Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease: a systematic review and meta-analysis.

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2 , and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P < 0.001) and functionality assessed with the sit-to-stand test (SMD -0.31 [95% CI -0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.

Model-Informed Precision Dosing of Antibiotics in Pediatric Patients: A Narrative Review.

Optimal pharmacotherapy in pediatric patients with suspected infections requires understanding and integration of relevant data on the antibiotic, bacterial pathogen, and patient characteristics. Because of age-related physiological maturation and non-maturational covariates (e.g., disease state, inflammation, organ failure, co-morbidity, co-medication and extracorporeal systems), antibiotic pharmacokinetics is highly variable in pediatric patients and difficult to predict without using population pharmacokinetics models. The intra- and inter-individual variability can result in under- or overexposure in a significant proportion of patients. Therapeutic drug monitoring typically covers assessment of pharmacokinetics and pharmacodynamics, and concurrent dose adaptation after initial standard dosing and drug concentration analysis. Model-informed precision dosing (MIPD) captures drug, disease, and patient characteristics in modeling approaches and can be used to perform Bayesian forecasting and dose optimization. Incorporating MIPD in the electronic patient record system brings pharmacometrics to the bedside of the patient, with the aim of a consisted and optimal drug exposure. In this narrative review, we evaluated studies assessing optimization of antibiotic pharmacotherapy using MIPD in pediatric populations. Four eligible studies involving amikacin and vancomycin were identified from 418 records. Key articles, independent of year of publication, were also selected to highlight important attributes of MIPD. Although very little research has been conducted until this moment, the available data on vancomycin indicate that MIPD is superior compared to conventional dosing strategies with respect to target attainment. The utility of MIPD in pediatrics needs to be further confirmed in frequently used antibiotic classes, particularly aminoglycosides and beta-lactams.

Early developmental changes in the timing of turn-taking: a longitudinal study of mother-infant interaction.

To accomplish a smooth transition in conversation from one speaker to the next, a tight coordination of interaction between speakers is required. Recent studies of adult conversation suggest that this close timing of interaction may well be a universal feature of conversation. In the present paper, we set out to assess the development of this close timing of turns in infancy in vocal exchanges between mothers and infants. Previous research has demonstrated an early sensitivity to timing in interactions (e.g., Murray and Trevarthen, 1985). In contrast, less is known about infants' abilities to produce turns in a timely manner and existing findings are rather patchy. We conducted a longitudinal study of 12 mother-infant dyads in free-play interactions at the ages of 3, 4, 5, 9, 12, and 18 months. Based on existing work and the predictions made by the Interaction Engine Hypothesis (Levinson, 2006), we expected that infants would begin to develop the temporal properties of turn-taking early in infancy but that their timing of turns would slow down at 12 months, which is around the time when infants start to produce their first words. Findings were consistent with our predictions: infants were relatively fast at timing their turn early in infancy but slowed down toward the end of the first year. Furthermore, the changes observed in infants' turn-timing skills were not caused by changes in maternal timing, which remained stable across the 3-18 months period. However, the slowing down of turn-timing started somewhat earlier than predicted: at 9 months.

Selective and faithful imitation at 12 and 15 months.

Research on imitation in infancy has primarily focused on what and when infants imitate. More recently, however, the question why infants imitate has received renewed attention, partly motivated by the finding that infants sometimes selectively imitate the actions of others and sometimes faithfully imitate, or overimitate, the actions of others. The present study evaluates the hypothesis that this varying imitative behavior is related to infants' social traits. To do so, we assessed faithful and selective imitation longitudinally at 12 and 15 months, and extraversion at 15 months. At both ages, selective imitation was dependent on the causal structure of the act. From 12 to 15 months, selective imitation decreased while faithful imitation increased. Furthermore, infants high in extraversion were more faithful imitators than infants low in extraversion. These results demonstrate that the onset of faithful imitation is earlier than previously thought, but later than the onset of selective imitation. The observed relation between extraversion and faithful imitation supports the hypothesis that faithful imitation is driven by the social motivations of the infant. We call this relation the King Louie Effect: like the orangutan King Louie in The Jungle Book, infants imitate faithfully due to a growing interest in the interpersonal nature of interactions.

Infants show stability of goal-directed imitation.

Previous studies have reported that infants selectively reproduce observed actions and have argued that this selectivity reflects understanding of intentions and goals, or goal-directed imitation. We reasoned that if selective imitation of goal-directed actions reflects understanding of intentions, infants should demonstrate stability across perceptually and causally dissimilar imitation tasks. To this end, we employed a longitudinal within-participants design to compare the performance of 37 infants on two imitation tasks, with one administered at 13 months and one administered at 14 months. Infants who selectively imitated goal-directed actions in an object-cued task at 13 months also selectively imitated goal-directed actions in a vocal-cued task at 14 months. We conclude that goal-directed imitation reflects a general ability to interpret behavior in terms of mental states.

CUE: the continuous unified electronic diary method.

In the present article, we introduce the continuous unified electronic (CUE) diary method, a longitudinal, event-based, electronic parent report method that allows real-time recording of infant and child behavior in natural contexts. Thirty-nine expectant mothers were trained to identify and record target behaviors into programmed handheld computers. From birth to 18 months, maternal reporters recorded the initial, second, and third occurrences of seven target motor behaviors: palmar grasp, rolls from side to back, reaching when sitting, pincer grip, crawling, walking, and climbing stairs. Compliance was assessed as two valid entries per behavior: 97 % of maternal reporters met compliance criteria. Reliability was assessed by comparing diary entries with researcher assessments for three of the motor behaviors: palmar grasp, pincer grip and walking. A total of 81 % of maternal reporters met reliability criteria. For those three target behaviors, age of emergence was compared across data from the CUE diary method and researcher assessments. The CUE diary method was found to detect behaviors earlier and with greater sensitivity to individual differences. The CUE diary method is shown to be a reliable methodological tool for studying processes of change in human development.

Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement.

Glaucoma is a progressive neurodegenerative disease of retinal ganglion cells (RGCs) associated with characteristic axon degeneration in the optic nerve. Clinically, our only method of slowing glaucomatous loss of vision is to reduce intraocular pressure (IOP), but lowering IOP is only partially effective and does not address the underlying susceptibility of RGCs to degeneration. We review the recent steps forward in our understanding of the pathophysiology of glaucoma and discuss how this understanding has given us a next generation of therapeutic targets by which to maintain RGC survival, protect or rebuild RGC connections in the retina and brain, and enhance RGC function.

Enzyme fragment complementation binding assay for p38alpha mitogen-activated protein kinase to study the binding kinetics of enzyme inhibitors.

The majority of protein kinase assays used in drug discovery research are enzyme activity assays. These assays are based on the measurement of phosphorylated protein or peptide substrate, which is the end product of the enzyme reaction. Since most kinase inhibitors are ATP competitive, prediction of the activity of compounds in cellular systems based on potency values in enzyme activity assays is complex, as this should take into account the affinity of the enzyme for ATP and the cellular ATP concentration. The fact that some of the most successful kinase inhibitors, such as STI 571 (imatinib mesylate, Gleevec, Novartis Pharmaceuticals, East Hanover, NJ), act through binding to the inactive isoform of the kinase provides another limitation of enzyme activity assays. Binding assays allow separate measurement of compound affinity to active and inactive kinase and do not require ATP or substrate in the reaction. Recently, a non-radioactive kinase binding assay for p38 mitogen-activated protein kinase has become available from DiscoveRx (Fremont, CA). The assay method, called HitHunter, utilizes enzyme fragment complementation of Escherichia coli beta-galactosidase to generate an assay signal by chemiluminescence. We have reconfigured the commercial assay kit to study the binding kinetics of two known reference inhibitors of the alpha-isoform of p38, the pyridinyl imidazole SB 203580 and the diaryl urea BIRB 796. Our data confirm the slow association kinetics of BIRB 796 as compared to SB 203580, which corresponded with the requirement of a relatively long preincubation time to obtain maximal effect in a cellular assay. Although neither of the two compounds showed preference for either active or inactive p38alpha, our data demonstrate that the HitHunter kinase binding assay can be used to select compounds that specifically target inactive kinase.

Mapping the distribution of 3-hydroxy oxylipins in the ascomycetous yeast Saturnispora saitoi.

The distribution of 3-hydroxy oxylipins in Saturnispora saitoi was mapped using immunofluorescence microscopy. Fluorescence was observed on aggregating ascospores, indicating the presence of 3-hydroxy oxylipins on the surface or between ascospores. The oxylipin was identified as 3-hydroxy 9:1 using gas chromatography mass spectrometry. Furthermore, ultrastructural studies using scanning and transmission electron microscopy on ascospores revealed a clear equatorial ledge surrounding oval-shaped ascospores.

The presence of novel 3-hydroxy oxylipins on surfaces of hat-shaped ascospores of Ascoidea africana Batra & Francke-Grosmann.

Immunofluorescence microscopy exposed the presence of novel 3-hydroxy oxylipins on the surfaces of aggregated hat-shaped ascospores of Ascoidea africana. These compounds were confirmed by gas chromatography - mass spectrometry analysis. Only the complete structure of a novel 3-hydroxy 10:1 could be determined.

Neamin as an immunogen for the development of a generic ELISA detecting gentamicin, kanamycin, and neomycin in milk.

A broad-specific ELISA using one antibody preparation for the detection of gentamicin, kanamycin, and neomycin in milk is reported for the first time. For the immunization of rabbits, neamin was used as the generic hapten on the basis of the facts that it is a two-ring fragment of neomycin and, in shape and charge, it resembles parts of kanamycin and gentamicin. Neamin was linked to the preactivated carrier protein keyhole limpet hemocyanin by EDC coupling. The specificity and sensitivity of the polyclonal antibodies for the aminoglycoside antibiotics were tested in a competitive assay using homologous and heterologous conjugates coupled by various conjugation procedures as the ELISA solid phase. In contrast to the homologous assay recognizing only neomycin, the heterologous assay could be used for the detection of the whole subclass of deoxystreptamin antibiotics in buffer and raw milk. Gentamicin, kanamycin, and neomcyin were detected in artificially contaminated undiluted raw milk (without sample pretreatment) with 50% inhibition levels at 9, 21, and 113 ng mL(-)(1), respectively. Neomycin levels were also measured in milk samples obtained from a cow suffering from mastitis and treated with an antibiotic cocktail including neomycin. Levels below the EU maximum residue levels for deoxystreptamin antibiotics could readily be measured in this generic ELISA.

High-throughput screening with immobilized metal ion affinity-based fluorescence polarization detection, a homogeneous assay for protein kinases.

Protein kinases are one of the most important target classes in high-throughput screening today. The use of generic assay technologies facilitates assay development for new targets and decreases the time needed for implementation of assays in robotic screening. For tyrosine kinases, several generic assay technology platforms are available. These technologies make use of high-affinity antibodies that discriminate between phosphorylated tyrosines and non-phosphorylated tyrosines. Similar generic antibodies specific for phosphoserine or phosphothreonine are lacking. Recently, a non-antibody-based fluorescence polarization assay for protein kinases has become available, called IMAP (Molecular Devices, Sunnyvale, CA). In this assay, a fluorescently labeled peptide substrate that is phosphorylated by kinase is captured on metal-derivatized nanoparticles. We have evaluated IMAP in high-throughput screening, and compared this technology with a competition fluorescence polarization immunoassay based on an antibody specific for a phosphorylated peptide substrate. A random collection of >250000 compounds was screened with the two assays. Fluorescent library compounds were identified by calculation of fluorescence intensity values from the screening data, and by assaying in the absence of fluorescent reagents. Fluorescence polarization artifacts were filtered out further by testing in an ELISA-based kinase assay. Our data show that IMAP is a robust technology for high-throughput screening of kinase targets, and suggest that it is less susceptible to fluorescence polarization artifacts than the competition fluorescence polarization immunoassay.

[Mandibular fractures in cattle--treatment and results]. / Unterkieferfrakturen beim Rind--Behandlung und Ergebnisse.

The results of a retrospective investigation of 25 cases of mandibular fractures in cattle are reported; 19 animals were treated and 6 slaughtered without therapy. Five cases of unilateral fracture of the pars molaris healed with conservative therapy, whereas the same method of treatment was unsuccessful in four cases with compound fractures (2 x pars incisiva, 1 x diastema, 1 x pars molaris) and in one with multiple fractures of the corpus and ramus of the mandible. For animals with symphyseal fractures, surgical fixation using cerclage wire (three cases) proved successful, as did percutaneous fixation in six animals with fractures of the diastema or body of the mandible. The fractures healed well in 14 out of 19 treated cattle and the animals were retained, on average, for a further four years.

[Occurrence and radiological studies of different teat changes in milk cows]. / Vorkommen und röntgenologische Untersuchungen verschiedener Zitzenveränderungen bei Milchkühen.

The aim of this study was to investigate the incidence of different teat lesions in cows that cause obstruction of milk flow. 18,400 teats were palpated in Konya slaughterhouse. From these 1000 hard milking or obstructed teats were found (5.4%). Based on the radiographical results, distal 1/3, proximal 2/3, complete teat lesions and congenital obstructions were found in 70.1, 16.6 and 0.7% respectively.

[Metacarpal and metatarsal fractures in cattle. Treatment and results]. / Metakarpal- und Metatarsalfrakturen beim Rind. Behandlung und Ergebnisse.

94 cattle with 97 metacarpal or metatarsal fractures were presented at the Department of Veterinary Surgery of the Ludwig-Maximilians-Universität, Munich, between 1970 and 1987. The cause of fracture was incorrect traction during assisted delivery in almost one third (30.9%) of cases. Eighty-two animals were treated. 59 out of 73 cattle treated conservatively and 7 out of 9 which were operated, could be healed. In 38 animals the fracture healed without malpositioning; 28 developed a shortening or bending of the affected limb, which, with the exception of one case, did not functionally impair the animals. Complications occurred in 22 patients (= 26.9%); in closed fractures the reason was predominantly due to dislocation of the fragments within the cast, whereas an osteomyelitis was usually the cause in the case of the open fractures.

[Nasolabioplasty after rupture of the nasal ring in cattle]. / Nasolabioplastik nach Ausriss des Nasenringes beim Rind.

In 25 cases of muzzle and nasal septum injuries operative treatment was performed by different methods. In conventional nasolabioplasty (n = 23) horizontal mattress sutures were used, the free parts of the thread passing through pieces of rubber tube. In two bulls, suffering from such a rupture the second time, a new surgical technique was applied. To prevent stenosis of the nostrils, the nasal septum was reconstructed by cutaneous pedicle graft. The techniques of both methods are described and illustrated. Healing was observed in all cases.