A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate

PURPOSE: The primary purpose of the clinical trial was to assess the safety and efficacy of once-a-day compared with three-times-a-day gentamicin in patients with serious infections who had protocol-determined peak serum aminoglycoside concentrations. PATIENTS AND METHODS: A total of 249 hospitalized patients with suspected or proven serious infections were randomized in a 2:2:1 ratio to gentamicin given three times a day with ticarcillin-clavulanate (TC), gentamicin once a day with TC, or ticarcillin-clavulanate (TC) alone. The gentamicin once-a-day dosage for patients with estimated creatinine clearance values of > or =80 mL/min was 5.1 mg/kg. With lower creatinine clearance estimates, the mg/kg dosage of gentamicin was decreased, and the dosage intervals (once daily or three times a day) were maintained. Evaluability required documentation of achievement of protocol-defined peak serum gentamicin levels. RESULTS: Of the total 175 evaluable patients, there were no significant differences found between treatment regimens with respect to clinical or microbiologic efficacy. Bedside audiometry proved impractical due to the frequency of altered mental state in ill patients. Based on the traditional increase in serum creatinine values from baseline values, no differences in renal toxicity between the treatment groups was identified. When changes in renal function were reanalyzed based on maintaining, as opposed to worsening, of renal function, preservation of renal function was better in the gentamicin once-a-day patients as opposed to the gentamicin three-times-a-day patients, P <0.01. CONCLUSIONS: Gentamicin once a day plus TC, gentamicin three times a day plus TC, and TC alone had similar effects in seriously ill hospitalized patients. The incidence of nephrotoxicity was similar in the three treatment groups. Using a nonvalidated post-hoc analysis, renal function was better preserved in gentamicin once-a-day + TC and TC-only patients as opposed to gentamicin three-times-a-day + TC.

Effects of hibernation on bone in yellow-bellied marmots

Disuse osteoporosis is a problem for people with spinal cord injury or stroke, patients confined to bed rest, and astronauts exposed to microgravity. Unlike most mammals however, bears have been shown to prevent bone loss during hibernation, a seasonal period of disuse. Similarly, studies in ground squirrels indicate preservation of whole bone strength during hibernation, though evidence suggests there may be some increased osteocytic osteolysis. Uncovering the mechanism by which these animals prevent bone loss during hibernation could lead to an improved treatment for osteoporosis in humans. Marmots are a good animal model for these studies because they are small enough to easily house in an animal facility yet still utilize intracortical remodeling like humans and bears, and unlike smaller rodents like squirrels. Marmots preserve bone mechanical and microstructural properties during hibernation. Bone mechanical and geometrical properties are not diminished in post-hibernation samples compared to pre-hibernation samples. Mineral content, measured by ash fraction, was higher in post-hibernation samples (p = 0.0003). Haversian porosity as well as remodeling cavity density were not different (p > 0.38) between pre- and post-hibernation samples. Similarly, average lacunar area, lacunar density, and lacunar porosity were all lower (p < 0.0001) in post-hibernation samples. Trabecular thickness was larger in posthibernation samples (p = 0.0058). Bone volume fraction was not different between groups, but approached significance (p = 0.0725). Further studies in marmots and other hibernators could help uncover the mechanism that allows hibernators to prevent disuse osteoporosis during hibernation.

Electron microscopy of high pressure frozen samples: bridging the gap between cellular ultrastructure and atomic resolution

Transmission electron microscopy has provided most of what is known about the ultrastructural organization of tissues, cells, and organelles. Due to tremendous advances in crystallography and magnetic resonance imaging, almost any protein can now be modeled at atomic resolution. To fully understand the workings of biological "nanomachines" it is necessary to obtain images of intact macromolecular assemblies in situ. Although the resolution power of electron microscopes is on the atomic scale, in biological samples artifacts introduced by aldehyde fixation, dehydration and staining, but also section thickness reduces it to some nanometers. Cryofixation by high pressure freezing circumvents many of the artifacts since it allows vitrifying biological samples of about 200 mum in thickness and immobilizes complex macromolecular assemblies in their native state in situ. To exploit the perfect structural preservation of frozen hydrated sections, sophisticated instruments are needed, e.g., high voltage electron microscopes equipped with precise goniometers that work at low temperature and digital cameras of high sensitivity and pixel number. With them, it is possible to generate high resolution tomograms, i.e., 3D views of subcellular structures. This review describes theory and applications of the high pressure cryofixation methodology and compares its results with those of conventional procedures. Moreover, recent findings will be discussed showing that molecular models of proteins can be fitted into depicted organellar ultrastructure of images of frozen hydrated sections. High pressure freezing of tissue is the base which may lead to precise models of macromolecular assemblies in situ, and thus to a better understanding of the function of complex cellular structures.

Reflection, refraction, and rejection : copper smelting heritage and the execution of environmental policy

This dissertation examines the global technological and environmental history of copper smelting and the conflict that developed between historic preservation and environmental remediation at major copper smelting sites in the United States after their productive periods ended. Part I of the dissertation is a synthetic overview of the history of copper smelting and its environmental impact. After reviewing the basic metallurgy of copper ores, the dissertation contains successive chapters on the history of copper smelting to 1640, culminating in the so-called German, or Continental, processing system; on the emergence of the rival Welsh system during the British industrial revolution; and on the growth of American dominance in copper production the late 19th and early 20th centuries. The latter chapter focuses, in particular, on three of the most important early American copper districts: Michigan’s Keweenaw Peninsula, Tennessee’s Copper Basin, and Butte-Anaconda, Montana. As these three districts went into decline and ultimately out of production, they left a rich industrial heritage and significant waste and pollution problems generated by increasingly more sophisticated technologies capable of commercially processing steadily growing volumes of decreasingly rich ores. Part II of the dissertation looks at the conflict between historic preservation and environmental remediation that emerged locally and nationally in copper districts as they went into decline and eventually ceased production. Locally, former copper mining communities often split between those who wished to commemorate a region’s past importance and develop heritage tourism, and local developers who wished to clear up and clean out old industrial sites for other purposes. Nationally, Congress passed laws in the 1960s and 1970s mandating the preservation of historical resources (National Historic Preservation Act) and laws mandating the cleanup of contaminated landscapes (CERCLA, or Superfund), objectives sometimes in conflict – especially in the case of copper smelting sites. The dissertation devotes individual chapters to the conflicts that developed between environmental remediation, particularly involving the Environmental Protection Agency and the heritage movement in the Tennessee, Montana, and Michigan copper districts. A concluding chapter provides a broad model to illustrate the relationship between industrial decline, federal environmental remediation activities, and the growth of heritage consciousness in former copper mining and smelting areas, analyzes why the outcome varied in the three areas, and suggests methods for dealing with heritage-remediation issues to minimize conflict and maximize heritage preservation.

Prevalence of nephrolithiasis in patients with ileal bladder substitutes

OBJECTIVES: To assess the effect of ileal bladder substitutes with preservation of the ileocecal valve and distal 25 cm of ileum on nephrolithiasis. METHODS: We reviewed a consecutive series of 518 patients (44 women and 474 men) with ileal orthotopic bladder substitution in whom 55 to 65 cm of ileum was resected but with preservation of the ileocecal valve and distal 25 cm of ileum, to determine prevalence of nephrolithiasis as well as bicarbonate, base excess, creatinine levels, and urinary pH at time of stone diagnosis and 2 years before it. RESULTS: Four male patients with a median age of 66 years (range, 50 to 70 years) developed nephrolithiasis after ileal bladder substitute, for a total of five calculi. The prevalence of nephrolithiasis in this retrospective cohort is thus 1% (5 of 518). They developed the calculi after a median follow-up of 8 years (range, 4 to 17 years). The four patients were diagnosed with calculi at 2.3, 3, 10, 10.3, and 14 years after bladder substitute. Two of the stones were uric acid calculi; the remaining three were calcium oxalate. None of our patients were acidotic or had elevated serum creatinines at time of stone formation. Urinary pH determined once in spontaneously voided urine at the time of stone diagnosis was pH 6.0 for the two uric acid calculi and pH 7.0 for the remaining calculi. CONCLUSIONS: The present study demonstrates a low prevalence of calculi in our cohort.

Resuspension of the aortic valve in acute type A dissection: long-term results

BACKGROUND AND AIM OF THE STUDY: Preservation of the aortic valve during the repair of acute type A aortic dissection (AADA) is a viable option to prevent lifelong oral anticoagulation. The study aim was to assess aortic valve function following resuspension and supracoronary ascending aortic grafting. METHODS: Among a collective of 210 consecutive patients undergoing surgery for AADA, 140 (66.7%) with resuspension of the aortic valve and supracoronary ascending graft were analyzed. Of these patients, 83 (59.3%) had a complete follow up (mean 61.2 +/- 40.8 months), with 65 of the subgroup (78.3%) being followed by computed tomography scanning and echocardiography. RESULTS: Reoperation due to severe aortic valve regurgitation was required in seven patients (10.8%). The perioperative characteristics were similar in these patients; notably, no significant difference was evident with regards to the aortic annulus diameter and the severity of regurgitation at the time of surgery. The left ventricular mass index was significantly higher in patients requiring reoperation due to aortic valve regurgitation (219.3 +/- 146.6 versus 123.9 +/- 146.6 g/m2; p <0.05). None of the patients died as a result of reoperation. CONCLUSION: The long-term functional results following resuspension of the aortic valve in AADA were very good. A close echocardiographic follow up was necessary, as reoperation of the aortic valve was required in more than 10% of the collective, with an average follow up of five years. Reoperation was mainly related to secondary dilatation of the aortic root.

Osteosynthesis and hemiarthroplasty of fractures of the proximal humerus: outcomes in a consecutive case series

HYPOTHESIS: This study addresses the outcome after osteosynthesis or hemiarthroplasty, using a cohort of patients that was enrolled in a previous prospective study on humeral head perfusion and was consequently treated using a common conceptual approach. MATERIALS AND METHODS: Between 1998 and 2001, 98 patients with 100 fractures of the proximal humerus were treated surgically by a single surgeon with open reduction and internal fixation (ORIF) (51/100, group A, median age 54 years; range, 21-88) or with hemiarthroplasty (49/100, group B, median age 66 years; range, 38-87). Seventy-six of 98 patients were available for re-evaluation at a mean follow-up of five years (3.3-7.3) using the Constant-Murley score (CMS), the Subjective Shoulder Value (SSV), and conventional radiographs. RESULTS: The median total CMS was 77 (range, 37-98) for group A and 70 (range, 39-84) for group B. The median SSV was 92 (range, 40-100) for group A and 90 (range, 40-100) for group B. Avascular necrosis occured in 6/40 fractures treated with ORIF. CONCLUSION: Osteosynthesis and hemiarthroplasty yield similar functional results and comparable patient satisfaction following the applied decision making process in this selected patient cohort. Osteosynthesis with preservation of the humeral head is worth considering when adequate reduction and stable conditions for revascularization can be obtained. In patients with osteopenic bone and/or comminuted fractures, hemiarthroplasty is a viable alternative. LEVEL OF EVIDENCE: Level 2; Prospective non-randomized comparison study.

Therapie des femoroazetabulären Impingements über die chirurgische Hüftluxation [Surgical dislocation of the hip for the treatment of femoroacetabular impingement. Technique and results]

Surgical dislocation of the hip is a safe and established technique for treating femoroacetabular impingement. The complication rate is low, and if the correct technique that respects the blood supply is used, femoral head necrosis does not occur. The most frequent complications are minor ectopic bone formation and nonunion of the greater trochanter. Surgical treatment includes the correction of femoral and acetabular pathology. Clinically, in approximately 75-80% of cases a good-to-excellent result can be obtained. However, patients with advanced degenerative changes (exceeding stage 1 osteoarthritis using the Tönnis score) have worse outcomes. It has also been shown that preservation of the labrum has a significant influence on both clinical outcome and progression of osteoarthritis: It seems that preservation of the labrum is mandatory.

Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces the proportion of patients infected and delays time to infection

INTRODUCTION: Cystic fibrosis (CF) almost always leads to chronic airway infection with Pseudomonas aeruginosa. Despite advances in antibiotic therapy, after chronic infection rapid deterioration in lung function occurs, increasing morbidity and mortality. Prevention of infection by vaccination is desirable, but earlier trials produced disappointing results. The promising short term immunogenicity and safety of a new P. aeruginosa vaccine prompted us to evaluate its long term efficacy. We conducted a 10-year retrospective analysis of outcomes in a group of vaccinated patients. MATERIALS AND METHODS: In 1989-1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. We report the follow-up of 26 of these patients from 1989 to 2001. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. Vaccinated patients and controls were attending a single CF clinic and received the same clinical management throughout the study period. Main outcomes were time to infection, proportion of patients infected, development of P. aeruginosa mucoid phenotype, lung function and body weight. RESULTS: The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients >/=18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study. CONCLUSION: Regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

Effect of phrenic nerve palsy on early postoperative lung function after pneumonectomy: a prospective study

BACKGROUND The issue of phrenic nerve preservation during pneumonectomy is still an unanswered question. So far, its direct effect on immediate postoperative pulmonary lung function has never been evaluated in a prospective trial. METHODS We conducted a prospective crossover study including 10 patients undergoing pneumonectomy for lung cancer between July 2011 and July 2012. After written informed consent, all consecutive patients who agreed to take part in the study and in whom preservation of the phrenic nerve during operation was possible, were included in the study. Upon completion of lung resection, a catheter was placed in the proximal paraphrenic tissue on the pericardial surface. After an initial phase of recovery of 5 days all patients underwent ultrasonographic assessment of diaphragmatic motion followed by lung function testing with and without induced phrenic nerve palsy. The controlled, temporary paralysis of the ipsilateral hemidiaphragm was achieved by local administration of lidocaine 1% at a rate of 3 mL/h (30 mg/h) via the above-mentioned catheter. RESULTS Temporary phrenic nerve palsy was accomplished in all but 1 patient with suspected catheter dislocation. Spirometry showed a significant decrease in dynamic lung volumes (forced expiratory volume in 1 second and forced vital capacity; p < 0.05) with the paralyzed hemidiaphragm. Blood oxygen saturation levels did not change significantly. CONCLUSIONS Our results show that phrenic nerve palsy causes a significant impairment of dynamic lung volumes during the early postoperative period after pneumonectomy. Therefore, in these already compromised patients, intraoperative phrenic nerve injury should be avoided whenever possible.

Combining sedimentological, trace metal (Mn, Mo) and molecular evidence for reconstructing past water-column redox conditions: The example of meromictic Lake Cadagno (Swiss Alps)

Here, we present sedimentological, trace metal, and molecular evidence for tracking bottom water redox-state conditions during the past 12,500 years in nowadays sulfidic and meromictic Lake Cadagno (Switzerland). A 10.5 m long sediment core from the lake covering the Holocene period was investigated for concentration variations of the trace metals Mn and Mo (XRF core scanning and ICP-MS measurements), and for the presence of anoxygenic phototrophic sulfur bacteria (carotenoid pigment analysis and 16S rDNA real time PCR). Our trace metal analysis documents an oxic-intermediate-sulfidic redox-transition period beginning shortly after the lake formation similar to 12.5 kyr ago. The oxic period is characterized by low sedimentary Mn and Mo concentrations, as well as by the absence of any remnants of anoxygenic phototrophic sulfur bacteria. Enhanced accumulation/preservation of Mn (up to 5.6 wt%) in the sediments indicates an intermediate, Mn-enriched oxygenation state with fluctuating redox conditions during a similar to 2300-year long transition interval between similar to 12.1 and 9.8 kyr BP. We propose that the high Mn concentrations are the result of enhanced Mn2+ leaching from the sediments during reducing conditions and subsequent rapid precipitation of Mn-(oxyhydr) oxide minerals during episodic and short-term water-column mixing events mainly due to flood-induced underflows. At 9800 +/- 130 cal yr BP, a rapid transition to fully sulfidic conditions is indicated by the marked enrichment of Mo in the sediments (up to 490 ppm), accompanied by an abrupt drop in Mn concentrations and the increase of molecular biomarkers that indicate the presence of anoxygenic photosynthetic bacteria in the water column. Persistently high Mo concentrations >80 ppm provide evidence that sulfidic conditions prevailed thereafter until modern times, without any lasting hypolimnetic ventilation and reoxygenation. Hence, Lake Cadagno with its persistently stable chemocline offers a framework to study in great temporal detail over similar to 12 kyr the development of phototrophic sulfur bacteria communities and redox processes in a sulfidic environment, possibly depicting analogous conditions in an ancient ocean. Our study underscores the value of combining sedimentological, geochemical, and microbiological approaches to characterize paleo-environmental and -redox conditions in lacustrine and marine settings.

Effects of exogenous surfactant on the non-heart-beating donor lung graft in experimental lung transplantation - a stereological study.

The use of non-heart-beating donor (NHBD) lungs may help to overcome the shortage of lung grafts in clinical lung transplantation, but warm ischaemia and ischaemia/reperfusion injury (I/R injury) resulting in primary graft dysfunction represent a considerable threat. Thus, better strategies for optimized preservation of lung grafts are urgently needed. Surfactant dysfunction has been shown to contribute to I/R injury, and surfactant replacement therapy is effective in enhancing lung function and structural integrity in related rat models. In the present study we hypothesize that surfactant replacement therapy reduces oedema formation in a pig model of NHBD lung transplantation. Oedema formation was quantified with (SF) and without (non-SF) surfactant replacement therapy in interstitial and alveolar compartments by means of design-based stereology in NHBD lungs 7 h after cardiac arrest, reperfusion and transplantation. A sham-operated group served as control. In both NHBD groups, nearly all animals died within the first hours after transplantation due to right heart failure. Both SF and non-SF developed an interstitial oedema of similar degree, as shown by an increase in septal wall volume and arithmetic mean thickness as well as an increase in the volume of peribron-chovascular connective tissue. Regarding intra-alveolar oedema, no statistically significant difference could be found between SF and non-SF. In conclusion, surfactant replacement therapy cannot prevent poor outcome after prolonged warm ischaemia of 7 h in this model. While the beneficial effects of surfactant replacement therapy have been observed in several experimental and clinical studies related to heart-beating donor lungs and cold ischaemia, it is unlikely that surfactant replacement therapy will overcome the shortage of organs in the context of prolonged warm ischaemia, for example, 7 h. Moreover, our data demonstrate that right heart function and dysfunctions of the pulmonary vascular bed are limiting factors that need to be addressed in NHBD.

The history of subaquatic volcanism recorded in the sediments of Lake Kivu

Subaquatic volcanic activity has been ongoing in Lake Kivu since the early Holocene and has a dynamic effect on the biological productivity in the surface water, and the preservation of carbonate in the deep anoxic water. Groundwater discharge into the lake’s deepwater propels the upward advection of the water column that ultimately supplies nutrients to the surface water for biological production. The amount of nutrients supplied from the deepwater can be increased suddenly by (1) a cold meteorological event that drives deep seasonal mixing resulting in increased nutrients from below and oxygen from above, or (2) subaquatic volcanic activity that induces a buoyant hydrothermal plume, which entrains nutrients from the deepwater and results in anoxia or suboxic conditions in the surface water. Previous sedimentological studies in Lake Kivu have hypothesized that regional climatic changes are responsible for sudden changes in the preservation of carbonates in the Main Basin. Here we reveal that sublacustrine volcanic events most likely induce the abrupt changes to the geochemistry in the sediment in Lake Kivu. An unprecedented look into the sediment stratigraphy and geochemistry from high-resolution seismic-reflection, and 15N-isotope analyses was conducted in the Main Basin. The results reveal that buoyant hydrothermal plumes caused by subaquatic volcanic activity are a possible trigger for increased biological productivity and organic matter preservation, and that ongoing hydrothermal activity increases the alkalinity in the deepwater, leading to carbonate preservation. The onset of carbonate preservation since the 1970s that is currently observed in the sediment could indicate that hydrothermal discharge has recently increased in the lake.

The Reform of the EC Audiovisual Media Regulation : Television Without Cultural Diversity

In the profoundly changing and dynamic world of contemporary audiovisual media, what has remained surprisingly unaffected is regulation. In the European Union, the new Audiovisual Media Services Directive (AVMS), proposed by the European Commission on December 13, 2005, should allegedly rectify this situation. Amending the existing Television without Frontiers Directive, it should offer a fresh approach and meet the challenge of appropriately regulating media in a complex environment. It is meant to achieve a balance between the free circulation of TV broadcast and new audiovisual media and the preservation of values of cultural identity and diversity, while respecting the principles of subsidiarity and proportionality inherent to the Community. The purpose of this paper is to examine whether and how the changes envisaged to the EC audiovisual media regime might influence cultural diversity in Europe. It addresses subsequently the question of whether the new AVMS properly safeguards the balance between competition and the public interest in this regard, or whether cultural diversity remains a mere political banner.

Ar-40/Ar-39 Evidence for Middle Proterozoic (1300-1500 Ma) Slow Cooling of the Southern Black Hills, South Dakota, Midcontinent, North America: Implications for Early Proterozoic P-T Evolution and Posttectonic Magmatism

Ar-40/Ar-39 total gas and plateau dates from muscovite and biotite in the southern Black Hills, South Dakota, provide evidence for a period of Middle Proterozoic slow cooling. Early Proterozoic (1600-1650 Ma) mica dates were obtained from metasedimentary rocks located in a synformal structure between the Harney Peak and Bear Mountain domes and also south of Bear Mountain. Metamorphic rocks from the dome areas and undeformed samples of the similar to 1710 Ma Harney Peak Granite (HPG) yield Middle Proterozoic mica dates (similar to 1270-1500 Ma). Two samples collected between the synform and Bear Mountain dome yield intermediate total gas mica dates of similar to 1550 Ma. We suggest two end-member interpretations to explain the map pattern of cooling ages: (1) subhorizontal slow cooling of an area which exhibits variation in mica Ar retention intervals or (2) mild folding of a Middle Proterozoic (similar to 1500 Ma) similar to 300 degrees C isotherm. According to the second interpretation, the preservation of older dates between the domes may reflect reactivation of a preexisting synformal structure (and downwarping of relatively cold rocks) during a period of approximately east-west contraction and slow uplift during the Middle Proterozoic. The mica data, together with hornblende data from the Black Hills published elsewhere, indicate that the ambient country-rock temperature at the 3-4 kbar depth of emplacement of the HPG was between 350 degrees C and 500 degrees C, suggesting that the average upper crustal geothermal gradient was 25 degrees-40 degrees C/km prior to intrusion. The thermochronologic data suggest HPG emplacement was followed by a similar to 200 m.y. period of stability and tectonic quiescence with little uplift. We propose that crust thickened during the Early Proterozoic was uplifted and erosionally(?) thinned prior to similar to 1710 Ma and that the HPG magma was emplaced into isostatically stable crust of relatively normal thickness. We speculate that uplift and crustal thinning prior to HPG intrusion was the result of differential thinning of the subcrustal lithosphere beneath the Black Hills. If so, this process would have also caused an increase in mantle heat flux across the Moho and triggered vapor-absent melting of biotite to produce the HPG magma. This scenario for posttectonic granite generation is supported, in part, by the fact that in the whole of the Black Hills, the HPG is spatially associated with the deepest exposed Early Proterozoic country rock.