Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence

Cyclosporin A is associated with an acute encephalopathy including seizures and alterations in mental status, herein referred to as cyclosporin A acute encephalopathy and seizure syndrome. The clinical history, electroencephalogram (EEG), and neuroimaging findings in 19 children with cyclosporin A acute encephalopathy and seizure syndrome over a 10-year period were reviewed in order to delineate clinical characteristics, imaging features, and to determine the risk of seizure recurrence in this population. All 19 had motor seizures associated with other features of cortical and subcortical dysfunction. The acute mean cyclosporin A level was 342 microg/L, but was within the "therapeutic" range in five cases. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) in the acute or subacute phase revealed lesions characteristic of cyclosporin A toxicity in 14 cases. Acute EEG abnormalities were present in all and included epileptiform discharges or focal slowing. Patients were followed for a median of 49 months (1-9 years). Follow-up imaging (n = 10) showed lesion resolution or improvement in the majority while EEG (n = 10) had normalized in only three. Seizures recurred in six patients and only in those with persistent EEG or imaging abnormalities. No patient had a second episode of cyclosporin A associated neurotoxicity or seizure. It appears that a significant risk of seizure recurrence exists following cyclosporin A acute encephalopathy and seizure syndrome and primarily in those children with persistent EEG or imaging abnormalities.     

Analysis of isomeric mixtures using blackbody infrared radiative dissociation: determining isomeric purity and obtaining individual tandem mass spectra simultaneously

A new method that makes possible, for the first time, simultaneous acquisition of individual dissociation mass spectra of isomeric ions in mixtures is presented. This method exploits the exquisite sensitivity of blackbody infrared radiative dissociation kinetics to minor differences in ion structure. Instead of separating precursor ions based on mass (isomers have identical mass), fragment ions are related to their original precursor ions on the basis of rate constants for dissociation. Mixtures of the peptide isomers des-R1 and des-R9 bradykinin are dissociated simultaneously at several temperatures. By fitting the kinetic data to double-exponential functions, the dissociation rate constant and abundance of each isomer in the mixture are obtained. To overcome the difficulty of fitting double-exponential functions, a novel global analysis method is used in which several dissociation data sets collected at different temperatures are simultaneously fit. The kinetic data measured at multiple temperatures are modeled with the preexponentials (corresponding to the abundance of each isomer) as "global" parameters which are constant for all data sets and the exponentials (rate constants) as "local" variables which differ for each data set. The use of global parameters significantly improves the accuracy with which abundances and dissociation rate constants of each individual compound can be obtained from the mixture data. Fragment ions produced from a mixture of these two isomers are related back to their respective precursor ions from the kinetic data. Thus, not only can the composition of the isomeric mixture be determined but an individual tandem mass spectrum of each component in the mixture can be obtained.     

Asp34 of PvuII endonuclease is directly involved in DNA minor groove recognition and indirectly involved in catalysis

The PvuII restriction endonuclease is a homodimer that recognizes and cleaves the DNA sequence 5'-CAGCTG-3' in double-stranded DNA, and the structure of this enzyme has been reported. In the wild-type enzyme, Asp34 interacts with the internal guanine of the recognition sequence on the minor groove side. The Asp34 codon was altered to specify Gly (D34G), and in vitro studies have revealed that the D34G protein has lost binding specificity for the central G.C base-pairs, and that it cuts the canonical sequence with 10(-4)-fold reduced activity as compared to the wild-type enzyme. We have now determined the structure at 1.59 A resolution of the D34G PvuII endonuclease complexed with a 12 bp duplex deoxyoligonucleotide containing the cognate sequence. The D34G alteration results in several structural changes relative to wild-type protein/DNA complexes. First, the sugar moiety of the internal guanine changes from a C2'-endo to C3'-endo pucker while that of the 3' guanine changes from C3'-endo to C2'-endo pucker. Second, the axial rise between the internal G.C base-pairs is reduced while that between the G.C and flanking base-pairs is expanded. Third, two distinct monomeric active sites are observed that we refer to as being "primed" and "unprimed" for phosphodiester bond cleavage. The primed and unprimed sites differ in the conformation of the Asp58 side-chain, and in the absence from unprimed sites of four networked water molecules. These water molecules, present in the primed site, have been implicated in the catalytic mechanism of this and other endonucleases; some of them can be replaced by the Mg2+ necessary for cleavage. Taken together, these structural changes imply that the Asp34 side-chains from the two subunits maintain a distinct conformation of its DNA substrate, properly situating the target backbone phosphates and indirectly manipulating the active sites. This provides some insight into how recognition of the specific DNA sequence is linked to catalysis by the highly specific restriction endonucleases, and reveals one way in which the structural conformation of the DNA is modulated coordinately with that of the PvuII protein.     

Effect of endurance training on cardiac morphology in Alaskan sled dogs

The cardiac morphology of 77 conscious Alaskan sled dogs before and after 5 mo of endurance training (20 km/day team pulling a sled and musher) was studied using two-dimensional and M-mode echocardiography. Subgroups included dogs with at least one season of previous training ("veterans") and dogs undergoing their first season of training ("rookies"). Training resulted in a significant (P < 0.05) decrease in resting heart rate (-15%) and significant increases in interventricular septal thickness (systole, 15%; diastole, 13%), left ventricular (LV) internal dimension in diastole (LVIDd, 4%), LV free wall thickness in systole (9%) and diastole (LVWd, 9%), and left atrial diameter (5%) in all dogs, but the increase in LVWd was greater in rookies (16%) than in veterans (7%). Training increased end-diastolic volume index (8%), LV mass index (24%), and heart weight index (24%) and decreased the LVIDd-to-LVWd ratio (-6%) but did not alter cardiac index. We conclude that increased LV mass attributable to LV dilation and hypertrophy is associated with endurance training in Alaskan sled dogs. Disproportionate LV wall thickening accompanying LV dilation suggests that cardiac morphological changes are due to volume and pressure loading. These training-induced changes are similar to those documented in human athletes undergoing combined isometric and isotonic training and differ from studies of dogs trained on treadmills.     

Tardive dyskinesia in a chronically institutionalized population of elderly schizophrenic patients: prevalence and association with cognitive impairment

We reported the immediate recovery period of 705 consecutive patients post general or head-neck-breast surgery, 590 were looked after in the recovery room (RR) and 115 were admitted into the intensive care unit (ICU) right after surgery. Group I were "young" (aged 15-45 years), group II were "middle aged" (46-60 years) and group III were "elderly" (> 60 years). Twenty-seven per cent of the elderly patients were sent to the ICU, whereas, 8.4 per cent of the young and 14.7 of the middle-aged group were looked after in the ICU. In RR patients, the young group were in better ASA class and had significantly fewer underlying diseases than the middle-aged and elderly groups; the most common of which were hypertension, diabetes and anemia. Elderly patients spent a significantly longer time in the RR than the young group but the risk of complication was not different. The most frequent complication was pain and elderly patients more frequently suffered from pain than the young group. Post-anesthetic recovery score (after Aldrete and Kroulik) was lower in the elderly on arrival and at 15, 30, 60 minutes in the RR but there was no clinical significance. In ICU patients, the 3 groups' intubation rates were not different and although the duration of intermittent positive pressure ventilation and duration of stay in the ICU were longest in the elderly group, there was no statistically significant difference. The mortality rate was highest in the elderly. We concluded that elderly patients had a worse immediate recovery period.     

Chemotherapy accelerates the development of acquired immune responses to Schistosoma haematobium infection

Treatment of 41 Schistosoma haematobium-infected children, 5-16 years old, with the drug praziquantel induced a switch from a predominantly IgA-specific antibody response to a predominantly IgG1 response within 12 weeks. A cross-sectional survey suggests that the same switch occurs naturally, but over several years, as children age (n = 251). The switch may be driven by alterations in cytokine levels in response to the release of antigens by dead or damaged parasites. Adults are more resistant to schistosome infection than children, and the switch to an "adult" response suggests that praziquantel treatment may have an immunizing effect, with benefits extending beyond a transient reduction in levels of infection.     

Shoe-surface interaction and the reduction of injury in rugby union

Medical schools, teaching hospitals, and managed care organizations have a vested interest in shaping the knowledge, skills, and attitudes of the next generation of physicians who must adapt to significant changes in the financing and delivery of health care. This article summarizes the rationale for educational partnerships between managed care and academic medicine based on a review of three decades of well-documented experimentation in the literature. Discussed are some of the most important characteristics of the successful partnerships being forged in the current healthcare environment based on new kinds of relationships between faculty and non-university clinician educators. What had been referred to in previous decades as the "teaching-HMO" is now being complemented by community-based links between academic health centers and managed care plans. Several public and private sources have been generous in providing venture capital to support many of these innovations. However, their continued operation will depend on models for health care networks that can identify and manage the revenue and costs associated with the missions of education, clinical services, and research.     

Continuous‐time Kalman filtering on the orthogonal group O(n)

This paper presents a continuous‐time O(n)‐constrained Kalman‐like filter. O(n) is the group of n × n orthonormal matrices. The O(n)‐constrained Kalman‐like filter is derived by posing a constrained optimization problem. The solution involves a projection of the unconstrained Kalman state estimate derivative onto the tangent space of O(n). Using this filter, an extended O(n)‐constrained Kalman‐like filter is developed for nonlinear systems where a portion of the states evolve on O(n). A numerical example demonstrates the effectiveness of the extended O(n)‐constrained Kalman‐like filter. Copyright © 2017 John Wiley & Sons, Ltd.     

Appendix to "Coulomb interactions in Ga LMIS" by Radlicka and Lencová

This appendix comments on the input data and simulation results of Radlicka and Lencová (RL), reported in the preceding paper. These simulations relate to the effects of space-charge on the full-width at half-maximum (FWHM) of the ion energy distribution from a gallium liquid metal ion source (LMIS), and on its virtual source size. Corrections are necessary to the input data, relating to LMIS shape, that were supplied by the present author. It is clear from RL's work that their simulations, when applied to the corrected shape data, would generate very good agreement between experimental results and numerical simulations concerning the FWHM. This work confirms that an inappropriate hydrodynamic condition has been used in past modelling programmes for LMIS shapes and current/voltage characteristics; consequently, some quantitative results from these old programmes must be considered unreliable in detail, especially at low emission currents, although qualitative trends have been correctly exhibited.