PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER: A GUIDE TO ASSESSMENT AND TREATMENT

Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent or persistent thoughts, impulses, or images that are experienced as intrusive or distressing (obsessions), and repetitive behaviors or mental acts (compulsions) often performed in response to an obsession. Recent epidemiological studies have found lifetime prevalence of pediatric OCD to be approximately 1-4% in the USA. OCD begins before the age of 18 years for as many as 80% of cases and follows a chronic, unremitting course. Due to the distressing, time-consuming, and debilitating nature of OCD, impairments in academic, social, and family functioning are often substantial. Despite the relatively high prevalence rate of OCD, dissemination about effective assessment and treatment has lagged. Increasing the awareness of OCD symptoms and its treatment among nurses and other health professionals will enhance identification of children presenting with unrecognized or untreated symptoms of OCD and will stimulate appropriate referrals for treatment to improve children's psychological functioning and overall quality of life. This paper reviews the nature, etiology, assessment, and treatment of OCD, highlighting clinical implications for nurses involved in mental health care.     

Boron neutron capture therapy for malignant gliomas

Boron neutron capture therapy (BNCT) represents a promising modality for a relatively selective radiation dose delivery to the tumour tissue. Boron-10 nuclei capture slow 'thermal' neutrons preferentially and, upon capture, promptly undergo 10B(n,alpha)7Li reaction. The ionization tracks of energetic and heavy lithium and helium ions resulting from this reaction are only about one cell diameter in length (approximately 14 microm). Because of their high linear energy transfer (LET) these ions have a high relative biological effectiveness (RBE) for controlling tumour growth. The key to effective BNCT of tumours, such as glioblastoma multiforme (GBM), is the preferential accumulation of boron-10 in the tumour, including the infiltrating GBM cells, as compared with that in the vital structures of the normal brain. Provided that a sufficiently high tumour boron-10 concentration (approximately 10(9) boron-10 atoms/cell) and an adequate thermal neutron fluence (approximately 10(12) neutrons/cm2) are achieved, it is the ratio of the boron-10 concentration in tumour cells to that in the normal brain cells that will largely determine the therapeutic gain of BNCT.     

Social norms and obesity prevalence: From cohort to system dynamics models

Group‐level obesity can be seen as an emergent property of a complex system, consisting of feedback loops between individual body weight perception, individual weight‐related behaviour and group‐level social norms (a product of group‐level ‘normal' body mass index (BMI) and sociocultural ‘ideal' BMI). As overweight becomes normal, the norm might be counteracting health awareness in shaping individual weight‐related behaviour. System dynamics modelling facilitates understanding and simulating this system's emergent behaviour. We constructed six system dynamics models (SDMs) based on an expert‐informed causal loop diagram and data from six sociocultural groups (Dutch, Moroccan and South‐Asian Surinamese men and women). The SDMs served to explore the effect of three scenarios on group‐level BMI: ‘what if' weight‐related behaviour were driven by (1) health awareness, (2) norms or (3) a combination of the two. Median BMI decreased approximately 50% and 30% less in scenarios 2 and 3, respectively, than in 1. In men, the drop in BMI was approximately two times larger in scenario 1 versus 3, whereas in women, the drop was approximately equal in these scenarios. This study indicates that the overweight norm in men holds group‐level BMI close to overweight despite health awareness. Since norms are counteracting health awareness less strongly in women, other drivers of obesity must be more relevant.     

The multiscale character of evoked cortical activity

Both the architecture and the dynamics of the brain have characteristic features at different spatial scales. However, the existence, nature and function of dynamical interdependencies between such scales have not been investigated. We studied the multiscale properties of functional magnetic resonance imaging (fMRI) data acquired while human subjects viewed a visual image. Traditional "region of interest" analysis of this data set revealed evoked activity in primary and extrastriate visual cortex. Wavelet transform in the spatial domain provides a multiscale representation of this evoked brain activity. Studying the correlation structure of this representation revealed strong and novel interdependencies in these data within and between different spatial scales. We found that such correlations are stronger than those evident in the original data and comparable in magnitude to those obtained after Gaussian smoothing. However, analysis of the data in the wavelet domain revealed additional structure such as positive correlations, strong anti-correlations and phase-lagged interdependencies. Statistical significance of these effects was inferred through nonparametric bootstrap techniques. We conclude that the spatial analysis of functional neuroimaging data in the wavelet domain provides novel information which may reflect complex spatiotemporal neuronal activity and information encoding. It also affords a quantitative means of testing hierarchical and multiscale models of cortical activity.     

Exopolysaccharide defects cause hyper-thymineless death in Escherichia coli via massive loss of chromosomal DNA and cell lysis

Thymineless death in Escherichia coli thyA mutants growing in the absence of thymidine (dT) is preceded by a substantial resistance phase, during which the culture titer remains static, as if the chromosome has to accumulate damage before ultimately failing. Significant chromosomal replication and fragmentation during the resistance phase could provide appropriate sources of this damage. Alternatively, the initial chromosomal replication in thymine (T)-starved cells could reflect a considerable endogenous dT source, making the resistance phase a delay of acute starvation, rather than an integral part of thymineless death. Here we identify such a low-molecular-weight (LMW)-dT source as mostly dTDP-glucose and its derivatives, used to synthesize enterobacterial common antigen (ECA). The thyA mutant, in which dTDP-glucose production is blocked by the rfbA rffH mutations, lacks a LMW-dT pool, the initial DNA synthesis during T-starvation and the resistance phase. Remarkably, the thyA mutant that makes dTDP-glucose and initiates ECA synthesis normally yet cannot complete it due to the rffC defect, maintains a regular LMW-dT pool, but cannot recover dTTP from it, and thus suffers T-hyperstarvation, dying precipitously, completely losing chromosomal DNA and eventually lysing, even without chromosomal replication. At the same time, its ECA⁺ thyA parent does not lyse during T-starvation, while both the dramatic killing and chromosomal DNA loss in the ECA-deficient thyA mutants precede cell lysis. We conclude that: 1) the significant pool of dTDP-hexoses delays acute T-starvation; 2) T-starvation destabilizes even nonreplicating chromosomes, while T-hyperstarvation destroys them; and 3) beyond the chromosome, T-hyperstarvation also destabilizes the cell envelope.

Acute starvation for thymidine triphosphate (dTTP), one of the four precursors for DNA synthesis, is lethal in both bacterial and eukaryotic cells (1). Following a short resistance phase, the rapid death of thyA auxotrophs in media lacking thymine or thymidine (“T-starvation”) known as thymineless death (TLD) was first described in Escherichia coli (2, 3) and since then was extensively studied to identify the cause of lethality (1, 4, 5). Because the bulk of thymidine (dT) in any cell is used for chromosomal DNA synthesis, lack of dT was always assumed to cause some form of chromosomal damage, and hence the role of DNA repair pathways during T-starvation was the focus of intense investigation (6–9). These studies revealed that certain pathways, like double-strand break repair initiated by the RecBCD helicase/nuclease, Holliday junction resolution by RuvABC, and antirecombination activity of the UvrD helicase, keep cells alive during the resistance phase of T-starvation. Other events, like attempted single-strand gap repair initiated by the RecFOR complex, the function of the RecQ helicase and RecJ exonuclease, and SOS induction of the cell division inhibitor SulA, are detrimental for T-starved E. coli cells (8, 10–12). However, the thyA mutants of E. coli inactivated for all of the latter “toxic DNA repair pathways” still die by two orders of magnitude during T-starvation (8), indicating some other yet-to-be-identified major lethality factors.Since actively growing cells continuously require a lot of dT to replicate chromosomal DNA, existing replication forks were inferred to be the points of TLD pathology (7, 8, 13–15). Indeed, T-starvation severely inhibits chromosomal DNA replication (15) and is associated with accumulation of single-stranded DNA, suggesting generation of single-strand (ss) gaps by attempted replication in the absence of dT (7, 16). These ss-gaps induce the SOS response (7, 8, 17), which contributes to the pathology of TLD by induction of the SulA cell division inhibitor (8). Also, replication initiation spike in the T-starved cells triggers the destruction of the origin-centered chromosomal subdomain during TLD, suggesting that it is the demise of the nascent replication bubbles, rather than the existing replication forks, that eventually kills the chromosome (15, 17).Although the thyA mutants cannot synthesize dT, they grow normally if supplemented with exogenous dT/T. Upon removal of dT from the growth medium, the E. coli thyA strain has a two-generation-long resistance phase (also called the lag phase) (1), when the colony-forming unit (CFU) titer of the culture stays constant (Fig. 1 A, Top). This is followed by the rapid exponential death (RED) phase, when the CFU titer falls by approximately three orders of magnitude within several hours (Fig. 1 A, Top).Open in a separate windowFig. 1.A significant endogenous pool of LMW dT decreases during T-starvation. (A) The phenomenon of TLD in E. coli suggests accumulation of chromosomal damage during the resistance phase (green) that would later kill cells during the RED phase (red). The data are adapted from ref. 16. Henceforth, the data are means (n ≥ 3) ± SEM. Cultures were grown at 37 °C in the presence of dT, which was removed at time = 0, while incubation in the growth medium continued. Top, cell death begins after 1-h-long resistance phase, during which the culture titer is stable. Bottom, during the same first hour without dT, cells manage to synthesize the amount of DNA equal to half of what they already had before dT removal. However, during the RED phase genomic DNA is gradually lost. (B) Scheme of 50% methanol fractionation of the intracellular thymidine into HMW dT (the dT content of the chromosomal DNA) and LMW dT. (C) A 0.7% agarose gel analysis of the HMW and LMW fractions of the 50% methanol-treated cells, as well as pure LB treated the same way, for DNA and RNA content (staining with ethidium bromide). Inverse images of stained gels are shown, in which the indicated samples were either incubated in the buffer or with the indicated enzyme (DNase I for the top gel, RNase A for the bottom gel). (D) The size of the LMW-dT pool, normalized to the HMW-dT content of the chromosome, either during normal growth in dT-supplemented medium or during T-starvation. Thymidine was removed at time = 0. The strain is KKW58.An obvious explanation for the resistance phase is existence of an intracellular source of dT to support slow replication; however, chromosomal DNA amount was consistently reported to remain flat during TLD (15, 18–20). Besides, the recent systematic test of potential candidates for a source of dT or its analogs supporting the resistance phase returned empty-handed (16). Thus, the mechanisms behind the initial resistance to T-starvation, followed by the sudden shift to the RED phase remain unclear, leading to a reasonable assumption that the resistance phase is an integral part of the TLD phenomenon, during which chromosomal damage accumulates until it becomes irreparable, ushering the RED phase (1, 5). Specific early events during the resistance phase of TLD that would later turn poisonous during the RED phase were proposed to be futile incorporation–excision cycles (1, 21), ss-gap accumulation causing the SOS induction (1, 8, 16), futile fork breakage-repair cycles (16, 22), and overinitiation from the origin (5, 15).Two recent observations, in combination with an old popular TLD explanation, further support the idea of the resistance phase as the TLD period during which chromosomal damage accumulates without affecting viability for the time being. First, the resistance phase coincides with accumulation of double-strand breaks in the chromosome, which then paradoxically disappear during the RED phase (7, 16). Second (and in contrast to the reports mentioned above of constant chromosomal DNA amount during T-starvation) (15, 18–20), we have found that during the resistance phase the amount of the chromosomal DNA actually increases ∼1.5 times over the prestarvation level, but then the chromosomal DNA is apparently destabilized during the RED phase, since it is slowly reduced to the original level (16) (Fig. 1 A, Bottom). Therefore, both the apparent chromosomal replication and the significant chromosome fragmentation during the resistance phase could lead to accumulation of chromosomal damage (SOS induction is an indicator of this accumulation) (7).On the other hand, the early DNA synthesis and the resistance phase in T-starved cells could reflect the existence of a source of dT, available early on during T-starvation, that fuels the initial DNA accumulation and delays viability loss until this pool is exhausted. In other words, the resistance phase could simply postpone TLD, rather than being an integral part of it. Previously, we have tested the two obvious high-molecular-weight (HMW) dT sources, namely, the stable RNAs and the chromosomal DNA, but found that incapacitation of neither one reduced the resistance phase or precluded the early DNA synthesis during T-starvation (16). Thus, the question of whether the resistance phase is a part of the TLD phenomenon remains unresolved.In the current study, we investigated a seemingly remote possibility of a substantial low-molecular-weight (LMW)-dT pool supporting the resistance phase of T-starvation in E. coli. While the bulk of dTTP in E. coli immediately incorporates into the chromosomal DNA, a fraction of dTTP is recruited into the dTDP-hexose pool (23), to participate in the synthesis of the exopolysaccharide (EPS) capsule, made of core lipopolysaccharide (LPS) (24), O-antigen (OA) (25), and enterobacterial common antigen (ECA) in E. coli (26). The first step of this recruitment is to conjugate dTTP with glucose; the hexose moiety of the resulting dTDP-glucose then undergoes several modifications, before eventually incorporating into oligosaccharide precursors of the outer antigens, while the activating dTDP handle is released back into the DNA precursor pools (26). We ignored LMW dT before because, if the total dT content of the chromosomal DNA is taken for 100%, the pool of dTTP constitutes ∼0.7% of it, while dTDP-glucose (unresolved from other dTDP-hexoses?) adds only another 2.4% (27). No more LMW-dT species are known in the cell, so the total expected LMW-dT pool comes to ∼3% of the total dT content of the chromosomal DNA, not nearly enough to support the resistance phase with its ∼50% increase in the chromosomal DNA mass (Fig. 1A).To investigate the role of the LMW-dT pool in TLD, we started by developing a simple protocol to extract the LMW-dT pool from growing cells and to compare it to the (HMW) chromosomal dT content. Here we show that early on during T-starvation the pool of dTDP-sugars becomes the major source of dTTP for the chromosomal DNA replication. This unexpected rebalancing of the dTTP pool with the help of cell envelope metabolism delays TLD and prevents T-hyperstarvation, a significantly more lethal phenomenon accompanied by complete chromosome destruction and cell lysis.     

The Intravascular Survival of Neutrophils Labeled In Vivo

The survival of blood neutrophils labeledin vivo was studied in the calf. Disappearance of labeled neutrophils from the bloodof calves was followed after a period ofcross circulation with their chimeric, immunologically tolerant twins, which hadbeen given tritiated thymidine 6 dayspreviously. Under these conditions, neutrophils were shown to leave the blood ina random exponential fashion, with half-disappearance times of between 6.4 and7.5 hr. Hydrocortisone given to one calf 48hr after cross circulation caused a neutrophilic leukocytosis, during which substantial numbers of labeled neutrophils reappeared in the blood.

Submitted on June 18, 1973 Revised on September 21, 1973 Accepted on September 22, 1973