Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Carbon in Humic Fractions of Organic Matter in Soil Treated with Organic Composts under Mango Cultivation

ABSTRACT Soil organic matter (SOM) plays a key role in maintaining the productivity of tropical soils, providing energy and substrate for the biological activity and modifying the physical and chemical characteristics that ensure the maintenance of soil quality and the sustainability of ecosystems. This study assessed the medium-term effect (six years) of the application of five organic composts, produced by combining different agro-industrial residues, on accumulation and chemical characteristics of soil organic matter. Treatments were applied in a long-term experiment of organic management of mango (OMM) initiated in 2005 with a randomized block design with four replications. Two external areas, one with conventional mango cultivation (CMM) and the other a fragment of regenerating Caatinga vegetation (RCF), were used as reference areas. Soil samples were collected in the three management systems from the 0.00-0.05, 0.05-0.10, and 0.10-0.20 m layers, and the total organic carbon content and chemical fractions of organic matter were evaluated by determining the C contents of humin and humic and fulvic acids. Organic compost application significantly increased the contents of total C and C in humic substances in the experimental plots, mainly in the surface layer. However, compost 3 (50 % coconut bagasse, 40 % goat manure, 10 % castor bean residues) significantly increased the level of the non-humic fraction, probably due to the higher contents of recalcitrant material in the initial composition. The highest increases from application of the composts were in the humin, followed by the fulvic fraction. Compost application increased the proportion of higher molecular weight components, indicating higher stability of the organic matter.

Shaping mechanisms of metal specificity in a family of metazoan Metallothioneins: evolutionary differentiation of Mollusc MTs.

Background: The degree of metal binding specificity in metalloproteins such as metallothioneins (MTs) can be crucial for their functional accuracy. Unlike most other animal species, pulmonate molluscs possess homometallic MT isoforms loaded with Cu+ or Cd2+. They have, so far, been obtained as native metal-MT complexes from snail tissues, where they are involved in the metabolism of the metal ion species bound to the respective isoform. However, it has not as yet been discerned if their specific metal occupation is the result of a rigid control of metal availability, or isoform expression programming in the hosting tissues or of structural differences of the respective peptides determining the coordinative options for the different metal ions. In this study, the Roman snail (Helix pomatia) Cu-loaded and Cd-loaded isoforms (HpCuMT and HpCdMT) were used as model molecules in order t o elucidate the biochemical and evolutionary mechanisms permitting pulmonate MTs to achieve specificity for their cognate metal ion. Results: HpCuMT and HpCdMT were recombinantly synthesized in the presence of Cd2+, Zn2+ or Cu2+ and corresponding metal complexes analysed by electrospray mass spectrometry and circular dichroism (CD) and ultra violet-visible (UV-Vis) spectrophotometry. Both MT isoforms were only able to form unique, homometallic and stable complexes (Cd6-HpCdMT and Cu12-HpCuMT) with their cognate metal ions. Yeast complementation assays demonstrated that the two isoforms assumed metal-specific functions, in agreement with their binding preferences, in heterologous eukaryotic environments. In the snail organism, the functional metal specificity of HpCdMT and HpCuMT was contributed by metal-specific transcription programming and cell-specific expression. Sequence elucidation and phylogenetic analysis of MT isoforms from a number of snail species revealed that they possess an unspecific and two metal-specific MT isoforms, whose metal specificity was achieved exclusively by evolutionary modulation of non-cysteine amino acid positions. Conclusion: The Roman snail HpCdMT and HpCuMT isoforms can thus be regarded as prototypes of isoform families that evolved genuine metal-specificity within pulmonate molluscs. Diversification into these isoforms may have been initiated by gene duplication, followed by speciation and selection towards opposite needs for protecting copper-dominated metabolic pathways from nonessential cadmium. The mechanisms enabling these proteins to be metal-specific could also be relevant for other metalloproteins.

Novel anesthetics and other treatment strategies for refractory status epilepticus

Refractory status epilepticus (RSE)-that is, seizures resistant to at least two antiepileptic drugs (AEDs)-is generally managed with barbiturates, propofol, or midazolam, despite a low level of evidence (Rossetti, 2007). When this approach fails, the need for alternative pharmacologic and nonpharmacologic strategies emerges. These have been investigated even less systematically than the aforementioned compounds, and are often used, sometimes in succession, in cases of extreme refractoriness (Robakis & Hirsch, 2006). Several possibilities are reviewed here. In view of the marked heterogeneity of reported information, etiologies, ages, and comedications, it is extremely difficult to evaluate a given method, not to say to compare different strategies among them. Pharmacologic Approaches Isoflurane and desflurane may complete the armamentarium of anesthetics,' and should be employed in a ''close'' environment, in order to prevent intoxication of treating personnel. c-Aminobutyric acid (GABA)A receptor potentiation represents the putative mechanism of action. In an earlier report, isoflurane was used for up to 55 h in nine patients, controlling seizures in all; mortality was, however, 67% (Kofke et al., 1989). More recently, the use of these inhalational anesthetics was described in seven subjects with RSE, for up to 26 days, with an endtidal concentration of 1.2-5%. All patients required vasopressors, and paralytic ileus occurred in three; outcome was fatal in three patients (43%) (Mirsattari et al., 2004). Ketamine, known as an emergency anesthetic because of its favorable hemodynamic profile, is an N-methyl-daspartate (NMDA) antagonist; the interest for its use in RSE derives from animal works showing loss of GABAA efficacy and maintained NMDA sensitivity in prolonged status epilepticus (Mazarati & Wasterlain, 1999). However, to avoid possible neurotoxicity, it appears safer to combine ketamine with GABAergic compounds (Jevtovic-Todorovic et al., 2001; Ubogu et al., 2003), also because of a likely synergistic effect (Martin & Kapur, 2008). There are few reported cases in humans, describing progressive dosages up to 7.5 mg/kg/h for several days (Sheth & Gidal, 1998; Quigg et al., 2002; Pruss & Holtkamp, 2008), with moderate outcomes. Paraldehyde acts through a yet-unidentified mechanism, and appears to be relatively safe in terms of cardiovascular tolerability (Ramsay, 1989; Thulasimani & Ramaswamy, 2002), but because of the risk of crystal formation and its reactivity with plastic, it should be used only as fresh prepared solution in glass devices (Beyenburg et al., 2000). There are virtually no recent reports regarding its use in adults RSE, whereas rectal paraldehyde in children with status epilepticus resistant to benzodiazepines seems less efficacious than intravenous phenytoin (Chin et al., 2008). Etomidate is another anesthetic agent for which the exact mechanism of action is also unknown, which is also relatively favorable regarding cardiovascular side effects, and may be used for rapid sedation. Its use in RSE was reported in eight subjects (Yeoman et al., 1989). After a bolus of 0.3 mg/kg, a drip of up to 7.2 mg/kg/h for up to 12 days was administered, with hypotension occurring in five patients; two patients died. A reversible inhibition of cortisol synthesis represents an important concern, limiting its widespread use and implying a careful hormonal substitution during treatment (Beyenburg et al., 2000). Several nonsedating approaches have been reported. The use of lidocaine in RSE, a class Ib antiarrhythmic agent modulating sodium channels, was reviewed in 1997 (Walker & Slovis, 1997). Initial boluses up to 5 mg/kg and perfusions of up to 6 mg/kg/h have been mentioned; somewhat surprisingly, at times lidocaine seemed to be successful in controlling seizures in patients who were refractory to phenytoin. The aforementioned dosages should not be overshot, in order to keep lidocaine levels under 5 mg/L and avoid seizure induction (Hamano et al., 2006). A recent pediatric retrospective survey on 57 RSE episodes (37 patients) described a response in 36%, and no major adverse events; mortality was not given (Hamano et al., 2006 Verapamil, a calcium-channel blocker, also inhibits P-glycoprotein, a multidrug transporter that may diminish AED availability in the brain (Potschka et al., 2002). Few case reports on its use in humans are available; this medication nevertheless appears relatively safe (under cardiac monitoring) up to dosages of 360 mg/day (Iannetti et al., 2005). Magnesium, a widely used agent for seizures elicited by eclampsia, has also been anecdotally reported in RSE (Fisher et al., 1988; Robakis & Hirsch, 2006), but with scarce results even at serum levels of 14 mm. The rationale may be found in the physiologic blockage of NMDA channels by magnesium ions (Hope & Blumenfeld, 2005). Ketogenic diet has been prescribed for decades, mostly in children, to control refractory seizures. Its use in RSE as ''ultima ratio'' has been occasionally described: three of six children (Francois et al., 2003) and one adult (Bodenant et al., 2008) were responders. This approach displays its effect subacutely over several days to a few weeks. Because ''malignant RSE'' seems at times to be the consequence of immunologic processes (Holtkamp et al., 2005), a course of immunomodulatory treatment is often advocated in this setting, even in the absence of definite autoimmune etiologies (Robakis & Hirsch, 2006); steroids, adrenocorticotropic hormone (ACTH), plasma exchanges, or intravenous immunoglobulins may be used alone or in sequential combination. Nonpharmacologic Approaches These strategies are described somewhat less frequently than pharmacologic approaches. Acute implantation of vagus nerve stimulation (VNS) has been reported in RSE (Winston et al., 2001; Patwardhan et al., 2005; De Herdt et al., 2009). Stimulation was usually initiated in the operation room, and intensity progressively adapted over a few days up to 1.25 mA (with various regimens regarding the other parameters), allowing a subacute seizure control; one transitory episode of bradycardia/asystole has been described (De Herdt et al., 2009). Of course, pending identification of a definite seizure focus, resective surgery may also be considered in selected cases (Lhatoo & Alexopoulos, 2007). Low-frequency (0.5 Hz) transcranial magnetic stimulation (TMS) at 90% of the resting motor threshold has been reported to be successful for about 2 months in a patient with epilepsia partialis continua, but with a weaning effect afterward, implying the need for a repetitive use (Misawa et al., 2005). More recently, TMS was applied in a combination of a short ''priming'' high frequency (up to 100 Hz) and longer runs of low-frequency stimulations (1 Hz) at 90-100% of the motor threshold in seven other patients with simple-partial status, with mixed results (Rotenberg et al., 2009). Paradoxically at first glance, electroconvulsive treatment may be found in cases of extremely resistant RSE. A recent case report illustrates its use in an adult patient with convulsive status, with three sessions (three convulsions each) carried out over 3 days, resulting in a moderate recovery; the mechanism is believed to be related to modification of the synaptic release of neurotransmitters (Cline & Roos, 2007). Therapeutic hypothermia, which is increasingly used in postanoxic patients (Oddo et al., 2008), has been the object of a recent case series in RSE (Corry et al., 2008). Reduction of energy demand, excitatory neurotransmission, and neuroprotective effects may account for the putative mechanism of action. Four adult patients in RSE were cooled to 31_-34_C with an endovascular system for up to 90 h, and then passively rewarmed over 2-50 h. Seizures were controlled in two patients, one of whom died; also one of the other two patients in whom seizures continued subsequently deceased. Possible side effects are related to acid-base and electrolyte disturbances, and coagulation dysfunction including thrombosis, infectious risks, cardiac arrhythmia, and paralytic ileus (Corry et al., 2008; Cereda et al., 2009). Finally, anecdotic evidence suggests that cerebrospinal fluid (CSF)-air exchange may induce some transitory benefit in RSE (Kohrmann et al., 2006); although this approach was already in use in the middle of the twentieth century, the mechanism is unknown. Acknowledgment A wide spectrum of pharmacologic (sedating and nonsedating) and nonpharmacologic (surgical, or involving electrical stimulation) regimens might be applied to attempt RSE control. Their use should be considered only after refractoriness to AED or anesthetics displaying a higher level of evidence. Although it seems unlikely that these uncommon and scarcely studied strategies will influence the RSE outcome in a decisive way, some may be interesting in particular settings. However, because the main prognostic determinant in status epilepticus appears to be related to the underlying etiology rather than to the treatment approach (Rossetti et al., 2005, 2008), the safety issue should always represent a paramount concern for the prescribing physician. Conclusion The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this paper is consistent with those guidelines.

Pavement Surface on Macadam Base: Adair County Final Report, Iowa Highway Reserach Board Project HR-209

The quality and availability of aggregate for pc concrete stone varies across Iowa. Southwest Iowa is one area of the state that is short of quality aggregates. The concrete stone generally available in the area is limestone from the Argentine or Winterset ledges with an overburden of up to 150 feet. This concrete stone is classified as Class 1 durability and is susceptible to 'ID"-cracking. In addition, the general engineering soil classification rates the soils of southwest Iowa as having the poorest subgrade bearing characteristics in the state. 1 The combination of poor soils and low quality aggregate has contributed to premature deterioration of many miles of portland cement concrete pavement. Research project HR-209 was initiated in 1979 to explore alternative construction methods that may produce better pavements for southwest Iowa.

Restoration of Fricitonal Characteristics on Older Portland Cement Concrete Pavement:Final Report for Iowa Highway Research Board Project HR-224, June 1986

Safety i s a very important aspect o f the highway program. The Iowa DOT initiated an inventory o f the friction values of all paved primary roadways i n 1969. This inventory, with an ASTM E-274 test unit, has continued to the present time. The t e s t i n g frequency varies based upon traffic volume and the previous friction value. Historically , the state o f Iowa constructed a substantial amount o f pcc pavement during the 1928-30 period t o "get Iowa out o f the mud". Some of that pavement has never been resurfaced and has been subjected to more than 50 years o f wear. The textured surface has been worn away and has subsequently polished. Even though some pavements from 15 t o 50 years old continue t o function structurally , because of the loss of friction , they do not provide the desired level o f safety to the driver. As a temporary measure, "Sl ippery -When -Wet " signs have been posted on many older pcc roads due to friction numbers below t h e desirable level. These signs warn the motorist of the current conditions. An economical method of restoring the high quality frictional properties i s needed.

Optimization of Soil Stabilization with Class C Fly Ash, January 1987

Previous Iowa DOT sponsored research has shown that some Class C fly ashes are ementitious (because calcium is combined as calcium aluminates) while other Class C ashes containing similar amounts of elemental calcium are not (1). Fly ashes from modern power plants in Iowa contain significant amounts of calcium in their glassy phases, regardless of their cementitious properties. The present research was based on these findings and on the hyphothesis that: attack of the amorphous phase of high calcium fly ash could be initiated with trace additives, thus making calcium available for formation of useful calcium-silicate cements. Phase I research was devoted to finding potential additives through a screening process; the likely chemicals were tested with fly ashes representative of the cementitious and non-cementitious ashes available in the state. Ammonium phosphate, a fertilizer, was found to produce 3,600 psi cement with cementitious Neal #4 fly ash; this strength is roughly equivalent to that of portland cement, but at about one-third the cost. Neal #2 fly ash, a slightly cementitious Class C, was found to respond best with ammonium nitrate; through the additive, a near-zero strength material was transformed into a 1,200 psi cement. The second research phase was directed to optimimizing trace additive concentrations, defining the behavior of the resulting cements, evaluating more comprehensively the fly ashes available in Iowa, and explaining the cement formation mechanisms of the most promising trace additives. X-ray diffraction data demonstrate that both amorphous and crystalline hydrates of chemically enhanced fly ash differ from those of unaltered fly ash hydrates. Calciumaluminum- silicate hydrates were formed, rather than the expected (and hypothesized) calcium-silicate hydrates. These new reaction products explain the observed strength enhancement. The final phase concentrated on laboratory application of the chemically-enhanced fly ash cements to road base stabilization. Emphasis was placed on use of marginal aggregates, such as limestone crusher fines and unprocessed blow sand. The nature of the chemically modified fly ash cements led to an evaluation of fine grained soil stabilization where a wide range of materials, defined by plasticity index, could be stabilized. Parameters used for evaluation included strength, compaction requirements, set time, and frost resistance.

Feasibility Study on Proposed Amtrak service from Chicago, to Iowa City, Iowa via Quad Cities, December 5, 2007

Soon after the Illinois Department of Transportation (“Ill. DOT”) requested Amtrak to conduct a feasibility study on proposed Amtrak service between Chicago and the Illinois Quad Cities, the Iowa Department of Transportation (“Iowa DOT”) asked that the study be extended to Iowa City and later to Des Moines. This report examines the feasibility of extending service to Iowa City. The completed report for the proposed Chicago – Quad Cities’ service was delivered to Ill. DOT in early January 2008. It assumes a stand-alone train operation strictly within the State of Illinois and makes no reference to extending the service into the State of Iowa. Therefore, there is no discussion about potential cost sharing allocations for capital improvements or operating losses between the two states which will become a matter of future negotiations between the two jurisdictions. That being said, this report on extending the service to Iowa City is simply an addendum to the Quad Cities report and covers such topics as additional capital infrastructure improvements that would be required in Iowa, impacts on operating expenses, revised ridership and revenue projections, and the like. With one minor exception, the recommended level of capital improvements within Illinois will still be required if the service to Iowa City is initiated. It is thus important for the readers of this report to refer to the Illinois study for detailed information on that state’s portion of the route alternatives.

Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.

Introduction: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. Methods: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Results: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). Conclusions: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.

An Investigation of the Interstate 80 Rutting in Adair County, October 1983

This investigation was initiated to determine the causes of a rutting problem that occurred on Interstate 80 in Adair County. 1-80 from Iowa 25 to the Dallas County line was opened to traffic in November, 1960. The original pavement consisted of 4-1/2" of asphalt cement concrete over 12" of rolled stone base and 12" of granular subbase. A 5-1/2" overlay of asphalt cement concrete was placed in 1964. In 1970-1972, the roadway was resurfaced with 3" of asphalt cement concrete. In 1982, an asphalt cement concrete inlay, designed for a 10-year life, was placed in the eastbound lane. The mix designs for all courses met or exceeded all current criteria being used to formulate job mixes. Field construction reports indicate .that asphalt usage, densities, field voids and filler bitumen determinations were well within specification limits on a very consistent basis. Field laboratory reports indicate that laboratory voids for the base courses were within the prescribed limits for the base course and below the prescribed limits for the surface course. Instructional memorandums do indicate that extreme caution should be exercised when the voids are at or near the lower limits and traffic is not minimal. There is also a provision that provides for field voids controlling when there is a conflict between laboratory voids and field voids. It appears that contract documents do not adequately address the directions that must be taken when this conflict arises since it can readily be shown that laboratory voids must be in the very low or dangerous range if field voids are to be kept below the maximum limit under the current density specifications. A rut depth survey of January, 1983, identified little or no rutting on this section of roadway. Cross sections obtained in October, 1983, identified rutting which ranged from 0 to 0.9" with a general trend of the rutting to increase from a value of approximately 0.3" at MP 88 to a rut depth of 0.7" at MP 98. No areas of significant rutting were identified in the inside lane. Structural evaluation with the Road Rater indicated adequate structural capacity and also indicated that the longitudinal subdrains were functioning properly to provide adequate soil support values. Two pavement sections taken from the driving lane indicated very little distortion in the lower 7" base course. Essentially all of the distortion had occurred in the upper 2" base course and the 1..;1/2" surface course. Analysis of cores taken from this section of Interstate 80 indicated very little densification of either the surface or the upper or lower base courses. The asphalt cement content of both the Type B base courses and the Type A surface course were substantially higher than the intended asphalt cement content. The only explanation for this is that the salvaged material contained a greater percent of asphalt cement than initial extractions indicated. The penetration and viscosity of the blend of new asphalt cement and the asphalt cement recovered from the salvaged material were relatively close to that intended for this project. The 1983 ambient temperatures were extremely high from June 20 through September 10. The rutting is a result of a combination of adverse factors including, (1) high asphalt content, (2) the difference between laboratory and field voids, (3) lack of intermediate sized crushed particles, (4) high ambient temperatures. The high asphalt content in the 2" upper base course produced an asphalt concrete mix that did not exhibit satisfactory resistance to deformation from heavy loading. The majority of the rutting resulted from distortion of the 2" upper base lift. Heater planing is recommended as an interim corrective action. Further recommendation is to design for a 20-year alternative by removing 2-1/2" of material from the driving lane by milling and replacing with 2-1/2" of asphalt concrete with improved stability. This would be .followed by placing 1-1/2" of high quality resurfacing on the entire roadway. Other recommendations include improved density and stability requirements for asphalt concrete on high traffic roadways.