Role of extracellular [Ca2+] in fatigue of isolated mammalian skeletal muscle

The possible role of altered extracellular Ca2+ concentration ([Ca2+]o) in skeletal muscle fatigue was tested on isolated slow-twitch soleus and fast-twitch extensor digitorum longus muscles of the mouse. The following findings were made. 1) A change from the control solution (1.3 mM [Ca2+]o) to 10 mM [Ca2+]o, or to nominally Ca2+-free solutions, had little effect on tetanic force in nonfatigued muscle. 2) Almost complete restoration of tetanic force was induced by 10 mM [Ca2+]o in severely K+-depressed muscle (extracellular K+ concentration of 10-12 mM). This effect was attributed to a 5-mV reversal of the K+-induced depolarization and subsequent restoration of ability to generate action potentials (inferred by using the twitch force-stimulation strength relationship). 3) Tetanic force depressed by lowered extracellular Na+ concentration (40 mM) was further reduced with 10 mM [Ca2+]o. 4) Tetanic force loss at elevated extracellular K+ concentration (8 mM) and lowered extracellular Na+ concentration (100 mM) was partially reversed with 10 mM [Ca2+]o or markedly exacerbated with low [Ca2+]o. 5) Fatigue induced by using repeated tetani in soleus was attenuated at 10 mM [Ca2+]o (due to increased resting and evoked forces) and exacerbated at low [Ca2+]o. These combined results suggest, first, that raised [Ca2+]o protects against fatigue rather than inducing it and, second, that a considerable depletion of [Ca2+]o in the transverse tubules may contribute to fatigue.     

An audit of a radiographer based ultrasound service

A general ultrasound service has evolved over several years. Radiographers undertake the general ultrasound lists, and show the request card and the hard copy films to a radiologist prior to the patient leaving the department. Whilst it is generally accepted for radiographers to carry the burden of obstetric scanning, this is less so for general work. This audit is of a sample of 100 patients out of the general ultrasound lists. These patients underwent the standard service examination by a radiographer and subsequent report by the radiologist. They also had a separate examination and report by an independent radiologist. 42 patients were agreed to have normal findings. 75 diagnoses or observations were made in the remaining 58 patients. Discrepancies arose between the two limbs of the audit in 20 of the observations. Review of the hard copy films and repeat scanning of patients where necessary identified one relevant error by the auditing radiologist and three relevant errors by the standard service. Whilst errors are made both by radiologists and radiographers, it is concluded that the existing radiographer based ultrasound service provides a satisfactory level of accuracy.     

Effect of computer-based alerts on the treatment and outcomes of hospitalized patients

BACKGROUND: Hospital computing systems play an important part in the communication of clinical information to physicians. We sought to determine whether computer-based alerts for hospitalized patients can affect physicians' behavior and improve patients' outcomes. METHODS: We performed a prospective time-series study to determine whether computerized alerts to physicians about rising creatinine levels in hospitalized patients receiving nephrotoxic or renally excreted medications led to more rapid adjustment or discontinuation of those medications, and to determine whether such alerts protected renal function. RESULTS: Laboratory data were observed for 20,228 hospitalizations, with documentation of 1573 events (instances of rising creatinine levels during treatment with a nephrotoxic or renally excreted drug). During the intervention period, doses were adjusted or medications discontinued an average of 21.6 hours sooner after such an event (P < .0001). For patients receiving nephrotoxic medications during the intervention period, the relative risk of serious renal impairment was 0.45 (95% confidence interval, 0.22 to 0.94) as compared with the control period, and the mean serum creatinine level was 14.1 mumol/L (0.16 mg/dL) lower on day 3 (P < .01) and 25.6 mumol/L (0.29 mg/dL) lower on day 7 (P < .05) after an event. Forty-four percent of physicians who responded to a questionnaire said that the alerts had been helpful in the care of their patients, whereas 28% found them annoying. Sixty-five percent wished to continue receiving alerts. CONCLUSIONS: Computer-based alerts regarding patients with rising creatinine levels affect physician behavior, prevent serious renal impairment, preserve renal function, and are accepted by clinicians.     

The Design of Potent,Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 Antagonists

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvβ1 inhibitors. We show that αvβ1 activity is embedded in a range of published α4β1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4β1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvβ1 in this case). We designed urea ligands with excellent selectivity over α4β1 and the other αv integrins (αvβ3, αvβ5, αvβ6, αvβ8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.     

Halogenated veneers: protein cross-linking and halogenation in the jaws of nereis, a marine polychaete worm

Mineralized tissues are produced by most living organisms for load and impact functions. In contrast, the jaws of the clam worm, Nereis, are hard without mineralization. However, they are peculiarly rich in halogens, which are associated with a variety of post-translationally modified amino acids, many of which are multiply halogenated by chlorine, bromine, and/or iodine. Several of these modified amino acids, namely dibromohistidine, bromoiodohistidine, chloroiodotyrosine, bromoiodotyrosine, chlorodityrosine, chlorotrityrosine, chlorobromotrityrosine, and bromoiodotrityrosine, have not been previously reported. We have found that the distributions of Cl, Br, and I differ: Cl is widespread whereas Br and I, although not colocalized, are concentrated in proximity to the external jaw surfaces. By using nanoindentation, we show that Br and I are unlikely to play a purely mechanical role, but that the local Zn and Cl concentrations and jaw microstructure are the prime determinants of local jaw hardness. Several of the post-translationally modified amino acids are akin to those found in various sclerotized structures of invertebrates, and we propose that they are part of a cross-linked protein casing.     

Estimating crop yields and production by integrating the FAO Crop Specific Water Balance model with real-time satellite data and ground-based ancillary data

An operational crop yield model was developed by introducing realtime satellite imagery into a Geographical Information System (GIS) and the Crop Specific Water Balance (CSWB) model of the Food and Agriculture Organization (FAO). Input databases were developed with three different resolutions; agro-ecological zone (AEZ) polygons, 7.6 km and 1.1 km pixels; from archived satellite data commonly used by Early Warning Systems (EWS) to simulate maize yield and production in Kenya from 1989 to 1997. Simulated production results from the GIS-based CSWB model were compared to historical maize production reports from two Government of Kenya (GoK) agencies. The coefficients of determination (r ²) between the model and GoK district reports ranged from 0.86 to 0.89. The results indicated the 7.6 km pixel-by-pixel analysis was the most favorable method due to the Rainfall Estimate (RFE) input data having the same resolution. The GIS-based CSWB model developed by this study could also be easily expanded for use in other countries, extended for other crops, and improved in the future as satellite technologies improve.