Adjunctive cognitive training with exposure enhances fear and neural outcomes in social anxiety.

Exposure-based cognitive behavioral therapy (CBT) is the gold standard for treating social anxiety disorder (SAD), yet response is not universal. CBT is thought to operate via extinction-related learning during exposure, which in turn relies on cognitive processes such as working memory. The present proof-of-concept study investigates the potential for training working memory to improve anxiety related outcomes following exposure. Thirty-three adults with elevated social anxiety were randomized to complete a working memory training or sham training condition. Post-training, participants completed a working memory assessment, speech exposure session, and two fMRI tasks. Participants who received working memory training demonstrated lower distress ratings by the end of the speech exposures and better performance on the fMRI working memory task than those in sham. Working memory training completers had greater neural activation in frontoparietal regions during an in-scanner working memory task and exhibited less neural activation in the fusiform gyrus in response to an emotional face processing task than those in sham. Adding working memory training to exposure procedures could strengthen functioning of frontoparietal regions and alter emotional processing - key mechanisms implicated in extinction learning. Findings provide preliminary evidence that training working memory in conjunction with exposure may enhance exposure success.

Change in neural response during emotion regulation is associated with symptom reduction in cognitive behavioral therapy for anxiety disorders.

BACKGROUND: Anxiety disorders are debilitating conditions that can be treated with cognitive behavioral therapy (CBT). Increased understanding of the neurobiological correlates of CBT may inform treatment improvements and personalization. Prior neuroimaging studies point to treatment-related changes in anterior cingulate, insula, and other prefrontal regions during emotional processing, yet to date the impact of CBT on neural substrates of "top down" emotion regulation remains understudied. We examined the relationship between symptom changes assessed over the course of CBT treatment sessions and pre- to post-treatment neural change during an emotion regulation task. METHOD: In the current study, a sample of 30 participants with panic disorder or generalized anxiety disorder completed a reappraisal-based emotion regulation task while undergoing fMRI before and after completing CBT. RESULTS: Reduced activation in the parahippocampal gyrus was observed from pre- to post-treatment during periods of reducing versus maintaining emotion. Parahippocampal activation was associated with change in symptoms over the course of treatment and post-treatment responder status. Results suggest that, from pre- to post-CBT, participants demonstrated downregulation of neural responses during effortful cognitive emotion regulation. LIMITATIONS: Effects were not observed in frontoparietal systems as would be hypothesized based on prior literature, suggesting that treatment-related change could occur outside of fronto-parietal and limbic regions that are central to most models of neural functioning in anxiety disorders. CONCLUSIONS: Continued work is needed to better understand how CBT affects cognitive control and memory processes that are hypothesized to support reappraisal as a strategy for emotion regulation.

Resting-State Functional MRI: Everything That Nonexperts Have Always Wanted to Know.

Resting-state fMRI was first described by Biswal et al in 1995 and has since then been widely used in both healthy subjects and patients with various neurologic, neurosurgical, and psychiatric disorders. As opposed to paradigm- or task-based functional MR imaging, resting-state fMRI does not require subjects to perform any specific task. The low-frequency oscillations of the resting-state fMRI signal have been shown to relate to the spontaneous neural activity. There are many ways to analyze resting-state fMRI data. In this review article, we will briefly describe a few of these and highlight the advantages and limitations of each. This description is to facilitate the adoption and use of resting-state fMRI in the clinical setting, helping neuroradiologists become familiar with these techniques and applying them for the care of patients with neurologic and psychiatric diseases.

Quantifying person-level brain network functioning to facilitate clinical translation.

Although advances in neuroimaging have yielded insights into the intrinsic organization of human brain networks and their relevance to psychiatric and neurological disorders, there has been no translation of these insights into clinical practice. One necessary step toward clinical translation is identifying a summary metric of network function that is reproducible, reliable, and has known normative data, analogous to normed neuropsychological tests. Our aim was therefore to establish the proof of principle for such a metric, focusing on the default mode network (DMN). We compared three candidate summary metrics: global clustering coefficient, characteristic path length, and average connectivity. Across three samples totaling 322 healthy, mostly Caucasian adults, average connectivity performed best, with good internal consistency (Cronbach's α=0.69-0.70) and adequate eight-week test-retest reliability (intra-class coefficient=0.62 in a subsample N=65). We therefore present normative data for average connectivity of the DMN and its sub-networks. These proof of principle results are an important first step for the translation of neuroimaging to clinical practice. Ultimately, a normed summary metric will allow a single patient's DMN function to be quantified and interpreted relative to normative peers.

Intolerance of uncertainty as a mediator of reductions in worry in a cognitive behavioral treatment program for generalized anxiety disorder.

Growing evidence suggests that intolerance of uncertainty (IU) is a cognitive vulnerability that is a central feature across diverse anxiety disorders, including generalized anxiety disorder (GAD). Although cognitive behavioral therapy (CBT) has been shown to reduce IU, it remains to be established whether or not reductions in IU mediate reductions in worry. This study examined the process of change in IU and worry in a sample of 28 individuals with GAD who completed CBT. Changes in IU and worry, assessed bi-weekly during treatment, were analyzed using multilevel mediation models. Results revealed that change in IU mediated change in worry (ab = -0.20; 95% CI [-.35, -.09]), but change in worry did not mediate change in IU (ab = -0.16; 95% CI [-.06, .12]). Findings indicated that reductions in IU accounted for 59% of the reductions in worry observed over the course of treatment, suggesting that changes in IU are not simply concomitants of changes in worry. Findings support the idea that IU is a critical construct underlying GAD.

Different suicide inactivation processes for the peroxidase and cyclooxygenase activities of prostaglandin endoperoxide H synthase-1.

Prostaglandin endoperoxide H synthases (PGHSs)-1 and -2 have a cyclooxygenase (COX) activity involved in forming prostaglandin G2 (PGG2) from arachidonic acid and an associated peroxidase (POX) activity that reduces PGG2 to PGH2. Suicide inactivation processes are observed for both POX and COX reactions. Here we report COX reaction conditions for PGHS-1 under which complete COX inactivation occurs but with > or = 60% retention of POX activity. The rates of POX inactivation were compared for native oPGHS-1 versus Y385F oPGHS-1, a mutant that cannot form the Tyr385 radical of COX Intermediate II; the rates were the same for both native and Y385F oPGHS-1. Our data indicate that a COX Intermediate II/acyl or product complex is the precursor in COX inactivation. However, another species, probably an Intermediate II-like species but with a radical centered on a tyrosine other than Tyr385, is the immediate precursor for POX inactivation.

The economic impact of breastfeeding.

Although breastfeeding is well accepted as the optimal method of infant feeding, the US failed to reach the goals set for the year 2000. Support from employers, health insurers, health providers, and society are required to reach the goals set forth in Healthy People 2010-75% of mothers initiate breastfeeding, 50% of infants still receive breast milk at 6 months, and 25% of infants are still breastfed at 1 year of age. In today's era of cost accountability and economic competition, these groups likely will desire information regarding the financial effects of breastfeeding and breastfeeding promotion from their perspectives. Although much research still is needed in this area, evidence suggests that a significant return on investment is likely with breastfeeding promotion. Also, the finances of health care must be viewed within the concept of value. In health care, value can be thought of as the cost required to achieve a specified outcome. In lay terms, this can be thought of as "how much bang we get for our buck." Breastfeeding clearly improves the health of infants and mothers and seems to result in cost savings for parents, insurers, employers, and society, which means that the medical and economic value of breastfeeding is high. To reap the health and economic benefits associated with breastfeeding, society must support breastfeeding promotion, which most likely will necessitate a coordinated US breastfeeding program. The US government is in a unique position to accomplish this goal as it views the associated costs from the joint perspectives of employer, health insurer, medical provider, and society. Through support of such a program, the US government likely will benefit significantly by improving the health of children and its financial bottom line.

Siblings, day-care attendance, and the risk of asthma and wheezing during childhood.

BACKGROUND: Young children with older siblings and those who attend day care are at increased risk for infections, which in turn may protect against the development of allergic diseases, including asthma. However, the results of studies examining the relation between exposure to other children and the subsequent development of asthma have been conflicting. METHODS: In a study involving 1035 children followed since birth as part of the Tucson Children's Respiratory Study, we determined the incidence of asthma (defined as at least one episode of asthma diagnosed by a physician when the child was 6 to 13 years old) and the prevalence of frequent wheezing (more than three wheezing episodes during the preceding year) in relation to the number of siblings at home and in relation to attendance at day care during infancy. RESULTS: The presence of one or more older siblings at home protected against the development of asthma (adjusted relative risk for each additional older sibling, 0.8; 95 percent confidence interval, 0.7 to 1.0; P=0.04), as did attendance at day care during the first six months of life (adjusted relative risk, 0.4; 95 percent confidence interval, 0.2 to 1.0; P=0.04). Children with more exposure to other children at home or at day care were more likely to have frequent wheezing at the age of 2 years than children with little or no exposure (adjusted relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) but were less likely to have frequent wheezing from the age of 6 (adjusted relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0; P=0.03) through the age of 13 (adjusted relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). CONCLUSIONS: Exposure of young children to older children at home or to other children at day care protects against the development of asthma and frequent wheezing later in childhood.

Office laboratory procedures, office economics, parenting and parent education, and urinary tract infection.

These authors review four areas of office pediatric practice: office laboratory procedures, office economics, parenting and parent education, and urinary tract infections. Thomas Ball reviews the literature published this past year on physician office laboratories, with updates on the Clinical Laboratories Improvement Amendments, laboratory utilization, and office diagnosis of infectious mononucleosis. Eve Shapiro offers an update on office economics, discussing physician organizations and managed care, and a medical ethics evaluation of medical economics. Burris Duncan provides an update on parenting and parent education, with emphasis on defining "the best interests of the child." Richard Wahl summarizes the past year's publications on pediatric urinary tract infections, reviewing the circumcision debate, dysfunctional voiding, vesicoureteral reflux, and the diagnosis and follow-up of acute pyelonephritis.

Health care costs of formula-feeding in the first year of life.

OBJECTIVE: To determine the excess cost of health care services for three illnesses in formula-fed infants in the first year of life, after adjusting for potential confounders. METHODS: Frequency of health service utilization for three illnesses (lower respiratory tract illnesses, otitis media, and gastrointestinal illness) in the first year of life was assessed in relation to duration of exclusive breastfeeding in the Tucson Children's Respiratory Study (n = 944) and the Dundee Community Study (Scottish study, n = 644). Infants in both studies were healthy at birth and represented nonselected, population-based samples. Children were classified as never breastfed, partially breastfed, or exclusively breastfed, based on their feeding status during the first 3 months of life. Frequency of office visits and hospitalizations for the three illnesses was adjusted for maternal education and maternal smoking, using analysis of variance. Cost estimates, from the perspective of the health care provider/payer, were based on the direct medical costs during 1995 within a large managed care health care system. RESULTS: In the first year of life, after adjusting for confounders, there were 2033 excess office visits, 212 excess days of hospitalization, and 609 excess prescriptions for these three illnesses per 1000 never-breastfed infants compared with 1000 infants exclusively breastfed for at least 3 months. These additional health care services cost the managed care health system between $331 and $475 per never-breastfed infant during the first year of life. CONCLUSIONS: In addition to having more illnesses, formula-fed infants cost the health care system money. Health care plans will likely realize substantial savings, as well as providing improved care, by supporting and promoting exclusive breastfeeding.

Transformation of the limonene synthase gene into peppermint (Mentha piperita L.) and preliminary studies on the essential oil profiles of single transgenic plants.

Agrobacterium-mediated and direct gene transfer into protoplasts using PEG were both successfully used to produce stable, transformed peppermint plants (Mentha×piperita L. cultivar Black Mitcham) with the limonene synthase gene. Stem internode explants found to possess a high level of organogenesis through adventitious shoot formation were subjected to Agrobacterium tumefaciens disarmed strain GV3101 (pMP90). Following the development of an efficient protoplast-to-plant cycle from stem-isolated protoplasts, they were used in direct gene transformations. In both cases the binary vector pGA643 carrying the nptII/GUS genes, both driven by the CaMV35S promoter, was used in preliminary plant-transformation studies. Later, GUS was replaced with the limonene synthase gene. Kanamycin was used as a selective agent in all transformation experiments to obtain both transformed protoplast-derived calli as well as putative transgenic shoots regenerated from internode explants. Both types of transformation resulted in transgenic plants which were detected using PCR and confirmed by Southern-blot hybridizations. Southern analysis revealed that the method of Agrobacterium-mediated transformation is superior to the direct DNA uptake into protoplasts with regard to the stability of the insert during the transformation event. Single transgenic plants were grown to 10% flowering in a greenhouse and the plants derived both by the Agrobacterium and the protoplast-derived methods were generally observed to have essential oil profiles characterized by a high-menthone, low-menthol, high-menthofuran and -pulegone content in comparison to a typical mid-west peppermint. Limonene varied only slightly, around 1.2%, in transgenic plants produced by both methods.

Office laboratory procedures, office economics, patient and parent education, and urinary tract infection.

This review provides an update on four areas of office practice: office laboratory procedures, office economics, patient and parent education, and urinary tract infection. Thomas Ball reviews physician office laboratories, with updates on the Clinical Laboratory Improvement Amendments, office proficiency testing, and office testing for streptococcal pharyngitis and Helicobacter pylori. Eve Shapiro reports on office economics, focusing on the influence of managed care on pediatric practice. Burris Duncan provides a review of the new National Institutes of Health asthma guidelines, and challenges us to become more involved in patient education. Richard Wahl reviews urinary tract infections, vesicoureteral reflux, dysfunctional voiding, and appropriate imaging studies. Our approach is to provide pediatricians with useful and practical information for their office practices.

Office laboratory procedures, office economics, patient and parent education, and urinary tract infection.

This review provides an update on four important areas in office pediatrics: office laboratory procedures, office economics, patient and parent education, and urinary tract infection. Ball reviews new information about physician office laboratories, with updates on the Clinical Laboratory Improvement Amendments, streptococcal pharyngitis, urinalyses, office stool examination, and information on Helicobacter pylori serology. Shapiro reports on office economics, highlighting new office technologies, physician operated networks, managed care, recent legislation, and the "cost versus quality" debate. Duncan provides a very thought provoking essay on parent and patient education, focusing on improving parenting skills. Wahl reviews the recent literature on urinary tract infections, with emphasis on host-bacteria interactions, diagnostic evaluations, pyelonephritis, renal cortical scarring, and long term follow-up of vesicoureteral reflux. We hope we have provided pediatricians with useful and practical information for their office practices.

Missed opportunities for vaccination and the delivery of preventive care.

OBJECTIVES: To evaluate the relative impact of 2 types of missed opportunities (MOs) for vaccination, acknowledged and unacknowledged, on the immunization status of children at 2 years of age and to measure the delivery of immunizations and health care maintenance (HCM) after these types of MOs. DESIGN: Case-control study. SETTING: A large multispecialty clinic serving primarily a managed care population in Tucson, Ariz. PATIENTS: Charts of 1165 patients, ages 2 to 4 years, were reviewed for immunization status by 2 years of age. Of these patients, 652 had received all of their medical care at the clinic during their first 2 years of life. The 76 patients found to be underimmunized (UI) at 2 years of age and 76 controls, who were fully immunized (FI) by 2 years of age, frequency matched for age, were studied. MAIN OUTCOME MEASURES: The charts were reviewed for the following information: sex, age, immunizations received, HCM visits, sick visits, MOs, and pediatrician-patient interchange regarding immunization status during visits. RESULTS: Of the children who received all their care at the study site, 88% were FI. The mean number of MOs per patient occurring during the first 2 years of life was 5.8 for the UI children and 2.6 for the FI children. Only an unacknowledged MO, defined as a visit when the patient's immunization status was not reviewed, was associated with having a deficient immunization status at 2 years of age (4.6 vs 1.7, P < .001). Acknowledged MOs did not differ between UI and FI children (0.95 vs 0.76, P = .67). Immunizations were received at the subsequent visit (within a month) twice as often following a visit at which the child's deficient immunization status was acknowledged and a plan for follow-up made (P < .001). However, HCM was often not completed at the return visit. Following acknowledged MOs, patients did not return as directed 25% of the time for UI children and 5% of the time for FI children. Only 30% of FI patients completed the number of HCM visits recommended by the American Academy of Pediatrics. CONCLUSIONS: In the population studied, lack of review of the patients' immunization status was the primary cause of MOs to vaccinate. Although patients returned significantly more frequently when informed of their child's deficient immunization status, poor follow-up remained a significant problem in children who were eventually found to be lacking immunizations at 2 years of age.

Arm circumference v. arm circumference/head circumference ratio in the assessment of malnutrition in rural Malawian children.

The arm circumference/head circumference ratio (AC/HC) was compared with arm circumference (AC) alone in the diagnosis of protein-energy malnutrition (PEM) in 685 Malawian children between the ages of 3 and 48 months. The AC/HC ratio correlates well, r = 0.6863 (P < 0.001), with weight-for-age (WA). The sensitivity and specificity were calculated for both indicators compared to the NCHS reference standard of WA. Compared to 80 per cent WA, the 0.310 AC/HC cut-off was 92 per cent sensitive and 41 per cent specific, while the 0.290 AC/HC cut-off was 75 per cent sensitive and 74 per cent specific. AC alone in the 6-12-month-old children was 75 per cent sensitive and 89 per cent specific at a cut-off of 12.5 cm. In the children from 12 to 48 months with a cut-off of 13.5 cm the AC was 82 per cent sensitive and 70 per cent specific. The AC alone was more sensitive than AC/HC at all levels of specificity. Adding the HC to AC offered no advantage in screening for PEM in these children. In fact, if one were to use the standard 0.310 cut-off for AC/HC, the resulting low (41 per cent) specificity would identify such a large proportion of false positives as to make this ratio impractical for field use where it is most needed--in primary health care programmes with low resources which serve populations with high prevalences of PEM.

Technical grade but not recrystallized alpha-naphthylthiourea potentiates superoxide release by rat neutrophils stimulated in vitro by phorbol myristate acetate.

alpha-Naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion in rats. It has been suggested that ANTU pneumotoxicity may be mediated by blood neutrophils (PMNs) via the release of reactive oxygen species. Accordingly, we tested the effect of technical grade ANTU (tANTU) on the ability of rat peritoneal PMNs to release superoxide (O2-). tANTU did not itself stimulate O2- production by PMNs, but it increased the O2- released in response to PMN stimulation by phorbol myristate acetate (PMA). This effect was dependent upon the amount of tANTU added. In PMNs activated in vitro by a submaximal PMA stimulus, addition of 20 micrograms/ml tANTU doubled superoxide release. When tANTU was recrystallized from ethanol, the purified ANTU was not effective in potentiating the effect of PMA on PMNs. This suggests that an impurity in technical grade ANTU is capable of increasing O2- release by stimulated PMNs. tANTU and recrystallized ANTU caused similar pneumotoxicity in rats in vivo, suggesting that the unidentified impurity does not markedly influence the biologic effects of ANTU.

Induction and repression of nitrate reductase in Neurospora crassa.

Synthesis of wild-type Neurospora crassa assimilatory nitrate reductase is induced in the presence of nitrate ions and repressed in the presence of ammonium ions. Effects of several Neurospora mutations on the regulation of this enzyme are shown: (i) the mutants, nit-1 and nit-3, involving separate lesions, lack reduced nicotinamide adenine dinucleotide (NADPH)-nitrate reductase activity and at least one of three other activities associated with the wild-type enzyme. The two mutants do not require the presence of nitrate for induction of their aberrant nitrate reductases and are constitutive for their component nitrate reductase activities in the absence of ammonium ions. (ii) An analog of the wild-type enzyme (similar to the nit-1 enzyme) is formed when wild type is grown in a medium in which molybdenum has been replaced by vanadium or tungsten; the resulting enzyme lacks NADPH-nitrate reductase activity. Unlike nit-1, wild type produced this analog only in the presence of nitrate. Contaminating nitrate does not appear to be responsible for the observed mutants' activities. Nitrate reductase is proposed to be autoregulated. (iii) Mutants (am) lacking NADPH-dependent glutamate dehydrogenase activity partially escape ammonium repression of nitrate reductase. The presence of nitrate is required for the enzyme's induction. (iv) A double mutant, nit-1 am-2, proved to be an ideal test system to study the repressive effects of nitrogen-containing metabolites on the induction of nitrate reductase activity. The double mutant does not require nitrate for induction of nitrate reductase, and synthesis of the enzyme is not repressed by the presence of high concentrations of ammonium ions. It is, however, repressed by the presence of any one of six amino acids. Nitrogen metabolites (other than ammonium) appear to be responsible for the mediation of "ammonium repression."