged 50-69 years, 6-36 months of use of natural and/or, to a much lesser extent, synthetic estrogens was equally common in the 2 groups. However, starting in 1967, 3-6 years of use became increasingly more common among cancer cases. For the period 1974-77, cancer cases had been on such a long-term regimen more than 5 times as commonly as controls. Additional progestagen treatment was equally rare in the 2 groups. Tumors in estrogen users were of a significantly lower grade than those of nonusers of the same age. While it cannot be concluded at this stage that estrogens are cocarcinogenic, the evident possibility motivates a somewhat cautious, restrictive approach to their prescription. Progestagens could be added sequentially, for although it is not yet verified that they abolish the association between endometrial cancer and estrogens, it is now recognized by many investigators.

Endometrial cancer and exogenous estrogens.

PIP: In 622 cases of endometrical adenocarcinoma treated between 1974-1977 and in 1428 age-matched controls, the total use of synthetic and conjugated estrogens was determined from case reports, interviews, and written enquiries. It was found that conjugated estrogen use has increased, especially in the cancer group. For the years 1974, 1975, 1976, and 1977 the percentage of cancer patients with more than 6 months use of estrogens (not contraceptives) was 8.1, 17.0, 23.0, and 35.6 respectively as compared to 6.6, 8.6, 12.6, and 16.7 for controls. Use of less than 3 years duration was similar in controls and cases, but use for 3-6 years increased significantly among cancer patients (during 1974, 1975, 1976, and 1977 respectively, 2.3%, 4.5%, 11.5%, and 20.2% of the cases used estrogen as compared with 1.6%, 1.3%, 2.5%, and 3.5% of the controls). These initial findings indicate that long-term administration of estrogen should be limited to patients with distinct indications.^ieng