Is there a role for bisphosphonates in vascular calcification in chronic kidney disease?

Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70-90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3-4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3-4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04-1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronate - treatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes.

High resolution anatomical and quantitative MRI of the entire human occipital lobe ex vivo at 9.4T.

Several magnetic resonance imaging (MRI) contrasts are sensitive to myelin content in gray matter in vivo which has ignited ambitions of MRI-based in vivo cortical histology. Ultra-high field (UHF) MRI, at fields of 7T and beyond, is crucial to provide the resolution and contrast needed to sample contrasts over the depth of the cortex and get closer to layer resolved imaging. Ex vivo MRI of human post mortem samples is an important stepping stone to investigate MRI contrast in the cortex, validate it against histology techniques applied in situ to the same tissue, and investigate the resolutions needed to translate ex vivo findings to in vivo UHF MRI. Here, we investigate key technology to extend such UHF studies to large human brain samples while maintaining high resolution, which allows investigation of the layered architecture of several cortical areas over their entire 3D extent and their complete borders where architecture changes. A 16 channel cylindrical phased array radiofrequency (RF) receive coil was constructed to image a large post mortem occipital lobe sample (~80×80×80mm3) in a wide-bore 9.4T human scanner with the aim of achieving high-resolution anatomical and quantitative MR images. Compared with a human head coil at 9.4T, the maximum Signal-to-Noise ratio (SNR) was increased by a factor of about five in the peripheral cortex. Although the transmit profile with a circularly polarized transmit mode at 9.4T is relatively inhomogeneous over the large sample, this challenge was successfully resolved with parallel transmit using the kT-points method. Using this setup, we achieved 60µm anatomical images for the entire occipital lobe showing increased spatial definition of cortical details compared to lower resolutions. In addition, we were able to achieve sufficient control over SNR, B0 and B1 homogeneity and multi-contrast sampling to perform quantitative T2* mapping over the same volume at 200µm. Markov Chain Monte Carlo sampling provided maximum posterior estimates of quantitative T2* and their uncertainty, allowing delineation of the stria of Gennari over the entire length and width of the calcarine sulcus. We discuss how custom RF receive coil arrays built to specific large post mortem sample sizes can provide a platform for UHF cortical layer-specific quantitative MRI over large fields of view.

Mechanisms of RNA-induced toxicity in CAG repeat disorders.

Several inherited neurodegenerative disorders are caused by CAG trinucleotide repeat expansions, which can be located either in the coding region or in the untranslated region (UTR) of the respective genes. Polyglutamine diseases (polyQ diseases) are caused by an expansion of a stretch of CAG repeats within the coding region, translating into a polyQ tract. The polyQ tract expansions result in conformational changes, eventually leading to aggregate formation. It is widely believed that the aggregation of polyQ proteins is linked with disease development. In addition, in the last couple of years, it has been shown that RNA-mediated mechanisms also have a profound role in neurotoxicity in both polyQ diseases and diseases caused by elongated CAG repeat motifs in their UTRs. Here, we review the different molecular mechanisms assigned to mRNAs with expanded CAG repeats. One aspect is the mRNA folding of CAG repeats. Furthermore, pathogenic mechanisms assigned to CAG repeat mRNAs are discussed. First, we discuss mechanisms that involve the sequestration of the diverse proteins to the expanded CAG repeat mRNA molecules. As a result of this, several cellular mechanisms are aberrantly regulated. These include the sequestration of MBNL1, leading to misregulated splicing; sequestration of nucleolin, leading to reduced cellular rRNA; and sequestration of proteins of the siRNA machinery, resulting in the production of short silencing RNAs that affect gene expression. Second, we discuss the effect of expanded CAG repeats on the subcellular localization, transcription and translation of the CAG repeat mRNA itself. Here we focus on the MID1 protein complex that triggers an increased translation of expanded CAG repeat mRNAs and a mechanism called repeat-associated non-ATG translation, which leads to proteins aberrantly translated from CAG repeat mRNAs. In addition, therapeutic approaches for CAG repeat disorders are discussed. Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases.

Impact of the American College of Cardiology/American Heart Association guidelines for interpretability of continuous electrocardiography on the association of silent ischemia with troponin release after major noncardiac surgery.

INTRODUCTION: Preexisting electrocardiographic abnormalities may limit accuracy of continuous electrocardiography (cECG) for ischemia determination. The American College of Cardiology/American Heart Association published criteria for the exclusion of unsuitable cECG curves from ST-segment interpretation. These criteria consider medication and 12-lead ECG findings (medication- and 12-lead ECG-based criteria) and cECG lead characteristics (cECG-based criteria). METHODS: We recorded cECG in 300 patients undergoing major noncardiac surgery. We determined postoperative troponin and 12-month outcome. We compared the associations of cECG-detected ischemia with troponin and 12-month outcome with and without adherence to the criteria. RESULTS: Adherence to the medication- and 12-lead ECG-based criteria enhanced the association between troponin and perioperative ischemia in CM5 (odds ratio, 3.74; 95% confidence interval, 1.88-7.44) and 7.03 (2.67-18.49), respectively; P = .049). Similarly, the association between ischemia in CM5 and 12-month outcome tended to increase (P = .081). CONCLUSIONS: Applying the guideline criteria for the interpretation of cECG enhanced cECG diagnostic value in surgical patients.

Sevoflurane decreases bispectral index values more than does halothane at equal MAC multiples.

At the minimum alveolar concentration (MAC) of inhaled anesthetics, 50% of subjects move in response to noxious stimulation. Similarly, at MAC-awake, 50% of subjects respond appropriately to command. The bispectral index (BIS) nominally measures the effect of anesthetics on wakefulness or consciousness. We postulated that the use of halothane with a larger MAC-awake/MAC ratio than sevoflurane would produce higher BIS values at comparable levels of MAC. We studied 33 unpremedicated patients anesthetized by inhalation, 18 with sevoflurane and 15 with halothane. We measured BIS before and during anesthesia at 1 MAC, both before and after tracheal intubation facilitated by fentanyl and rocuronium and then at 1.5 MAC. BIS measurements were made after meeting steady-state conditions. No surgery was performed during this study. BIS values in awake patients did not differ between the sevoflurane and halothane groups (96 +/- 2 and 96 +/- 2, mean +/- sd, respectively). At 1 MAC without and with neuromuscular blockade and at 1.5 MAC, BIS values for patients anesthetized with halothane (54 +/- 7, 56 +/- 7, and 49 +/- 7, respectively) exceeded those for patients anesthetized with sevoflurane (34 +/- 6, 34 +/- 6, and 29 +/- 5, respectively) (P < 0.0001). This finding adds to other evidence indicating that BIS is drug specific.

RadStation: client-based digital dictation system and integrated clinical information display with an embedded Web-browser.

RadStation is a digital dictation system having an integrated display of clinical information. The three-tiered system architecture provides robust performance, with most information displayed within one second after a request. The multifunctional client tier is a unique client/browser hybrid. A Web browser display window functions as the client application's data display window for clinical information, radiology reports, and laboratory and pathology results. RadStation provides a robust platform for digital dictation functionality. The system's internal status checks ensure operational integrity in a clinical environment. Also, the programmable dictation microphone and bar-code reader supplant the mouse as the system's primary input device. By merging information queries into existing work flow, radiologist's interpretation efficiency is maintained with instant access to essential clinical information. Finally, RadStation requires minimal training and has been enthusiastically accepted by our radiologists in an active clinical practice.

Radiologist's clinical information review workstation interfaced with digital dictation system.

Efficient access to information systems integrated into the radiologist's interpretation workflow will result in a more informed radiologist, with an enhanced capability to render an accurate interpretation. We describe our implementation of radStation, a radiologist's clinical information review workstation that combines a digital dictation station with a clinical information display. radStation uses client software distributed to the radiologist's workstation and central server software, both running Windows NT (Microsoft, Redmond, WA). The client system has integrated digital dictation software. The bar-code microphone (Boomerang, Dictaphone Corp, Stratford, CT) also serves as a computer input device forwarding the procedure's accession number to the server software. This initiates multiple queries to available legacy databases, including the radiology information system (RIS), laboratory information system, clinic notes, hospital discharge, and operative report system. The three-tier architecture then returns the clinical results to the radStation client for display. At the conclusion of the dictation, the digital voice file is transferred to the dictation server and the client notifies the RIS to update the examination status. The system is efficient in its information retrieval, with queries displayed in about 1 second. The radStation client requires less than 5 minutes of radiologist training in its operation, given that its control interface integrates with the well-learned dictation process. The telephone-based dictation system, which this new system replaced, remains available as a back-up system in the event of an unexpected digital dictation system failure. This system is well accepted and valued by the radiologists. The system interface is quickly mastered. The system does not interrupt dictation workflow with the display of all information initiated with examination bar-coding. This system's features could become an accepted model as a standard tool for radiologists.

Integration of radiologist peer review into clinical review workstation.

Professional peer review of random prior radiologist's interpretations is mandated by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). The JCAHO expects documentation of 5% rate of random peer-review cases. Countless hours are spent in departments fulfilling these requirements. The integration of the peer-review process into the radiologist's interpretation workflow was expected to increase the percentage of documented peer review, yet decrease the time and effort for this documentation. radStation clinical review workstations are deployed at every reading station. When a requisition is bar-coded, radStation retrieves the patient's clinical information and automatically displays the prior comparison report. If the radiologist agrees with the prior report, a single click on a "quality assurance' agree box documents the agreement. In the case of a discordance, an additional dialog box automatically appears and the radiologist enters the reason for disagreement and then submits the case as a discrepancy. The system holds the discordance for 3 to 5 working days, then notifies the original radiologist via E-mail that a prior interpretation has been submitted for peer review, lists the submitted discrepancy reason, and provides a link to display the discordant report. The peer-review database is separate from the existing radiology information system (RIS). At the end of every month, summary reports of all peer-review activity are generated automatically. Initial benchmarks of our deployed system anticipate documentation of long-term random peer-review rate at greater than 50% of interpreted cases. The system enhances the peer-review process by integrating it with the normal interpretation workflow. The time to complete peer review using radStation is less than 1 second per normal case and less than 60 seconds for a discordant case. The E-mail notification system is fully automated, eliminating the need for secretarial involvement in the data collection. This system has completely replaced a manual paper-based system. The integration of peer review directly into the radiologist's interpretation workstation greatly enhances the capability to easily exceed JCAHO standards. The overall increase in peer-review documentation should continue to improve the ability to document a consistent high quality of patient care.

Morphologic changes and xanthine oxidase activity in the equine jejunum during low flow ischemia and reperfusion.

OBJECTIVE: To determine whether xanthine oxidase and dehydrogenase activities are altered during low flow ischemia and reperfusion of the small intestine of horses. ANIMALS: 5 clinically normal horses without histories of abdominal problems. PROCEDURE: With the horse under general anesthesia, a laparotomy was performed and blood flow to a segment of the distal jejunum was reduced to 20% of baseline for 120 minutes and was then reperfused for 120 minutes. Biopsy specimens were obtained before, during, and after ischemia for determination of xanthine oxidase and dehydrogenase activities, and for histologic and morphometric analyses. RESULTS: Percentage of xanthine oxidase activity (as a percentage of xanthine oxidase and dehydrogenase activity) was not altered during ischemia and reperfusion. An inflammatory response developed and progressed during ischemia and reperfusion. Mucosal lesions increased in severity after ischemia and reperfusion. Mucosal surface area and volume decreased during ischemia and continued to decrease during reperfusion. Submucosal volume increased slightly during ischemia, and continued to increase during reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE: Evidence for conversion of xanthine dehydrogenase to xanthine oxidase during ischemia was not found. Factors other than production of reactive oxygen metabolites may be responsible for progressive epithelial loss, decrease in mucosal surface area and volume, and increase in submucosal volume observed in this study. Other methods of determining xanthine oxidase activity that detect the enzyme in sloughed epithelial cells should be used to better define the importance of this pathway in jejunal reperfusion injury in horses.

Effects of U-74389G, a novel 21-aminosteroid, on small intestinal ischemia and reperfusion injury in horses.

OBJECTIVE: To determine the effects of the 21-aminosteroid, U-74389G, on reperfusion of the equine jejunum, using total (TVO) and partial (PVO) vascular occlusion during the ischemic period. DESIGN: TVO: 16 healthy horses were randomly allotted to 3 groups-4 horses received the vehicle alone, 6 horses received a low dosage (3 mg/kg o body weight), and 6 horses a high dosage (10 mg/kg) of U-7438G. PVO: 10 healthy horses were randomly allotted to 2 groups--5 horses received the vehicle alone, and 5 horses received the low dosage (3 mg/kg) of U-74389G. PROCEDURES: TVO was induced for 1 hour followed by 2 hours of reperfusion. During PVO, blood flow was reduced to 20% of baseline for 2 hours, followed by 2 hours of reperfusion. For both models, either the vehicle alone or the drug was given 15 minutes prior to reperfusion. Samples were obtained before, during, and after ischemia for determination of myeloperoxidase (MPO) activity, malondealdehyde (MDA) concentration, concentration of conjugated dienes (PVO experiment only), and morphometric analysis. RESULTS: TVO: tissue concentration of MDA and MPO activity were not altered in any group by ischemia or reperfusion. During ischemia, mucosal volume and surface area were reduced. After reperfusion, no further reduction occurred. After initial decrease in submucosal volume during ischemia, there was a significant increase after reperfusion in the vehicle-only group (P < 0.05). PVO: there were no alterations in the concentration of either MDA or conjugated dienes. There was significant increase in the activity of MPO during ischemia and reperfusion (P < 0.05). These effects were similar for the vehicle-only and drug groups. During ischemia, there was a significant decrease in mucosal surface area and volume (P < 0.05), that was continued during reperfusion for the vehicle-only (P < 0.05). Submucosal volume increased during ischemia and reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE: Reduced blood flow during ischemia (PVO group) caused continued loss in mucosal volume and surface area during reperfusion. At the dosage given, the 21-aminosteroid, U-74389G, was not effective in preventing continued reduction in mucosal volume and surface area after restoration of blood supply in the horses subjected to reduced blood flow.

Surgical treatment for colic in the foal (67 cases): 1980-1992.

Sixty-seven foals age < 150 days underwent a ventral celiotomy for colic. Of the 67 foals, 51 foals (82%) recovered from anaesthesia and 42 (63%) were subsequently released from the hospital. Three (6%) of the 51 foals were subjected to a repeat celiotomy. Long term follow-up was available on 36 foals. Twenty-nine (57%) of the 51 foals recovered from anaesthesia, were alive at least 2 years following surgery. Adhesions were identified in 8 (17%) of the foals which recovered from general anaesthesia but were subsequently subjected to euthanasia due to recurrent colic. Strangulating lesions were associated with a lower survival rate. Nineteen per cent of foals with strangulating intestinal lesions survived > 2 years following surgery, compared to 69% of foals with nonstrangulating lesions. The age of foals on admission had a significant effect on survival. Only 10% of foals less than 14 days of age survived, compared to 45.8% of foals between age 15 and 150 days.

[Minimally invasive surgery of large bullous pulmonary emphysema]. / Minimal invasive Chirurgie beim grossbullösen Lungenemphysem.

An enormous pulmonary cyst (phi approx. 20 cm) in a 72-year-old male patient with large bullous pulmonary emphysema caused compression of the right lung and the mediastinum with consecutive, O2-dependent dyspnoea at rest. The symptoms did not improve under conservative therapy of an accompanying COPD. Thus, in spite of two heart attacks in the previous history, an operation with bullectomy was indicated. A thoracotomy had to be avoided because of the very high cardiac risk. In the present case, a minimally invasive procedure enabled the complete cyst resection with a smooth postoperative course and an excellent functional therapeutic result.

Allometry of pharmacokinetics and pharmacodynamics of the muscle relaxant metocurine in mammals.

We investigated the effects of body size on the pharmacokinetics and pharmacodynamics of the renally cleared muscle relaxant metocurine. We hypothesized that pharmacokinetics of the drug would change allometrically in proportion to physiological time [infinity Mb0.25, where Mb is body mass] and that pharmacodynamics would be independent of size because of the highly conserved structure of the acetylcholine receptor. Metocurine effects during general anesthesia were examined in 17 rats, 8 cats, 6 dogs, 5 pigs, 7 sheep, and 12 horses. Allometric analysis demonstrated size dependence for pharmacokinetics, which were affected by physiological time (Mb0.25). Pharmacodynamics were size independent, except for the value for effect compartment concentration associated with 50% twitch paralysis (IC50). Data from individual species had a bimodal distribution that was significant: pigs and sheep were more sensitive than other large species, and their IC50 appeared size independent. IC50 was size dependent in more active species (horse, dog, cat, rat). Although the mechanism is unknown, we speculate that this trend might relate to receptor density within the end plate. Thus pharmacokinetics changed in proportion to physiological time, and pharmacodynamics were in part size independent.

Interaction of gentamycin and atracurium in anaesthetised horses.

Evoked hind limb digital extensor tension (hoof twitch) was maintained at 40% of baseline for 1 h by atracurium infusion in 7 horses anaesthetised with halothane. After 1 h, atracurium was discontinued and hoof twitch allowed to recover to 75%. Atracurium was again given by infusion to maintain 40% twitch for a second hour, then 2 mg gentamycin/kg bwt were given i.v. Atracurium infusion was continued for a third hour, and then hoof twitch was again allowed to recover spontaneously to 75%. Gentamycin reduced twitch strength from 40 +/- 1% (mean +/- sem) to 29 +/- 4% within 7.0 +/- 1.5 min (P = 0.02). Twitch gradually returned to pre-gentamycin strength over the course of the next hour. Recovery of hoof twitch from 50% to 75% took 7.7 +/- 0.7 min for atracurium alone and 11.5 +/- 2.7 min for atracurium plus gentamycin (P = 0.03). Recovery from 50% twitch to 75% fade recovery took 13.8 +/- 0.8 min for atracurium alone and 13.7 +/- 1.2 min for atracurium plus gentamycin. At 75% recovery of fade, hoof twitch was 87 +/- 3% for atracurium alone and 82 +/- 4% for atracurium plus gentamycin. Reversal of the block with edrophonium and subsequent recovery of the horses from anaesthesia were uneventful. It was concluded that, although gentamycin did augment the neuromuscular blockade of atracurium, the effect was minimal.

Effects of the 21-aminosteroid U-74389G on ischemia and reperfusion injury of the ascending colon in horses.

Sixteen horses were allotted at random to 3 groups: vehicle only; low dosage (vehicle and 3 mg of U-74389G/kg of body weight); high dosage (vehicle and 10 mg of U-74389G/kg). These solutions were given prior to reperfusion. The ascending colon was subjected to 2 hours of ischemia followed by 2 hours of reperfusion. Before, during, and after ischemia, full-thickness colonic tissue biopsy specimens were obtained for measurement of malondealdehyde (MDA) concentration and myeloperoxidase activity and for morphologic evaluation. Although increases were not significant, MDA concentration and myeloperoxidase activity increased during ischemia and reperfusion. Administration of U-74389G did not have significant effects on MDA concentration and myeloperoxidase activity. However, the lower dosage tended (P = 0.08) to reduce myeloperoxidase activity at 30 and 60 minutes of reperfusion. In horses of the vehicle-only group, ischemia induced a decrease in mucosal surface area that was continued into the reperfusion period (P < or = 0.05). Administration of U-74389G at both dosages (3 and 10 mg/kg) prevented the reperfusion-induced reduction in mucosal surface area, which was significant at 60 minutes (high dosage; P = 0.05) and 90 minutes (low and high dosages; P = 0.02). After initial reduction in horses of all groups, mucosal volume increased for the initial 60 minutes of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)