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Reducing injuries to youth players is of primary importance to academies, as injuries can result in a significant loss in both training and match time, as well as, negatively affecting player development. In total, 76 talented young football players were analysed over two full competitive seasons. The injury incidence and burden for all non-contact and overuse injuries were recorded. Exposure was calculated as the total number of competitive matches hours played. Somatic maturation was estimated by expressing the current height of each player as a percentage of their predicted adult height [Roche, A. F., Tyleshevski, F., & Rogers, E. (1983). Non-invasive measurements of physical maturity in children. Research Quarterly for Exercise and Sport , 54 (4), 364-371.]. The period of circa-peak height velocity (PHV) (24.5 injuries per 1000 h) was associated with a significantly higher injury incidence rate and burden compared to pre-PHV (11.5 injuries per 1000 h; RR:2.15, 95%CI:1.37-3.38, P  < .001). No significant differences in injury risk between maturity timing groups were observed. The interaction effect between maturity status and maturity timing confirmed there is a risk period circa-PHV, but this was not dependent on maturity timing. The main practical application of this study is that football academies should regularly assess the maturity status of young footballers to identify those players with increased susceptibility to injury. Moreover, academies should individualise training and injury prevention strategies based on maturation.

Competition bioassays were conducted with the filth fly pupal parasitoids Muscidurax raptor (Girault & Sanders) and M. raptorellus (Kogan & Legner) (Hymenoptera: Pteromalidae) using house fly Musca domestica L. (Diptera: Muscidae) hosts at different host densities. Muscidifurax raptor had a significant impact on M. raptorellus when hosts were limiting in sequential parasitism tests. Fewer than six M. raptorellus adult progeny emerged from groups of 50 fly pupae that were parasitized by M. raptor at the same time or when M. raptor parasitism preceded M. raptorellus by 48 h, respectively, compared with 42-55 M. raptorellus progeny produced when this species was tested alone. Production of M. raptor was significantly lower when parasitism by this species was preceded by M. raptorellus (25) than when M. raptor was tested alone (43). When the two species parasitized hosts at the same time in different proportions at low host:parasitoid densities (5:1), M. raptorellus produced 13 progeny per parent female when it was the sole species present and fewer than two when M. raptor was present. No negative impact of M. raptorellus on M. raptor was observed. Neither species had a substantial effect on the success of the other at higher host:parasitoid densities., (© 2014 The Society for Vector Ecology.)

This paper used farm income tax returns (Schedule F) data from 62 dairy farmers who milked 200 cows or fewer in western and central Maryland and southwestern Pennsylvania (hereafter, the mid-Atlantic region) to assess the relative financial performance of management-intensive grazing (MIG) and confinement dairy operations over the 15-yr period from 1995 through 2009. Data were not available from all farmers in all years; on average, the sample analyzed contained 11 MIG farms and 26 confinement farms. Management-intensive grazing operators were more profitable on a per hundredweight, per cow, and per acre basis, and no less profitable on a whole-farm basis. Even though the confinement operators had higher gross income than MIG operators, their expenses exceeded those of MIG operators. Profits of MIG operations were less variable as well, so that MIG operators faced less income risk. Increased reliance on grazing has other benefits as well. Grazing seems to be a much healthier practice for dairy cows. Veterinary, breeding, and medicine costs per cow are much less for cows that are pastured than those raised in confinement systems. Because they are healthier, cows that are grazed can be milked longer (or culled less frequently). As a result, MIG operators have a larger number of higher quality animals for sale (e.g., bred heifers). Management-intensive operations are also less labor intensive. Reductions in crop production and in the time cows spend in the barn led to significant reductions in field work and cleaning operations in the barn. Costs of hired labor were thus substantially lower in MIG operations than in confinement operations. Land requirements likely impose the principal limitation on the size of intensive grazing operations. In the mid-Atlantic, for instance, grazing operations need 1.5 to 2.0 acres of pasture for every dairy cow/calf equivalent to provide sufficient grass to support a dairy operation. Pasture land for MIG operators must be contiguous to the milking parlor and located no farther than a cow can walk to and from twice a day. That requirement likely limits the maximum size of an intensive grazing operation, especially in areas where land prices and rents are high, as they are in much of the mid-Atlantic., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds., Methods: Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I(Ks) blocker (JNJ303; 0.2 mgkg(-1)min(-1) for 3 min) and adrenaline (0.06 mgkg(-1)min(-1) for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVP(end) interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats., Results: Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than -50 ms) negative electro-mechanical windows and were accompanied by aftercontractions., Discussion: The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk of new chemical entities at the early stages of drug discovery., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Evaluation of drug-related effects on cardiovascular function is part of the core battery described in the ICH S7A guideline. Anesthetized guinea-pigs are excellent models for the evaluation of drug-induced prolongation of ventricular repolarization; however less information is available regarding other cardio-hemodynamic parameters in this model. The current study aimed to document cardio-hemodynamic responses in anesthetized guinea-pigs after administration of a number of reference drugs with known pharmacological actions., Methods: Experiments were carried out in closed chest pentobarbital anesthetized female guinea-pigs. Compounds were administered intravenously while arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were measured continuously. The rate of LVP contraction (LV dP/dt(max)) was used to evaluate cardiac performance; and was compared to the QA interval; which has previously been proposed as an indirect measurement of cardiac function., Results: Baseline values for heart rate and blood pressure were lower in anesthetized animals compared to literature data of conscious guinea-pigs. Heart rate increased after administration of adrenaline, isoprenaline and salbutamol, but not after L-phenylephrine. Verapamil and amiodarone decreased heart rate and blood pressure. Zatebradine infusion led to a decrease in heart rate with minimal effects on blood pressure. Sodium nitroprusside (SNP) caused a reduction in mean blood pressure at higher doses followed by reflex tachycardia. Both adrenaline and L-phenylephrine increased arterial blood pressure. Furthermore, adrenaline, isoprenaline and salbutamol increased LV dP/dt(max) and decreased the QA interval. L-phenylephrine increased LV dP/dt(max), but transiently prolonged the QA interval. Both verapamil and amiodarone decreased LV dP/dt(max) and prolonged the QA interval, whereas zatebradine did not affect this parameter., Discussion: In addition to its utility for the assessment of test compounds on ventricular repolarization the pentobarbital anesthetized guinea-pig model shows promise for early stage cardio-hemodynamic screening. Furthermore, the QA interval shows potential for prediction of adverse effects on cardiac contractility., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A negative electro-mechanical (E-M) window has recently been proposed as an alternative risk marker for TdP in a canine LQT1 model. Here, we evaluated the E-M window in anaesthetized guinea pigs as a screening marker for TdP in humans., Experimental Approach: The effects of various reference drugs and changes in body temperature on the E-M window were assessed in instrumented guinea pigs. The E-M window was defined as the delay between the duration of the electrical (QT interval) and mechanical (QLVP(end) ) systole., Key Results: Drugs with known TdP liability (quinidine, haloperidol, domperidone, terfenadine, thioridazine and dofetilide), but not those with no TdP risk in humans (salbutamol and diltiazem) consistently decreased the E-M window. Interestingly, drugs with known clinical QT prolongation, but with low risk for TdP (amiodarone, moxifloxacin and ciprofloxacin) did not decrease the E-M window. Furthermore, the E-M window was minimally affected by changes in heart rate or body temperature., Conclusions and Implications: A decreased E-M window was consistently observed with drugs already known to have high TdP risk, but not with drugs with low or no TdP risk. These results suggest that the E-M window in anaesthetized guinea pigs is a risk marker for TdP in humans., (© 2011 Bio-Plus Services. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Unreliability of the data streams generated by RFID readers is among the primary factors which limit the widespread adoption of the RFID technology. RFID data cleaning is, therefore, an essential task in the RFID middleware systems in order to reduce reading errors, and to allow these data streams to be used to make a correct interpretation and analysis of the physical world they are representing. In this paper we propose an adaptive sliding-window based approach called WSTD which is capable of efficiently coping with both environmental variation and tag dynamics. Our experimental results demonstrate the efficacy of the proposed approach.

Adequate water transport is necessary to prevent stomatal closure and allow for photosynthesis. Dysfunction in the water transport pathway can result in stomatal closure, and can be deleterious to overall plant health and survival. Although much is known about small branch hydraulics, little is known about the coordination of leaf and stem hydraulic function. Additionally, the daily variations in leaf hydraulic conductance (K(leaf)), stomatal conductance and water potential (Ψ(L)) have only been measured for a few species. The objective of the current study was to characterize stem and leaf vulnerability to hydraulic dysfunction for three eastern U.S. tree species (Acer rubrum, Liriodendron tulipifera and Pinus virginiana) and to measure in situ daily patterns of K(leaf), leaf and stem Ψ, and stomatal conductance in the field. Sap flow measurements were made on two of the three species to compare patterns of whole-plant water use with changes in K(leaf) and stomatal conductance. Overall, stems were more resistant to hydraulic dysfunction than leaves. Stem P50 (Ψ resulting in 50% loss in conductivity) ranged from -3.0 to -4.2 MPa, whereas leaf P50 ranged from -0.8 to -1.7 MPa. Field Ψ(L) declined over the course of the day, but only P. virginiana experienced reductions in K(leaf) (nearly 100% loss). Stomatal conductance was greatest overall in P. virginiana, but peaked midmorning and then declined in all three species. Midday stem Ψ in all three species remained well above the threshold for embolism formation. The daily course of sap flux in P. virginiana was bell-shaped, whereas in A. rubrum sap flux peaked early in the morning and then declined over the remainder of the day. An analysis of our data and data for 39 other species suggest that there may be at least three distinct trajectories of relationships between maximum K(leaf) and the % K(leaf) at Ψ(min). In one group of species, a trade-off between maximum K(leaf) and % K(leaf) at Ψ(min) appeared to exist, but no trade-off was evident in the other two trajectories.

We built an ultra-low-noise angle sensor by combining a folded optical lever and a Sagnac interferometer. The instrument has a measured noise floor of 1.3 prad/√Hz at 2.4 kHz. We achieve this record angle sensitivity using a proof-of-concept apparatus with a conservative N=11 bounces in the optical lever. This technique could be extended to reach subpicoradian/√Hz sensitivities with an optimized design.

316L stainless steel (316L SS) has been extensively used for making orthopedic, dental and cardiovascular implants. The use of phosphonic acid self-assembled monolayers (SAMs) on 316L SS has been previously explored for potential biomedical applications. In this study, we have investigated the long-term stability of methyl (-CH(3)) and carboxylic acid (-COOH)-terminated phosphonic acid SAMs on 316L under physiological conditions. The stability of SAMs on mechanically polished and electropolished 316L SS was also investigated as a part of this study. Well-ordered and uniform -CH(3)- and -COOH-terminated SAMs were coated on mechanically polished and electropolished 316L SS surfaces. The long-term stability of SAMs on 316L SS was investigated for up to 28 days in Tris-buffered saline (TBS) at 37 degrees C using x-ray photoelectron spectroscopy, atomic force microscopy and contact angle goniometry. A significant amount of phosphonic acid molecules was desorbed from the 316L SS surfaces within 1 to 7 days of TBS immersion followed by a slow desorption of molecules over the remaining days. The -COOH-terminated SAM was found to be more stable than the -CH(3)-terminated SAM on both mechanically and electropolished surfaces. No significant differences in the desorption behavior of SAMs were observed between mechanically and electropolished 316L SS surfaces.

We demonstrate serrodyne frequency shifting of light from 200 MHz to 1.2 GHz with an efficiency of better than 60%. The frequency shift is imparted by an electro-optic phase modulator driven by a high-frequency high-fidelity sawtooth waveform that is passively generated by a commercially available nonlinear transmission line. We also implement a push-pull configuration using two serrodyne-driven phase modulators, allowing for continuous tuning between -1.6 GHz and +1.6 GHz. Compared with competing technologies, this technique is simple and robust, and it offers the largest available tuning range in this frequency band.

Adequate leaf hydraulic conductance (Kleaf) is critical for preventing transpiration-induced desiccation and subsequent stomatal closure that would restrict carbon gain. A few studies have reported midday depression of Kleaf (or petiole conductivity) and its subsequent recovery in situ, but the extent to which this phenomenon is universal is not known. The objectives of this study were to measure Kleaf, using a rehydration kinetics method, (1) in the laboratory (under controlled conditions) across a range of water potentials to construct vulnerability curves (VC) and (2) over the course of the day in the field along with leaf water potential and stomatal conductance (gs). Two broadleaf (one evergreen, Arbutus menziesii Pursh., and one deciduous, Quercus garryana Dougl.) and two coniferous species (Pinus ponderosa Dougl. and Pseudotsuga menziesii [Mirbel]) were chosen as representative of different plant types. In addition, Kleaf in the laboratory and leaf water potential in the field were measured for three tropical evergreen species (Protium panamense (Rose), Tachigalia versicolor Standley and L.O. Williams and Vochysia ferruginea Mart) to predict their daily changes in field Kleaf in situ. It was hypothesized that in the field, leaves would close their stomata at water potential thresholds at which Kleaf begins to decline sharply in laboratory-generated VC, thus preventing substantial losses of Kleaf. The temperate species showed a 15-66% decline in Kleaf by midday, before stomatal closure. Although there were substantial midday declines in Kleaf, recovery was nearly complete by late afternoon. Stomatal conductance began to decrease in Pseudotsuga, Pinus and Quercus once Kleaf began to decline; however, there was no detectable reduction in gs in Arbutus. Predicted Kleaf in the tropical species, based on laboratory-generated VC, decreased by 74% of maximum Kleaf in Tachigalia, but only 22-32% in Vochysia and Protium. The results presented here, from the previous work of the authors and from other published studies, were consistent with two different strategies regarding daily maintenance of Kleaf: (1) substantial loss and subsequent recovery or (2) a more conservative strategy of loss avoidance.

The gravitational component of water potential and frictional resistance during transpiration lead to substantial reductions in leaf water potential (Psi(l)) near the tops of tall trees, which can influence both leaf growth and physiology. We examined the relationships between morphological features and gas exchange in foliage collected near the tops of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) trees of different height classes ranging from 5 to 55 m. This sampling allowed us to investigate the effects of tree height on leaf structural characteristics in the absence of potentially confounding factors such as irradiance, temperature, relative humidity and branch length. The use of cut foliage for measurement of intrinsic gas-exchange characteristics allowed identification of height-related trends without the immediate influences of path length and gravity. Stomatal density, needle length, needle width and needle area declined with increasing tree height by 0.70 mm(-2) m(-1), 0.20 mm m(-1), 5.9 x 10(-3) mm m(-1) and 0.012 mm(2) m(-1), respectively. Needle thickness and mesophyll thickness increased with tree height by 4.8 x 10(-2) mm m(-1) and 0.74 microm m(-1), respectively. Mesophyll conductance (g(m)) and CO(2) assimilation in ambient [CO(2)] (A(amb)) decreased by 1.1 mmol m(-2) s(-1) per m and 0.082 micromol m(-2) s(-1) per m increase in height, respectively. Mean reductions in g(m) and A(amb) of foliage from 5 to 55 m were 47% and 42%, respectively. The observed trend in A(amb) was associated with g(m) and several leaf anatomic characteristics that are likely to be determined by the prevailing vertical tension gradient during foliar development. A linear increase in foliar delta(13)C values with height (0.042 per thousand m(-1)) implied that relative stomatal and mesophyll limitations of photosynthesis in intact shoots increased with height. These data suggest that increasing height leads to both fixed structural constraints on leaf gas exchange and dynamic constraints related to prevailing stomatal behavior.

Background and Purpose: Inferior petrosal sinus sampling (IPSS) is a useful diagnostic technique in adrenocorticotropic hormone (ACTH)-dependent hypercortisolism with normal or equivocal MR imaging. The procedure is believed to be safe, with mostly minor complications. However, there are rare, but severe, neurologic complications that need to be considered., Materials and Methods: We performed an institutional review board-approved retrospective review of our institutional IPSS experience from July 2001 to January 2007. IPSS was performed for the evaluation of Cushing disease. The end points of particular interest were the indications for IPSS and the incidence of associated complications., Results: During the study period of 5(1/2) years, 44 patients underwent IPSS for evaluation of Cushing disease. There were 33 women and 11 men with a mean age of 43.1 years. Because of equivocal imaging and endocrine testing, 36 of 44 patients underwent IPSS, and 8 of 44 underwent IPSS after failed transsphenoidal exploration. The only complication was injury to the brain stem that occurred after an unremarkable procedure in a 42-year-old woman. She developed clinical evidence of pontomedullary dysfunction with MR imaging consistent with brain stem infarction. The cause of this injury is unclear, but a venous variant leading to transient venous hypertension or thrombosis is suspected., Conclusion: Neurologic injury is a rare but serious complication associated with IPSS. Despite this, if performed under a strict paradigm, IPSS is both accurate and safe and can be very useful in the management of Cushing disease.

Acute spontaneous subdural hematoma without the presence of a subarachnoid hemorrhage as a result of a ruptured aneurysm is rare. We present the case of a patient with an aneurysm of the intrasellar anterior communicating artery that caused hemorrhage solely into the subdural space. The hemorrhage then migrated down the spinal canal. Our case is unique because all these 3 rare processes occurred in a single patient. Identification of the cause of this type of hemorrhage in a timely fashion is crucial to the management of such a patient.

The potential of biosolid colloids to transport metals associated with organic-waste amendments through subsurface soil environments was investigated with leaching experiments involving undisturbed soil monoliths. The monoliths (25 cm in height and 18 cm in diameter) were carved from the upper solum of an Alfisol, a Mollisol, and an Entisol in the Bluegrass region of Kentucky. Biosolid colloids were fractionated from two municipal wastes (lime-stabilized/LSB, and aerobically-digested/ADB), and a poultry-manure (PMB) organic waste and applied onto the monoliths at a rate of approximately 0.7 cm/h. Eluents were monitored for soluble and sorbed Cd, Cr, and Mo concentrations over 16-24 pore volumes of leaching. Colloid-free solutions with metal concentrations similar to those of the biosolid colloids were used as controls. The results indicated significantly (P<0.05) higher (up to 4 orders of magnitude) cationic and anionic metal elutions in association with the biosolid colloids in both, total and soluble fractions, over the control treatments. The elution of significant soluble metal loads in association with the biosolid colloids is attributed to increasing organic-metal complexation and exclusion processes, and emphasizes their importance as contaminant carriers and facilitators. Eluted metal loads varied with metal, colloid, and soil type, following the sequences Mo>Cd>Cr for the metals, and ADB>PMB>LSB (Cd and Cr) or ADB>LSB>PMB (Mo) for the colloids. Metal elution was generally enhanced by soil macroporosity and increasing OM content, while pH and Fe-Al oxides had significant, but opposite effects for the elution of cationic and anionic metal forms. Colloid and metal breakthrough curves were correlated well, being mostly asymmetrical with several maxima and minima caused by multiple clogging and flushing cycles. Soil- and colloid-metal sorption affinities were not reliable predictors of metal attenuation/elution loads, underscoring the dynamic nature of transport processes. The findings demonstrate the important role of biosolid colloids as contaminant carriers and the significant risk they pose, if unaccounted, for soil and ground water contamination in areas receiving heavy applications of biosolid waste amendments.

Background: Only 10% of dietary iron is absorbed in the duodenum which implies that 90% (approximately 9 mg day(-1)) reaches the lower small intestine and colon. Therefore the purpose of this study was to assess the iron transport capacity of the rat proximal colon and to determine whether iron absorption is regulated by changes in dietary iron content., Materials and Methods: Rats were fed for 14 days on either iron adequate (44 mg Fe kg(-1) diet) or iron-deficient (< 0.5 mg Fe kg(-1) diet) diets. The 59Fe transport across the colonic epithelium and its subsequent appearance in the blood were measured in vivo. In separate studies the colon was excised and used to measure divalent metal transporter expression., Results: Divalent metal transporter (DMT1) was expressed at the apical membrane of the surface epithelium in rat proximal colon. In animals fed an iron-deficient diet, DMT1 mRNA and protein expression were increased. This was accompanied by a significant increase in tissue 59Fe uptake., Conclusions: The proximal colon can absorb non-haem iron from the intestinal lumen. The purpose of this mechanism remains to be elucidated.

Increasing land applications of biosolid wastes as soil amendments have raised concerns about potential toxic effects of associated metals on the environment. This study investigated the ability of biosolid colloids to transport metals associated with organic waste amendments through subsurface soil environments with leaching experiments involving undisturbed soil monoliths. Biosolid colloids were fractionated from a lime-stabilized, an aerobically digested, and a poultry manure organic waste and applied onto the monoliths at a rate of 0.7 cm/h. Eluents were monitored for Cu, Zn, Pb, and colloid concentrations over 16 to 24 pore volumes of leaching. Mass-balance calculations indicated significantly higher (up to 77 times) metal elutions in association with the biosolid colloids in both total and soluble fractions over the control treatments. Eluted metal loads varied with metal, colloid, and soil type, following the sequences Zn = Cu > Pb, and ADB > PMB > LSB colloids. Colloid and metal elution was enhanced by decreasing pH and colloid size, and increasing soil macroporosity and organic matter content. Breakthrough curves were mostly irregular, showing several maxima and minima as a result of preferential macropore flow and multiple clogging and flushing cycles. Soil- and colloid-metal sorption affinities were not reliable predictors of metal attenuation/elution loads, underscoring the dynamic nature of transport processes. The findings demonstrate the important role of biosolid colloids as contaminant carriers and the significant risk they pose, if unaccounted, for soil and ground water contamination in areas receiving heavy applications of biosolid waste amendments.

The assessment of orally administered antimicrobial susceptibilities of common pathogens that cause community-acquired respiratory tract infections (CARTI) has become exceedingly important due to the number of office visits for this indication. Numerous local, regional and global studies have documented the susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, the most common CARTI pathogens. SENTRY Antimicrobial Surveillance Program sites in North and Latin America, and Europe were requested to send a combined total of 100 isolates of these pathogens to the local monitor for reference broth microdilution testing (1997-2001). This study compared the susceptibility profiles of H. influenzae and M. catarrhalis isolates (13,370 strains) from the three geographic regions over a five year period. beta-lactamase mediated ampicillin resistance among H. influenzae was highest among North American isolates (27.9%) compared to Latin America and Europe (16.2 to 16.3%), although it was noted that during the five year study period, ampicillin resistance was steadily increasing in the latter two regions. Cefprozil (84.3% susceptible) and clarithromycin (81.1% susceptible) were also less active against North American H. influenzae isolates. Latin American isolates were much less susceptible to trimethoprim/sulfamethoxazole (T/S; 59.3%) compared to the other regions (75.8 to 78.6%). M. catarrhalis isolates were also significantly less susceptible to T/S in Latin America (10.5% resistance). The production of beta-lactamase enzymes among the M. catarrhalis isolates exceeded >95% in all three regions during the five year period. The fluoroquinolones (FQ) remained very active against these two respiratory pathogens with rare isolates with elevated FQ MIC results. It is apparent from this investigation that many commonly prescribed empiric treatments remain viable therapeutic options for CARTI caused by these two Gram-negative respiratory tract pathogens.

Objective: To study the safety and efficacy of infliximab plus leflunomide combination therapy in adult rheumatoid arthritis (RA)., Methods: Twenty patients with active RA received leflunomide 100 mg for 3 days followed by 20 mg daily for 32 weeks. At week 2 all patients started infliximab 3 mg/kg, and received a further four infusions at weeks 4, 8, 16 and 24., Results: Adverse events led to 11 patients being withdrawn before the end of the study. The commonest adverse event was pruritus associated with an eczematous rash. Other serious reactions included infliximab infusion reactions in four patients and Stevens-Johnson syndrome in one. There was no relationship between the serum concentration of A77 1726, the active metabolite of leflunomide, and adverse events. The mean Disease Activity Score (DAS28) fell from 7.18 at week 0 to 5.18 (P<0.0001, paired t-test) at week 4 and remained between 3.85 and 4.85 up to week 32. In those patients remaining on treatment, more than 80% achieved an ACR20 response from week 8 to week 28, and up to 46% achieved an ACR70 response., Conclusion: Infliximab plus leflunomide combination therapy appears to be highly efficacious in the treatment of adult RA. However, widespread use may be limited by adverse events, which were common and in some cases severe.

Previous research has shown that both prosodic and content variations in speech register are important when addressing all individuals. Motherese speech register has been associated with higher levels of perceived disability and is viewed more negatively by individuals with a history of head injury. This research was conducted to investigate the separate contributions of content and prosody in producing differential response to speech by individuals with and without a history of head injury. Participants included 210 introductory psychology students with and without head injuries. No significant demographic differences were found between these groups. Participants listened to 4 sets of audiotaped instructions from afictitious home economics teacher containing prosodic and content variations. Afterward, they rated the teacher on the following dimensions: liking, positive impact, negative impact, grade level being taught, and whether they would recommend hiring this teacher. Analysis of variance revealed there were no significant group differences between participants rating with normal speech. As expected, both groups favored the normal speech register over motherese. However, the group with head injuries consistently rated the speech with motherese content as more negative, less likable, less likely to hire, and aimed at a lower grade level. Participants with head injuries also rated the speech register with motherese prosody as less likable and less likely to hire. These results suggest that when addressing individuals with head injuries, both what you say and how you say it are important.

Background: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values., Methods: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in approximately 1.9 min. Cutoffs for each marker were set at 6-13 SD above the population mean., Results: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 methylcrotonyl-CoA carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g., Conclusions: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.

The anterior part of the piriform cortex (the APC) has been the focus of cortical-level studies of olfactory coding and associative processes and has attracted considerable attention as a result of a unique capacity to initiate generalized tonic-clonic seizures. Based on analysis of cytoarchitecture, connections, and immunocytochemical markers, a new subdivision of the APC and an associated deep nucleus are distinguished in the rat. As a result of its ventrorostral location in the APC, the new subdivision is termed the APC(VR). The deep nucleus is termed the pre-endopiriform nucleus (pEn) based on location and certain parallels to the endopiriform nucleus. The APC(VR) has unique features of interest for normal function: immunostaining suggests that it receives input from tufted cells in the olfactory bulb in addition to mitral cells, and it provides a heavy, rather selective projection from the piriform cortex to the ventrolateral orbital cortex (VLO), a prefrontal area where chemosensory, visual, and spatial information converges. The APC(VR) also has di- and tri-synaptic projections to the VLO via the pEn and the submedial thalamic nucleus. The pEn is of particular interest from a pathological standpoint because it corresponds in location to the physiologically defined "deep piriform cortex" ("area tempestas") from which convulsants initiate temporal lobe seizures, and blockade reduces ischemic damage to the hippocampus. Immunostaining revealed novel features of the pEn and APC(VR) that could alter excitability, including a near-absence of gamma-aminobutyric acid (GABA)ergic "cartridge" endings on axon initial segments, few cholecystokinin (CCK)-positive basket cells, and very low gamma-aminobutyric acid transporter-1 (GAT1)-like immunoreactivity. Normal functions of the APC(VR)-pEn may require a shaping of neuronal activity by inhibitory processes in a fashion that renders this region susceptible to pathological behavior.

Women with inadequate prenatal care were recruited to a multi-component parenting intervention study. Because it was anticipated that this high-risk population might present challenges to retention, a variety of strategies were employed to maintain their participation in the study. This report reviews the results of these retention efforts and compares the population that completed the study versus those that terminated prior to study completion. Two hundred and eighty-six women were randomized to an intervention or control group. Careful tracking of the mothers, offering incentives for completing various study activities and providing a culturally competent staff were among the strategies employed to maintain participation. Comparison was made of those mothers terminating before study completion versus those retained, and of those terminating early in the study period versus later. Despite retention efforts, attrition at a level of 41% occurred. A few characteristics of mothers terminating early from the study were significant including older maternal age, a larger number of children, and incidence of no prenatal care. Despite comprehensive tracking procedures, some mothers were lost to follow up after change of residence. Other reasons for attrition included child outplacement and refusal of services or data collection procedures.

BI 397, a semi-synthetic amide derivative of the experimental glycopeptide, MDL 62,476 (A40926), has excellent in vitro activity against a wide range of Gram-positive organisms. In this extensive study, 630 contemporary (1998-2000) Gram-positive isolates were selected from various resistance surveillance studies for their resistance patterns to fluoroquinolones, macrolides-lincosamides-streptogramins, beta-lactams and glycopeptide agents. The BI 397 spectrum of activity was similar to that of other glycopeptides with a MIC90 of < or =0.5 microg/ml for all tested isolates with the exception of vancomycin-resistant enterococci Van A; (MIC90, 32 microg/ml). BI 397 was more potent than vancomycin and teicoplanin against Staphylococcus aureus (2- to 8-fold), beta-haemolytic streptococci (equal to >16-fold), viridans group streptococci (equal to >32-fold), and Corynebacterium spp. including C. jeikeium (8- to >16-fold). BI 397 was also more active than quinupristin/dalfopristin against all Gram-positive organisms tested with the exception of oxacillin-susceptible S. aureus, against which it had equal activity. BI 397 has little activity against Haemophilus influenzae (MIC90, 64 microg/ml) or other Gram-negative bacilli (MIC90, >64 microg/ml). BI 397 exhibited bacteriostatic activity (like the vancomycin control) versus most species, but was bactericidal against tested Streptococcus pneumoniae. In vitro testing conditions with blood supplemented or free protein containing media elevated BI 397 MIC results, and the 30-microg disk seems acceptable for further disk diffusion test development. Animal pharmacokinetic data published elsewhere suggest that BI 397 may be dosed less frequently than teicoplanin and the results of early studies in humans are awaited with interest, especially when treating teicoplanin-refractory coagulase-negative staphylococci.

Overhaul is the stage in which firefighters search for and extinguish possible sources of reignition. It is common practice not to wear respiratory protection during overhaul. Fifty-one firefighters in two groups, 25 without respiratory protection and 26 wearing cartridge respirators, were monitored for exposure to products of combustion and changes in spirometric measurements and lung permeability following overhaul of a structural fire. Testing at baseline and 1 hour after overhaul included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), serum Clara cell protein (CC16), and serum surfactant-associated protein A (SP-A). Overhaul increased CC16 in both groups, indicating increased alveolarcapillary membrane permeability. Contrary to expectations, SP-A increased and FVC and FEV1 decreased in the firefighters wearing cartridge respirators. Changes in FEV1, CC16, and SP-A were associated with concentrations of specific products of combustion or carboxyhemoglobin levels. Firefighter exposures during overhaul have the potential to cause changes in spirometric measurements and lung permeability, and self-contained breathing apparatus should be worn during overhaul to prevent lung injury.

A review of studies, including both articles published in peer-reviewed journals and reports that were not peer reviewed, regarding occupational exposure to benzene and total hydrocarbons in the downstream petroleum industry operations was performed. The objective was to provide a broad estimate of exposures by compiling exposure data according to the following categories: refinery, pipeline, marine, rail, bulk terminals and trucks, service stations, underground storage tanks, tank cleaning, and site remediations. The data in each category was divided into personal occupational long-term and short-term samples. The summarized data offers valuable assistance to hygienists by providing them with an estimate and range of exposures. The traditional 8-hour time-weighted average (TWA) exposure and the 40-hour workweek do not generally coincide with exposure periods applicable to workers in marine, pipeline, railcar, and trucking operations. They are more comparable with short-term exposure or task-based exposure assessments. The marine sector has a large number of high exposures. Although relatively few workers are exposed, their exposures to benzene and total hydrocarbons are sometimes an order of magnitude higher than the respective exposure limits. It is recommended that in the future, it would be preferable to do more task-based exposure assessments and fewer traditional TWA long-term exposure assessments within the various sectors of the downstream petroleum industry.

Meeting the wellness needs of high school students reporting high-risk behaviors above national averages was the purpose of a community partnership between the county school district and West Virginia University School of Nursing. Although the school district and School of Nursing were the primary partners, other programs in the university provided additional support. The school nurse, school of nursing faculty, and nursing students provided wellness programs to students, faculty, and staff. Positive evaluations and high demand for the services demonstrated the school community's need for the program and the success of the partnership.

Objective: Two main questions were asked: (1) what abuse characteristics relate to PTSD, depressive, and dissociative severity in adult survivors of child sexual abuse (CSA); and (2) what abuse characteristics influence the severity of dissociation during CSA., Method: 89 female CSA survivors' current symptoms of PTSD, depression, and dissociation were assessed with standardized measures. Additionally, abuse characteristics (e.g., age of onset, peritraumatic dissociation) were assessed with a structured interview., Results: Correlational analyses indicated that peritraumatic dissociation was most strongly related to all three types of symptom severity. Additional posthoc correlational analyses revealed that women who experienced penile penetration, believed someone/thing else would be killed, and/or were injured as a result of the abuse exhibited more severe peritraumatic dissociation. Regression analyses indicated that peritraumatic dissociation was the only variable to significantly predict symptom severity across symptom type or disorder. Furthermore, different abuse characteristics predicted adult symptom severity and peritraumatic dissociation., Conclusions: The relation between peritraumatic dissociation and adult symptomatology was most intriguing and has two main clinical implications: (1) teaching engagement strategies to some CSA survivors in hopes of containing dissociative symptoms immediately following the abuse and (2) the inclusion of exposure-based interventions in the treatment of some adult CSA survivors where indicated.

Associational connections of pyramidal cells in rat posterior piriform cortex were studied by direct visualization of axons stained by intracellular injection in vivo. The results revealed that individual cells have widespread axonal arbors that extend over nearly the full length of the cerebral hemisphere. Within piriform cortex these arbors are highly distributed with no regularly arranged patchy concentrations like those associated with the columnar organization in other primary sensory areas (i.e., where periodically arranged sets of cells have common response properties, inputs, and outputs). A lack of columnar organization was also indicated by a marked disparity in the intrinsic projection patterns of neighboring injected cells. Analysis of axonal branching patterns, bouton distributions, and dendritic arbors suggested that each pyramidal cell makes a small number of synaptic contacts on a large number (>1000) of other cells in piriform cortex at disparate locations. Axons from individual pyramidal cells also arborize extensively within many neighboring cortical areas, most of which send strong projections back to piriform cortex. These include areas involved in high-order functions in prefrontal, amygdaloid, entorhinal, and perirhinal cortex, to which there are few projections from other primary sensory areas. Our results suggest that piriform cortex performs correlative functions analogous to those in association areas of neocortex rather than those typical of primary sensory areas with which it has been traditionally classed. Findings from other studies suggest that the olfactory bulb subserves functions performed by primary areas in other sensory systems.

Previous studies have characterized firefighter exposures during fire suppression. However, minimal information is available regarding firefighter exposures during overhaul, when firefighters look for hidden fire inside attics, ceilings, and walls, often without respiratory protection. A comprehensive air monitoring study was conducted to characterize City of Phoenix firefighter exposures during the overhaul phase of 25 structure fires. Personal samples were collected for aldehydes; benzene; toluene; ethyl benzene; xylene; hydrochloric acid; polynuclear aromatic hydrocarbons (PNA); respirable dust; and hydrogen cyanide (HCN). Gas analyzers were employed to continuously monitor carbon monoxide (CO), HCN, nitrogen dioxide (NO2), and sulfur dioxide (SO2). Area samples were collected for asbestos, metals (Cd, Cr, Pb), and total dust. During overhaul the following exceeded published ceiling values: acrolein (American Conference of Governmental Industrial Hygienists [ACGIH] 0.1 ppm) at 1 fire; CO (National Institute for Occupational Safety and Health [NIOSH] 200 ppm) at 5 fires; formaldehyde (NIOSH 0.1 ppm) at 22 fires; and glutaraldehyde (ACGIH 0.05 ppm) at 5 fires. In addition, the following exceeded published short-term exposure limit values: benzene (NIOSH 1 ppm) at two fires, NO2 (NIOSH 1 ppm) at two fires, and SO2 (ACGIH 5 ppm) at five fires. On an additive effects basis, PNA concentrations exceeded the NIOSH recommended exposure limits (0.1 mg/M3) for coal tar pitch volatiles at two fires. Maximum concentrations of other sampled substances were below their respective permissible exposure limits. Initial 10-min average CO concentrations did not predict concentrations of other products of combustion. The results indicate that firefighters should use respiratory protection during overhaul. In addition, these findings suggest that CO should not be used as an indicator gas for other contaminants found in this atmosphere.

Cefditoren, a third generation orally administered aminothiazolyl cephalosporin, has demonstrated bactericidal activity against many Gram positive and negative bacterial pathogens and stability against clinically important beta-lactamases. Cefditoren was compared to cefaclor, cefixime, and penicillins against 1 435 recently isolated strains of streptococci (312 Streptococcus pneumoniae, 165 viridans group streptococci, 142 beta-haemolytic streptococci), Haemophilus influenzae (521 strains), and Moraxella catarrhalis (295 strains). Streptococcus pneumoniae and viridans group streptococci had penicillin nonsusceptible rates of 37.8 and 35.8%, respectively. Cefditoren (MIC(90) in microg/ml/% susceptible) activity against all tested H. influenzae (0.03/100) and M. catarrhalis (0.06-0.5/100) was comparable to cefixime and significantly greater than cefaclor. Cefditoren (MIC(90), 0.5 microg/ml) was 4- to 128-fold more active than comparison beta-lactams against the pneumoococci and was the most potent beta-lactam (including penicillin) versus beta-haemolytic streptococci. Cefditoren pharmacokinetics demonstrate a T(1/2) of 1.5-2 h and C(max) values of 2.8 and 4.6 microg/ml, respectively with 200 or 400 mg doses of cefditoren pivoxil; plasma concentrations exceed 1 microg/ml for 4 to 6 hours (33-50% of dosing interval). Consequently, a susceptible MIC of /= 18 and >/= 15 mm (5-microg disk) for all cited fastidious species tested. Categorical agreement between MIC and disk tests was 94.6 to 100% with a correlation coefficient (r) range of 0.50 to 0.90 for streptococci. H. influenzae intermethod comparison results using the same interpretive criteria were in complete agreement, but exhibited a low r = 0.39. Cefditoren clearly possesses the most potent activity among currently studied oral cephalosporins or penicillin against commonly isolated bacterial pathogens causing bronchitis, pneumonia, sinusitis, or pharyngitis and was active against nearly all penicillin-resistant streptococci at

Cefditoren (formerly ME-1206) is an investigational, orally administered cephalosporin ester with bactericidal activity against many Gram-positive and -negative organisms. Cefditoren potency against nearly 1000 non-fastidious species was determined by National Committee for Clinical Laboratory Standards (NCCLS) reference broth microdilution and standardized disk diffusion methods. Against staphylococci, usable cefditoren activity was completely correlated with oxacillin with respect to potency and susceptibility interpretation (mec A-negative strains). Cefditoren was very active against Klebsiella spp., Proteus mirabilis, Salmonella spp., and Escherichia coli (MIC(90) range, 0.12-1 microg/ml; median zone, 23-26 mm). Cefditoren had more limited activity against Citrobacter spp., Enterobacter spp., Serratia marcescens, and indole-positive Proteae (MIC(50) range, 0.12-1 microg/ml; MIC(90), > 16 microg/ml; median zone, 18-25 mm). Against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp., and other non-fermentors, cefditoren was inactive (MIC(90), > 16 microg/ml; zone, 6 mm). Pharmacokinetic analysis of cefditoren showed that utilized dosages produce a plasma concentration that exceeds 0.5 microg/ml for 5 to 8 h and 1 microg/ml for 4 to 6 hours (T(1/2) ranges from 1.5-2 h). The following interpretive criteria were suggested: /= 15 mm (susceptible) and >/= 8 microg/ml or /= 18 mm (susceptible) and >/= 4 microg/ml or

Occupational exposures to benzene and total hydrocarbons (THC) in the Canadian upstream petroleum industry are described in this article. A total of 1547 air samples taken by 5 oil companies in various sectors (i.e., conventional oil/gas, conventional gas, heavy oil processing, drilling and pipelines) were evaluated and summarized. The data includes personal long- and short-term samples and area long-term samples. The percentage of samples over the occupational exposure limit (OEL) of 3.2 mg/m3 or one part per million for benzene, for personal long-term samples ranges from 0 to 0.7% in the different sectors, and area long-term samples range from 0 to 13%. For short-term personal samples, the exceedance for benzene is at 5% with respect to the OEL of 16 mg/m3 or five parts per million in the conventional gas sector and none in the remaining sectors. THC levels were not available for all sectors and had limited data points in others. The percentage exceedance of the OEL of 280 mg/m3 or 100 parts per million for THC as gasoline ranged from 0 to 2.6% for personal long-term samples. It is recommended that certain operations such as glycol dehydrators be carefully monitored and that a task-based monitoring program be included along with the traditional long- and short-term personal exposure sampling.

The acquisition and extinction of Pavlovian conditioned fear have been shown to be mediated by the N-methyl-D-aspartate (NMDA) glutamate receptor. This study found that the NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) blocked the reinstatement of Pavlovian conditioned fear in rats. The role of nitric oxide (NO) in the acquisition and extinction of Pavlovian fear conditioning was also examined. L-NAME, an NO synthase inhibitor, failed to block the acquisition or extinction of Pavlovian fear conditioning. The results are discussed in the context of hierarchical associations and the array of NMDA and calcium mediated mechanisms of synaptic strengthening.

Paclitaxel, a relatively new antineoplastic agent, is associated with numerous side effects, including two reported cases of pancreatitis. Our patient also developed paclitaxel-associated pancreatitis. Several companion drugs, including steroids, diphenhydramine, histamine2 blockers, serotonin type 3 antagonists, and other chemotherapeutic agents administered with paclitaxel, must be considered as possible causes of pancreatitis. In addition, paclitaxel is a hydrophobic agent that requires a vehicle, cremophor (CrEL), for solubility. Intravenous cyclosporine also requires CrEL and has been associated with pancreatitis. In the cerulein-induced pancreatitis rat model, paclitaxel with dimethyl sulfoxide as a vehicle prevents pancreatitis, suggesting that another causal agent is responsible. Animal studies of CrEL as a single agent may be required to settle this question, but for now, awareness that paclitaxel may be associated with pancreatitis may lead to earlier treatment of this potentially fatal complication.

The introduction of cephalosporins has had an important impact on the resistance rates to several clinically utilized beta-lactam antimicrobial agents. Most Thailand medical centers have not documented the levels of emerging resistant pathogens causing invasive infections. This study shows using reference-quality MIC techniques (Etest, AB BIODISK, Solna, Sweden), that carbapenem), "fourth-generation" cephalosporins (cefepime and cefpirome), and piperacillin/tazobactam were the most active agents tested against Gram-negative bacilli (Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp., indole-positive Proteae, Acinetobacter spp., Pseudomonas aeruginosa, and oxacillin-susceptible Staphylococcus spp. when compared to "third-generation" cephalosporins (ceftazidime and ceftriaxone). The rank order of activity for all species was imipenem (2.9% resistant) > cefepime (7.7%) > piperacillin/tazobactam (11.1%) > cefpirome (13.4%) > ceftriaxone (21.1%) > ceftazidime (29.9%). The incidence of extended spectrum beta-lactamase production among E. coli (15.7%) and K. pneumoniae (45.6%) was significant. Cefepime and imipenem were active against the majority of these isolates. The activity of cefepime was also shown to be very good against, 1) organisms capable of producing AmpC enzymes, 2) staphylococci species that were susceptible to oxacillin, and 3) many strains of nonfermentative Gram-negative bacilli. The prevalence of antimicrobial resistance in Thailand seems to be quite high among certain commonly encountered pathogens, and imipenem and cefepime have activity (susceptible and intermediate potency) against > 90% of these organisms.

Cefepime is a potent broad-spectrum "fourth-generation" cephalosporin. The in vitro activity of cefepime was compared to that of cefpirome, ceftazidime, ceftriaxone, imipenem, and piperacillin/tazobactam in a multilaboratory (nine medical centers) Philippine surveillance project from March through October 1998. A total of 626 Gram-positive and Gram-negative organisms (10 species groups) were tested by the Etest method (AB BIODISK, Solna, Sweden) with results validated by current quality control strain analysis. The overall rank order of usable spectrum of activity was imipenem (4.2% resistance), cefepime (4.5%), cefpirome (5.0%), piperacillin/tazobactam (5.8%) > ceftriaxone (11.2%) > ceftazidime (15.3%), and results did not differ significantly between medical centers. Ceftazidime-resistant Escherichia coli and Klebsiella spp. occurred at rates of 13.3% and 31.1%, respectively, indicating extended-spectrum beta-lactamase (ESBL) activity. Imipenem (100% susceptible), cefepime, and cefpirome (both > or = 97.8% susceptible) were active in vitro against these ESBL phenotypes. Organisms with ceftazidime and/or ceftriaxone-resistant profiles consistent for hyper-production of Amp C cephalosporinases were detected at high rates among the Citrobacter spp. (29.2%) and Enterobacter spp. (45.8%); however, imipenem (100.0% susceptible) and cefepime (98.9%) remained active. Cefepime and imipenem (both 87.5% susceptible) were the most active agents tested against Acinetobacter spp. whereas piperacillin/tazobactam was most effective against P. aeruginosa (80.0% susceptible). Most tested beta-lactams (except ceftazidime) were active versus oxacillin-susceptible staphylococci. These data should be used as a guide for treatment selection with beta-lactam compounds in the Philippines and to serve as a resistance benchmark in comparisons with future studies in this nation.

The rates of resistance to commonly used antimicrobial agents have been documented to be at alarmingly high levels in Taiwan for both Gram-positive and Gram-negative species. This study was conducted to assess the current resistance patterns in six medical centers strictly controlled using a common MIC methodology and quality assurance measures. Cefepime, a new clinically introduced broad-spectrum "fourth-generation" cephalosporin, was compared to other members in this class including ceftazidime, cefpirome, ceftriaxone, piperacillin/tazobactam, and imipenem. These antimicrobials were tested against ten species groups of common clinical isolates of Enterobacteriaceae, non-enteric Gram-negative bacilli, and oxacillin-susceptible Staphylococcus spp. The results confirmed that extended spectrum beta-lactamase (ESBL) production in Klebsiella spp. (21.7%) and Escherichia coli (16.7%) was common in all medical centers surveyed. Cefepime was more active against these two species as well as against Amp C producing species, indole-positive Proteae, and Acinetobacter species. The activity of cefepime was comparable although slightly less than that of ceftazidime against Serratia spp. and Pseudomonas aeruginosa strains. All or nearly all staphylococci isolates were susceptible to the beta-lactam antimicrobial agents, except for ceftazidime. Overall, these antimicrobial agents had descending spectrums of activity as follows: imipenem > cefepime > cefpirome > piperacillin/tazobactam > ceftazidime > ceftriaxone for the 550 isolates tested. Cefepime seems to be an important broad-spectrum beta-lactam that can be used with confidence against many important pathogens in Taiwan, including those harboring resistance mechanisms. A continued surveillance program seems prudent for this geographic area.

Potent investigational fluoroquinolones require convenient, but accurate, diagnostic tests for initially applied clinical trials. For this purpose, gemifloxacin (formerly SB-265805, LB20304a) was tested by the reference dilution tests and standardized disk diffusion methods of the National Committee for Clinical Laboratory Standards (NCCLS) to establish interpretive criteria. For rapid-growing pathogens, 986 organisms were tested by broth microdilution MIC, and 5- and 10-microgram disk diffusion tests. Correlation (r) between 5- and 10-microgram disk zone diameters was 0.99 (y = -0.12 to 0.99x) and the preferred 5-microgram disk zone/MIC scattergram produced a regression of y = 14.8 to 0.41x (r = 0.93). At potential pharmacodynamics (Cmax = 1.3 micrograms/mL for 320 mg dose) validated breakpoints of < or = 0.5 microgram/mL for susceptible and > or = 2 micrograms/mL for resistant, correlate zones of > or = 17 mm and < or = 13 mm produced rare serious interpretive errors (0.1%) and 96.7% absolute categorical agreement. For 304 Streptococcus pneumoniae and 305 strains of other streptococci, the same breakpoints produced 100 and 99.1% categorical accuracy even when testing levofloxacin-resistant (MIC, > or = 4 micrograms/mL) strains. Interpretive breakpoints were proposed for Hemophilus influenzae (300 strains tested), with complete correlation between tests. Etest (AB BIODISK, Solna, Sweden) was compared in all experiments with the fastidious species and showed a trend toward higher values (twofold). Gemifloxacin in vitro susceptibility test methods seem to be accurate and with very acceptable intermethod agreement, supported by previously reported functional quality control guidelines.

Cartilage matrix protein (CMP) is the prototype of the newly discovered matrilin family, all of which contain von Willebrand factor A domains. Although the function of matrilins remain unclear, we have shown that, in primary chondrocyte cultures, CMP (matrilin-1) forms a filamentous network, which is made up of two types of filaments, a collagen-dependent one and a collagen-independent one. In this study, we demonstrate that the collagen-independent CMP filaments are enriched in pericellular compartments, extending directly from chondrocyte membranes. Their morphology can be distinguished from that of collagen filaments by immunogold electron microscopy, and mimicked by that of self-assembled purified CMP. The assembly of CMP filaments can occur from transfection of a wild-type CMP transgene alone in skin fibroblasts, which do not produce endogenous CMP. Conversely, assembly of endogenous CMP filaments by chondrocytes can be inhibited specifically by dominant negative CMP transgenes. The two A domains within CMP serve essential but different functions during network formation. Deletion of the A2 domain converts the trimeric CMP into a mixture of monomers, dimers, and trimers, whereas deletion of the A1 domain does not affect the trimeric configuration. This suggests that the A2 domain modulates multimerization of CMP. Absence of either A domain from CMP abolishes its ability to form collagen-independent filaments. In particular, Asp22 in A1 and Asp255 in A2 are essential; double point mutation of these residues disrupts CMP network formation. These residues are part of the metal ion-dependent adhesion sites, thus a metal ion-dependent adhesion site-mediated adhesion mechanism may be applicable to matrilin assembly. Taken together, our data suggest that CMP is a bridging molecule that connects matrix components in cartilage to form an integrated matrix network.

Gatifloxacin (formerly AM-1155 or CG 5501) is a new 8-methoxy fluoroquinolone with enhanced activity against Gram-positive cocci, especially Streptococcus pneumoniae and other streptococci. Recent clinical strains (599 isolates) were tested against gatifloxacin, three comparison fluoroquinolones, and penicillin by the reference broth microdilution, Etest (AB BIODISK, Solna, Sweden) and standardized disk diffusion methods (5 micrograms gatifloxacin disk). Gatifloxacin (MIC90, 0.5 microgram/ml) activity was generally comparable to that of trovafloxacin (MIC90, 0.25 microgram/ml), or sparfloxacin (MIC90, 0.5 microgram/ ml) and markedly superior to ofloxacin (MIC90, 2-4 micrograms/ml) against the streptococci. Rates of penicillin non-susceptibility were 41.9, 38.0, and 16.2% for S. pneumoniae (301 strains), viridans group streptococci (150 strains), and beta-haemolytic streptococci (148 strains). Etest results correlated well (95.7-100.0% +/- one log2 dilution) with the reference MIC results, but Etest tended to have elevated gatifloxacin MIC results compared to the broth microdilution method for the highly resistant isolates (MICs, > 2 micrograms/ml). Gatifloxacin disk zone diameters correlate well to reference MICs for all streptococci and proposed interpretive criteria (susceptible at < or = 1 microgram/ml or > or = 18 mm, and resistant at > or = 4 micrograms/ml or < or = 14 mm) did not produce discords between method results (absolute agreement). A nine laboratory quality control (QC) study conforming to the National Committee for Clinical Laboratory Standards (NCCLS) Guideline M23-T3 studied S. pneumoniae ATCC 49619 and gatifloxacin. Proposed ranges for QC of NCCLS tests were 0.12-0.5 microgram/ml for the broth microdilution test and 24-31 mm for the disk diffusion method. These reported results indicate that gatifloxacin was a potent fluoroquinolone with extensive activity against streptococcal isolates. In vitro test methods to measure this activity appear accurate and comparable; and QC guidelines have been established for routine clinical laboratory use pending approval by the NCCLS and the Food and Drug Administration (FDA).

SB-265805 (formerly LB20304) is a novel C-7 pyrrolidine-substituted naphthyridone that has a broad spectrum of activity, especially against Gram-positive cocci. SB-265805 activity was compared with ciprofloxacin, grepafloxacin, moxifloxacin, sparfloxacin, and penicillin against 599 Streptococcus spp. isolated recently from more than 30 medical centers in North and South America. These included 70 isolates with decreased susceptibility to recently released fluoroquinolones (levofloxacin MIC, > or = 4 micrograms/mL). All strains were tested by reference microdilution methods in lysed horse blood-supplemented Mueller-Hinton broth. Sixteen percent of 148 beta-haemolytic streptococci (strains of gr. B and C) were not susceptible to penicillin, whereas 38% and 42% of viridans group streptococci and Streptococcus pneumoniae were resistant to penicillin, respectively. SB-265805 potency against 301 pneumococci (MIC90, 0.06 microgram/mL) was fourfold more active than moxifloxacin and was > or = eightfold more potent than other quinolones. Against beta-haemolytic streptococci, SB-265805 and moxifloxacin were the most active (MIC90, 0.06 and 0.25 microgram/mL, respectively), whereas sparfloxacin, grepafloxacin, and ciprofloxacin (MIC90, 0.5-1 microgram/mL) were less potent. SB-265805 MICs versus viridans group streptococci (MIC90, 0.12 microgram/mL) were fourfold lower than sparfloxacin or grepafloxacin, and twofold more active than moxifloxacin. A nine-laboratory quality control (QC) protocol conforming to NCCLS M23-T3 guidelines demonstrated a modal SB-265805 MIC of 0.016 microgram/mL for S. pneumoniae ATCC 49619 (proposed QC range, 0.008 to 0.03 microgram/mL). The SB-265805 disk (5-microgram) QC range was 28-34 mm (97.3% of qualifying results). In general, SB-265805 in vitro activity against Streptococcus species was superior to sparfloxacin, grepafloxacin, and moxifloxacin and markedly greater than ciprofloxacin. This degree of antimicrobial potency warrants further investigation of this newer drug for its potential human clinical application against streptococcal infections.

Streptococcus pneumoniae strains have emerged that are resistant to penicillin (MICs >0.06 microg/mL) and many other beta-lactams. However, some older compounds such as amoxicillin have potency against these pneumococci with altered penicillin-binding proteins, but are labile to beta-lactamases produced by other prevalent respiratory tract pathogens. The interactions of amoxicillin with an enzyme-stable cephalosporin (cefixime) with a long elimination half-life were examined by the checkerboard dilution method versus 39 S. pneumoniae strains (13 resistant, 15 intermediate, and 11 susceptible to penicillin). Among 24 strains with evaluable drug interaction tests, 17 (71%) demonstrated partial or complete synergy. This favorable interaction produces a cefixime susceptibility category change from resistant or intermediate to susceptible for 16 of 28 strains (57%), when combined with < or = 1 microg/mL amoxicillin. Thus, the use of two currently available oral beta-lactams (amoxicillin twice a day + cefixime once a day; three total doses) appears to be a potential alternative treatment with greater spectrum for community-acquired respiratory tract infections pending clinical trial results.

Sparfloxacin, a recently marketed oral fluoroquinolone, was tested against 24,940 recent clinical strains isolated from blood stream and respiratory tract cultures at 187 hospitals in the USA and Canada. Sparfloxacin activity was compared with 5 to 13 antimicrobial agents using either Etest (AB BIODISK, Solna, Sweden) and a reference broth microdilution or a standardized disk diffusion method. When applying recommended MIC breakpoint criteria of sparfloxacin susceptibility (< or = 0.5 microgram/mL) for Streptococcus pneumoniae (4,410 strains) and other Streptococcus spp. (554 isolates), 93% and 88% were inhibited, respectively. Furthermore, at < or = 1 microgram/mL sparfloxacin susceptibility rates for streptococci increased to 98% overall and 99.3% for S. pneumoniae. In contrast, only 46% and 68% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/mL; susceptible at < or = 1 microgram/mL) and penicillin (MIC90, 1.5 microgram/mL; susceptible at < or = 0.06 microgram/mL), respectively. Differences between regions in the USA for rates of penicillin-resistant pneumococcal strains were observed (greatest resistances in southeast and midwest), but results indicate that the sparfloxacin potency was not adversely influenced (MIC90, 0.5 microgram/mL). Also pneumococcal isolates from the lower respiratory tract were more resistant to penicillin and other beta-lactams. Nearly all Haemophilus species and Moraxella catarrhalis strains, including those harboring beta-lactamases, were susceptible to tested fluoroquinolones (sparfloxacin, ciprofloxacin), amoxicillin/clavulanic acid, and newer oral cephalosporins. Sparfloxacin was very active against oxacillin-susceptible Staphylococcus aureus (MIC90, 0.12 microgram/mL; 96-97% susceptible), Klebsiella spp. (MIC90 0.12 microgram/mL), and other tested enteric bacilli (92-95% susceptible). Comparisons between the broth microdilution MIC and disk diffusion interpretive results demonstrated excellent intermethod susceptibility category agreement (> 95%) using current sparfloxacin breakpoints, but some compounds (cefpodoxime disk diffusion tests for S. aureus) may require modifications. These results demonstrate that new Gram-positive focused fluoroquinolones (sparfloxacin) possess an excellent in vitro activity and spectrum against pathogens that cause respiratory tract infections. This spectrum of activity includes strains resistant to other antimicrobial classes, including the oral cephalosporins, macrolides, amoxicillin/clavulanic acid, and earlier fluoroquinolones (ciprofloxacin, ofloxacin). Overall, sparfloxacin inhibited 89% to nearly 100% of the isolates (species variable) tested against those species against which it has Food and Drug Administration indications for clinical use.

Sparfloxacin, a new orally administered fluoroquinolone, was tested against 14,182 clinical strains isolated (generally blood stream and respiratory tract cultures) at nearly 200 hospitals in the United States (USA) and Canada. Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK, Solna, Sweden), broth microdilution, or a standardized disk diffusion method. Using the Food and Drug Administration/product package insert MIC breakpoint for sparfloxacin susceptibility (< or = 0.5 microgram/ml), 94% of Streptococcus pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were susceptible. However, at < or = 1 microgram/ml (the breakpoint for all nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and 98%, respectively, for the two groups of streptococci. Only 50% and 65% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/ml) and penicillin (MIC90, 1.5 micrograms/ml), respectively. Although there were significant differences between regions in the USA in the frequency of penicillin-resistant pneumococcal strains, results indicate that the overall sparfloxacin MIC90 was uniformly at 0.5 microgram/ml. Nearly all (> or = 99%) Haemophilus species and Moraxella catarrhalis, including those harboring beta-lactamases, were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid. Only cefprozil and macrolides demonstrated lower potency and spectrum against these two species. Sparfloxacin was active against oxacillin-susceptible Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested enteric bacilli (93%). Comparison between broth microdilution MIC and disk diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the Enterobacteriaceae showed an absolute intermethod categorical agreement of > 95% using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for S. aureus where a conspicuous discord (98% versus 59%) between methods was discovered. These results demonstrate that sparfloxacin possesses sufficient in vitro activity and spectrum versus pathogens that cause respiratory tract infections (indications), especially strains resistant to other drug classes such as the earlier fluoroquinolones, oral cephalosporins, macrolides, and amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for streptococci may require modification (< or = 1 microgram/ml) based on the MIC population analysis presented here. A modal MIC (0.38 to 0.5 microgram/ml) was observed at the current breakpoint. Regardless, sparfloxacin inhibited 89% (nonpneumococcal Streptococcus spp.) to 100% (Haemophilus spp., M. catarrhalis) of the isolates tested with a median activity of 97% against indicated species.

RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 micrograms/ml and 0.5 to 2 micrograms/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC90, < or = 0.5 microgram/ml) and quinupristin/dalfopristin (MIC90, < or = 0.25 microgram/ml). Against all streptococcal strains tested (including penicillin-resistant pneumococcus), RPR 106972 was highly active with MIC results at < or = 1 microgram/ml. RPR 106972 inhibited Corynebacterium jeikeium (MIC90, 0.5 microgram/ml). Moraxella catarrhalis (MIC90, 0.25 microgram/ml), and some Haemophilus influenzae (MIC50, 2 micrograms/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC90s, 4 to 32 micrograms/ml) as compared to Enterococcus faecium (MIC90s, 0.5 to 1 microgram/ml) and other Enterococcus ssp. (MIC90s, 1 microgram/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 micrograms/ml; for S. aureus ATCC 29213, 0.25 to 1 microgram/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 microgram/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics.