Which treatment for whom for ADHD? Moderators of treatment response in the MTA

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.     

Improved In Vitro Excystation Procedure for Giardia lamblia Cysts

Giardia lamblia cysts obtained from human symptomatic and asymptomatic donors were excysted in vitro. Excystation averaged 87% for cysts from symptomatic donors and 70% for cysts from asymptomatic donors.     

Epidemiologic analysis of sporadic Salmonella typhi isolates and those from outbreaks by pulsed-field gel electrophoresis.

Pulsed-field gel electrophoresis (PFGE) was used to compare and analyze 158 isolates of Salmonella typhi from five well-defined outbreaks of typhoid fever in Malaysia and also isolates involved in sporadic cases of typhoid fever occurring during the same period. Digestion of chromosomal DNAs from these S. typhi isolates with the restriction endonucleases XbaI (5'-TCTAGA-3'), SpeI (5'-ACTAGT-3'), and AvrII (5'-CCTAGG-3') and then PFGE produced restriction endonuclease analysis (REA) patterns consisting of 11 to 24 DNA fragments ranging in size from 20 to 630 kbp. Analysis of the REA patterns generated by PFGE after digestion with XbaI and SpeI indicated that the S. typhi isolates obtained from sporadic cases of infection were much more heterogeneous (at least 13 different REA patterns were detected; Dice coefficient, between 0.73 and 1.0) than those obtained during outbreaks of typhoid fever. The clonal nature and the close genetic identities of isolates from outbreaks in Alor Setar, Penang, Kota Kinabalu, Johor Bahru, and Kota Bahru were suggested by the fact that only a limited number of REA patterns, which mostly differed by only a single band, were detected (one to four patterns; Dice coefficient, between 0.82 and 1.0), although a different pattern was associated with each of these outbreaks. Comparison of REA patterns with ribotyping for 18 S. typhi isolates involved in sporadic cases of infection showed a good correlation, in that 72% of the isolates were in the same group. There was no clear correlation of phage types with a specific REA pattern. We conclude that PFGE of s. typhi chromosomal DNA digested with infrequently cutting restriction endonucleases is a useful method for comparing and differentiating S. typhi isolates for epidemiological purposes.     

Proportional Jerk: A New Measure of Motion as Applied to Eye Movements in Sleep and Waking

The third derivative of motion or the change in the rate of acceleration (also known as jerk) is examined in terms of its applicability to the study of psychophysiological function. An algorithm of this third derivative is presented to show that jerk can be derived from the arithmetic difference of two slopes which constitute the portion of motion being differentiated. By modifying the algorithm, a new parameter termed “proportional jerk’ or PJ is formulated whereby one slope is measured relative to the other slope; this PJ provides information about the smoothness of movement without being influenced by the velocity as is the traditional jerk measure. A practical application of the PJ to waking saccades and REMs in 11 human subjects revealed that REMs are significantly “jerkier’ or less smooth than waking calibration eye movements. Whereas the waking eye movements had a well-defined negative phase of the PJ, the REMs did not show such stereotypical behavior. This is in accord with previous work which showed that waking saccade velocity increases to a maximum and then decreases whereas REMs maintain their peak or near peak velocities for varying periods. It was suggested that PJ can be useful in detecting subtle temporal changes in the course of movements and may be used as a parameter of motion even when the absolute amplitude is unknown.     

Experimental Adenovirus Infection of the Mouse Adrenal Gland: II. Electron Microscopic Observations

A strain of mouse adenovirus, found to have a striking tropism for the weanling mouse adrenal gland, enabled electron microscopic examination of adrenals in various stages of infection. Nucleolar hypertrophy and the successive formation of three types of inclusion bodies in association with nucleoli preceded virion production. Angular crystals of virions formed in the affected nuclei. Virus was released by lysis of nuclear membranes; rapid degeneration of cytoplasmic organelles followed. Rupture of external cell membranes released virus into the extracellular spaces where virions crossed vascular basement membranes to enter endothelial cells. Virions were also phagocytized by inflammatory cells which reentered vascular sinusoids, and by adrenal parenchymal cells. Disruption of virus-laden phagocytic vacuoles in parenchymal cells released virions into the cytoplasm. Typical viral inclusion bodies also formed in vascular endothelial cells and in inflammatory cells, but virion replication was not detected. The possibility that virus directly entered parenchymal cells through the external cell membrane without phagocytosis is discussed.     

Mutation analysis of feline Niemann-Pick C1 disease

Niemann-Pick C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder that results in defective intracellular transport of cholesterol. The major form of human NPC (NPC1) has been mapped to chromosome 18, the NPC1 gene (NPC1) has been sequenced and several mutations have been identified in NPC1 patients. A feline model of NPC has been characterized and is phenotypically, morphologically, and biochemically similar to human NPC1. Complementation studies using cultured fibroblasts from NPC affected cats and NPC1 affected humans support that the gene responsible for the NPC phenotype in this colony of cats is orthologous to human NPC1. Using human-based PCR primers, initial fragments of the feline NPC cDNA were amplified and sequenced. From these sequences, feline-specific PCR primers were generated and designed to amplify six overlapping bands that span the entire feline NPC1 open reading frame. A single base substitution (2864G-C) was identified in NPC1 affected cats. Obligate carriers are heterozygous at the same allele and a PCR-based assay was developed to identify the geneotype of all cats in the colony. The mutation results in an amino acid change from cysteine to serine (C955S). Several of the mutations identified in people occur in the same region. Marked similarity exists between the human and feline NPC1 cDNA sequences, and is greater than that between the human and murine NPC1 sequences. The human cDNA sequence predicts a 1278aa protein with a lysosomal targeting sequence, several trans-membrane domains and extensive homology with other known mediators of cholesterol homeostasis.     

Simultaneous inhibition of caudal medullary raphe and retrotrapezoid nucleus decreases breathing and the CO2 response in conscious rats

The medullary raphe (MR) and the retrotrapezoid nucleus (RTN) in the ventral medulla are two of many central chemoreceptor sites. We examine their combined function in conscious rats by focal inhibition using microdialysis. Inhibition of RTN neurons with the GABA_A receptor agonist muscimol, with simultaneous dialysis of artificial cerebrospinal fluid (ACSF) in or near to the caudal MR, causes hypoventilation (decrease in the ratio of minute ventilation to oxygen consumption,     ) and reduces the ventilatory response to 7% CO₂ by 24%. Inhibition of caudal MR serotonergic neurons with the 5-HT_1A receptor agonist ( R )-(+)-8-hydroxy-2(di- n -propylamino)tetralin (8-OH-DPAT), with simultaneous dialysis of ACSF in or near to the RTN, causes hypoventilation but has no significant effect on the CO₂ response. Inhibition of both the RTN and the caudal MR simultaneously produces enhanced hypoventilation and a 51% decrease in the CO₂ response. The effects of treatment on the CO₂ response are similar in wakefulness and in non-rapid eye movement sleep. Comparison of the effect of 8-OH-DPAT microdialysed into a more rostral portion of the MR, where the CO₂ response is reduced by 22%, demonstrates heterogeneity within the MR of the function of serotonergic neurons in breathing. We conclude that serotonergic neurons within the caudal MR provide a non-CO₂-dependent tonic drive to breathe and potentiate the effects of RTN neurons that contribute to a resting chemical 'drive to breathe' as well as the response to added CO₂. These effects of caudal MR serotonergic neurons could be at a chemoreceptor site, e.g. the RTN, or at 'downstream' sites involved in rhythm and pattern generation.     

Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens.

Unrelated umbilical cord blood (UCB) transplantation has recently been explored in an increasing number of adult patients. The relative ease of procurement and the lower-than-anticipated risk of severe acute graft-versus-host disease has made UCB transplantation an appealing alternative to bone marrow-derived hematopoietic stem cells. The use of reduced-intensity or nonmyeloablative preparative regimens to allow engraftment of UCB broadens the scope of patients who may benefit from allogeneic immunotherapy, including elderly and medically infirm patients with no matched sibling donor. This review summarizes the available data on the use of UCB as an alternative source of hematopoietic stem cell transplantation in adult patients.     

Immunologic Mimicry Between Mouse Tissue and Enterobacterial Common Antigen

Organs of Swiss white albino and C57BL/6Ha mice were assessed for an antigen (CRA) which cross-reacts with common enterobacterial antigen (CA) of To this end, supernatant fluids (HKS) and ethanol-soluble fractions (ES) of heated homogenates of spleens, kidneys, and livers were examined for their capacities to react with CA hemagglutinins and to engender humoral and cellular events in the rabbit. The immunogenicity of CRA in the rabbit can not be predicted on the basis of CA hemagglutinin neutralization studies alone; although CRA was identified in the liver extracts of both mouse strains, according to this parameter, only the liver fraction of Swiss white albino mice elicited significant numbers of rosette-forming cells (RFC) in the spleens of rabbits. Also, kidney fractions, which primed the rabbits for booster with CA, were less effective in stimulating RFC in the spleens of the identical animals. Moreover, although extracts of mouse spleens failed to inhibit CA hemagglutination and did not prime rabbits for a CA hemagglutinin response, these same preparations clearly evoked RFC in rabbit spleens. Thus, the antigenicity and immunogenicity of CRA in target organs of mice reflect the mouse strain, extraction procedure, and testing method employed.