Implementing Evidence Based Practices for Children's Mental Health: A Case Study in Implementing Modular Treatments in Community Mental Health.

There is strong enthusiasm for utilizing implementation science in the implementation of evidence-based programs in children's community mental health, but there remains work to be done to improve the process. Despite the proliferation of implementation frameworks, there is limited literature providing case examples of overcoming implementation barriers. This article examines whether the use of three implementations strategies, a structured training and coaching program, the use of professional development portfolios for coaching, and a progress monitoring data system, help to overcome barriers to implementation by facilitating four implementation drivers at a community mental health agency. Results suggest that implementation is a process of recognizing and adapting to both predictable and unpredictable barriers. Furthermore, the use of these implementation strategies is important in improving implementation outcomes.

Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Low utilization of prenatal and pre-implantation genetic diagnosis in Huntington disease - risk discounting in preventive genetics.

Huntington disease (HD) is a late-onset, fatal neurodegenerative disorder caused by a (CAG) triplet repeat expansion in the Huntingtin gene that enlarges during male meiosis. In 1996 in this journal, one of us (J. D. S.) presented a methodology to perform pre-implantation genetic diagnosis in families at-risk for HD without revealing the genetic status of the at-risk parent. Despite the introduction of accurate prenatal and pre-implantation genetic testing which can prevent transmission of the abnormal HD gene in the family permanently, utilization of these options is extremely low. In this article, we examine the decision-making process regarding genetic testing in families with HD and discuss the possible reasons for the low uptake among this group.

The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

Assessing practical implementation of modular psychotherapy for youth in community-based settings using benchmarking.

Background: Achieving high quality outcomes in a community context requires the strategic coordination of many activities in a service system, involving families, clinicians, supervisors, and administrators. In modern implementation trials, the therapy itself is guided by a treatment manual; however, structured supports for other parts of the service system may remain less well-articulated (e.g., supervision, administrative policies for planning and review, information/feedback flow, resource availability). This implementation trial investigated how a psychosocial intervention performed when those non-therapy supports were not structured by a research team, but were instead provided as part of a scalable industrial implementation, testing whether outcomes achieved would meet benchmarks from published research trials. Method: In this single-arm observational benchmarking study, a total of 59 community clinicians were trained in the Modular Approach to Therapy for Children (MATCH) treatment program. These clinicians delivered MATCH treatment to 166 youth ages 6 to 17 naturally presenting for psychotherapy services. Clinicians received substantially fewer supports from the treatment developers or research team than in the original MATCH trials and instead relied on explicit process management tools to facilitate implementation. Prior RCTs of MATCH were used to benchmark the results of the current initiative. Client improvement was assessed using the Top Problems Assessment and Brief Problem Monitor. Results: Analysis of client symptom change indicated that youth experienced improvement equal to or better than the experimental condition in published research trials. Similarly, caregiver-reported outcomes were generally comparable to those in published trials. Conclusions: Although results must be interpreted cautiously, they support the feasibility of using process management tools to facilitate the successful implementation of MATCH outside the context of a formal research or funded implementation trial. Further, these results illustrate the value of benchmarking as a method to evaluation industrial implementation efforts.Plain Language Summary: Randomized effectiveness trials are inclusive of clinicians and cases that are routinely encountered in community-based settings, while continuing to rely on the research team for both clinical and administrative guidance. As a result, the field still struggles to understand what might be needed to support sustainable implementation and how interventions will perform when brought to scale in community settings without those clinical trial supports. Alternative approaches are needed to delineate and provide the clinical and operational support needed for implementation and to efficiently evaluate how evidence-based treatments perform. Benchmarking findings in the community against findings of more rigorous clinical trials is one such approach. This paper offers two main contributions to the literature. First, it provides an example of how benchmarking is used to evaluate how the Modular Approach to Therapy for Children (MATCH) treatment program performed outside the context of a research trial. Second, this study demonstrates that MATCH produced comparable symptom improvements to those seen in the original research trials and describes the implementation strategies associated with this success. In particular, although clinicians in this study had less rigorous expert clinical supervision as compared with the original trials, clinicians were provided with process management tools to support implementation. This study highlights the importance of evaluating the performance of intervention programs when brought to scale in community-based settings. This study also provides support for the use of process management tools to assist providers in effective implementation.

Transcrural coeliac plexus block simulated on 200 computed tomography images.

BACKGROUND: We previously reported a modified transcrural coeliac plexus block (tCPB) case, using parameters obtained from a pre-procedural computed tomography (CT) image of that patient for the subsequent tCPB under fluoroscopy. In this study, we performed the same tCPB simulation on 200 CT images to determine optimal needle placement parameters with a comparison to the classic technique. METHODS: On each CT image across the coeliac trunk, the tCPB was simulated on both sides with the needle trajectory placed between the vertebra and organs targeting the coeliac trunk. The distances of the needle entrance from the midline, the insertion angles, and depths were measured and analysed in the groups: laterality, gender, intra-abdominal condition, and coeliac-aortic-vertebral (c-a-v) distribution. RESULTS: Thirty placements failed to avoid organ penetration. The left-sided placements required a shorter distance, 3.58 (1.02) cm, with a steeper angle, 84.1° (6.0°), than those for the right placements [7.04 (1.56) cm, 61.1° (6.2°)] (P<0.00001). The shortest distances, 3.1 (0.8) cm, with the steepest angles, 87.7° (4.5°), were seen in the patients whose c-a-v distributions were left-left located (P<0.00001). Males required longer distance for needle insertion (P≤0.05). Cancer patients required a shorter distance with a steeper angle for the right needle placements (P<0.05). CONCLUSIONS: Needle placement parameters for tCPB vary in laterality, gender, pathologies, and c-a-v distributions. We would advocate a simulated block on individual patient's CT image to obtain relevant measurements for subsequent tCPB, although a clinical outcome study is warranted.

The Winning with Wellness pilot project: rural Appalachian elementary student physical activity and eating behaviors and program implementation 4 years later.

School-based efforts to promote physical activity and healthier eating are a potentially effective approach to decreasing child obesity in rural populations. This article describes follow-up data on student activity and eating behaviors 4 years after implementation of the Winning with Wellness obesity prevention initiative. This project was based on the Centers for Disease Control and Prevention's coordinated school health model and used a community-based participatory research approach to address health behaviors in rural Appalachian elementary students. Results suggest significant increases in daily pedometer steps and healthier food selections by students as well as teacher support for continued health promotion efforts.

Multicenter long-term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin.

BACKGROUND AND PURPOSE: Long-term follow-up of children with idiopathic West syndrome (WS) treated with adrenocorticotropic hormone (ACTH) or vigabatrin. METHODS: Records of 28 normal magnetic resonance imaging (MRI) WS cases were reviewed for seizure development and cognitive outcome in relation to treatment type and lag. RESULTS: Average age at disease onset was 5.5 months, and average lag time to treatment was 25 days. Fourteen patients were treated with ACTH (eight early and six late), and 14 with vigabatrin (without delay). Response rates were 88% for ACTH and 80% for vigabatrin. Short-term outcomes for seizure cessation and electroencephalography normalization were identical between the groups. In the long-term, early ACTH treatment was better than the rest combined. Average follow-up time was 9 years. A normal cognitive outcome was achieved in 100% of the early-ACTH group, 67% of the late-ACTH group and 54% of the vigabatrin group (P = 0.03). Seizures subsequently developed in 54% of the vigabatrin group, in 33% of the late ACTH group, and 0% of the early ACTH group (P < 0.05). CONCLUSIONS: Idiopathic WS with normal MRI is associated with a good cognitive outcome. Early ACTH treatment, administered within 1 month, yields a better cognitive and seizure outcome than vigabatrin or late ACTH.

The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003.

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

A coordinated school health approach to obesity prevention among Appalachian youth: the Winning with Wellness Pilot Project.

Childhood obesity has been an increasing problem in the United States, especially in rural areas. Effective prevention approaches are needed. This article describes the development, implementation, effectiveness, feasibility, and sustainability of a school-based obesity prevention pilot project, Winning with Wellness. The program was based on the coordinated school health model and included a community-based participatory research approach aimed at promoting healthy eating and physical activity in a rural Appalachian elementary school. Findings from this preliminary project revealed improvements in nutrition offerings and increased physical activity during the school day. In addition, the program was found to be acceptable to teachers, successfully implemented utilizing both existing and newly developed resources, and sustainable as evidenced in continued practice and expansion to other area schools.

Functional characterization of the Bcl-2 gene family in the zebrafish.

Members of the Bcl-2 protein family control the intrinsic apoptosis pathway. To evaluate the importance of this family in vertebrate development, we investigated it in the zebrafish (Danio rerio). We found that the zebrafish genome encodes structural and functional homologs of most mammalian Bcl-2 family members, including multi-Bcl-2-homology (BH) domain proteins and BH3-only proteins. Apoptosis induction by gamma-irradiation required zBax1 and zPuma, and could be prevented by overexpression of homologs of prosurvival Bcl-2 family members. Surprisingly, zebrafish Bax2 (zBax2) was homologous to mammalian Bax by sequence and synteny, yet demonstrated functional conservation with human Bak. Morpholino knockdown of both zMcl-1a and zMcl-1b revealed their critical role in early embryonic zebrafish development, and in the modulation of apoptosis activation through the extrinsic pathway. These data indicate substantial functional similarity between zebrafish and mammalian Bcl-2 family members, and establish the zebrafish as a relevant model for studying the intrinsic apoptosis pathway.

Delineation of the cell-extrinsic apoptosis pathway in the zebrafish.

The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression.

Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

Effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in patients at high risk for colon cancer.

High fecal pH level has been suggested as a risk factor for colorectal cancer. We previously demonstrated that, although sodium sulfate did not affect the proliferation rate of colonic mucosa, as indicated by thymidine-labeling index, it did lower fecal pH in subjects at average risk for colon cancer. In the current study, we evaluated the effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in subjects at high risk for colon cancer. Fifty-seven patients who had had colonic polyps removed were randomly assigned to two groups to receive either sodium sulfate (27 patients) or a placebo (25 patients) at a mean dose of 4 g/day for 14 days. Age, sex, height, and weight were comparable in both groups. Before intervention, levels of fecal pH were similar in the two groups, but after intervention, fecal pH was reduced only in the sodium sulfate group (mean decrease, 0.3 U; P less than .01). Thymidine-labeling index (number of labeled cells per number of cells counted) was similar in the two groups prior to intervention and did not change significantly after intervention (mean increase, 0.9%; P = .35). Regression analysis revealed no correlation between the change in labeling index and the change in fecal pH. We conclude that high fecal pH level is only indirectly associated with the development of colon cancer and, therefore, may be a secondary, rather than a primary, measure of cancer risk.

Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons.

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomatous polyps, the precursors to colorectal cancer. APC and ras gene mutations have been shown to be important early molecular events in the development of colorectal neoplasms. The objective of this study was to establish the nature and frequency of these two genetic alterations in ACF harvested from human colorectal resection specimens. One hundred and fifty-four ACF comprised of between 1 and 56 crypts were harvested from the grossly normal mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colons were screened for the presence of K-ras codon 12 mutations with a polymerase chain reaction/restriction enzyme-based method. The APC gene mutation cluster region was screened in 65 ACF from 20 colons using a polymerase chain reaction/single strand conformation polymorphism technique. Putative mutations were confirmed by direct sequencing. K-ras codon 12 mutations were identified in 13% (16 of 125) of ACF. We also identified APC mutations in 4.6% (3 of 65) of ACF. The results of this study demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precursor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.

Comparative dual label study of first and second generation antitumor-associated glycoprotein-72 monoclonal antibodies in colorectal cancer patients.

Radiolabeled first-generation anti-tumor-associated glycoprotein-72 (TAG-72) monoclonal antibody (MAb), B72.3, has proven useful in detecting primary and secondary colorectal carcinoma. It has been anticipated that the development of second-generation, higher affinity, anti-TAG-72 MAbs, CC49 and CC83, would be of greater use in cancer detection and of value in radioimmunotherapy of human cancer. We compared the pharmacokinetics, biodistribution, and immune responses of 131I-labeled CC49 and CC83 to 125I-labeled B72.3 by preoperatively coninjecting dual-labeled MAbs into 16 colorectal cancer patients. The imaging properties of radiolabeled CC49 and CC83 were also assessed. Pharmacokinetics of all three MAbs were identical, and there were no differences in the uptake of any of three MAbs in tumor and normal tissues. Maximum tumor uptake was 0.0041% of the injected dose/g for 125I-B72.3, 0.0024% for 131I-CC49, and 0.0029% for 131I-CC83. Radiolabeled CC49 and CC83 detected most known tumor sites on scintigrams without any clear advantage for either MAb. Nonspecific splenic and testicular uptake was frequently observed. Anti-idiotypic human anti-mouse antibody responses were seen more frequently with B72.3 than with CC49 or CC83. We conclude that higher affinity, radiolabeled anti-TAG-72 MAbs can detect colorectal cancer but do not penetrate these tumors more effectively than B72.3. Improvements in tumor detection and radioimmunotherapeutic strategies will likely require the administration of smaller fragments of MAb molecules or novel delivery systems rather than the continued development of higher affinity MAbs.

Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome.

Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Across evolution, maternal care is a key source of environmental sensory signals to the developing brain, and a vast body of work has linked quantitative and qualitative aspects of maternal care to emotional outcome in children and animals. However, the fundamental properties of maternal signals, that promote advantageous vs pathological outcomes in the offspring, are unknown and have been a topic of intense study. We studied emotional outcomes of adolescent rats reared under routine or impoverished environments, and used mathematical approaches to analyze the nurturing behaviors of the dams. Unexpectedly, whereas the quantity and typical qualities of maternal care behaviors were indistinguishable in the two environments, their patterns and rhythms differed drastically and influenced emotional outcomes. Specifically, unpredictable, fragmented maternal care patterns translated into high-entropy rates of sensory signals to the offspring in the impoverished cages. During adolescence, these offspring had significant reductions in sucrose preference and in peer-play, two independent measures of the ability to experience pleasure. This adolescent anhedonia, often a harbinger of later depression, was not accompanied by measures of anxiety or helplessness. Dopaminergic pleasure circuits underlying anhedonia are engaged by predictable sequences of events, and predictable sensory signals during neonatal periods may be critical for their maturation. Conversely, unpredictability maternal-derived signals may disrupt these developmental processes, provoking anhedonia. In sum, high-entropy and fragmented patterns of maternal-derived sensory input to the developing brain predicts, and might promote, the development of anhedonia in rodents, with potential clinical implications.

Myocardial viability assessed by positron emission tomography in infants and children after the arterial switch operation and suspected infarction.

OBJECTIVES: The aim of the study was to assess regional glucose metabolism and contractile function by gated positron emission tomography using fluoro-18-deoxyglucose (FDG-PET) in pediatric patients after the arterial switch operation and suspected myocardial infarction. BACKGROUND: Morbidity and mortality after the arterial switch operation for transposition of the great arteries are often related to impaired coronary function. Justification of high-risk revascularization procedure in infancy requires thorough evaluation of myocardial viability. Although PET is state-of-the-art for evaluation of myocardial viability in adults there are no reports on its impact and feasibility in infants and children. METHODS: We applied electrocardiogram-triggered FDG-PET for assessment of metabolic and functional status of the myocardium in seven infants and seven children. Glucose metabolism, wall motion and wall thickening were evaluated visually and quantitatively on the basis of parametric 3-D images. Additionally, single-photon emission computed tomography perfusion scan was performed in six children. RESULTS: In two of seven infants, FDG-PET demonstrated viable myocardium in akinetic or hypokinetic regions corresponding to a coronary artery stenosis or occlusion. Therefore, indication for revascularization was derived from this finding. In six of the seven children, impaired glucose uptake reflecting myocardial scarring was present. Two patients had pathological findings on coronary angiography and signs of ischemia but were not suitable for revascularization. CONCLUSIONS: Myocardial viability and contractile function can be assessed simultaneously by gated FDG-PET even in infant hearts. This method contributes pertinent information to guide further therapy after the arterial switch operation and suspected myocardial infarction.

Antibodies to glutamate receptor subtype 3 (GluR3) are found in some patients suffering from epilepsy as the main disease, but not in patients whose epilepsy accompanies antiphospholipid syndrome or Sneddon's syndrome.

Autoantibodies (Ab's) to the "B" peptide (amino acids 372-395) of glutamate/AMPA receptor subtype 3 (GluR3) are found in serum and cerebrospinal fluid of some patients with different types of epilepsy. Since such anti-GluR3B Ab's can activate and/or kill neurons in vitro and in vivo, they may contribute to epilepsy. To investigate whether anti-GluR3B Ab's may also be relevant to epilepsy when it accompanies some autoimmune-diseases, we tested for these Ab's in patients suffering from epilepsy that accompanies anti-phospholipid syndrome (APS) or Sneddon's syndrome (SNS), both being autoimmune-diseases with frequent neurological complications. We tested 77 pediatric patients whose epilepsy is their main disease; 31 adult patients whose epilepsy accompanies APS (primary or SLE-associated) or SNS; 45 epilepsy-free APS and SNS patients; and 90 healthy controls. Compared to the controls, significantly elevated anti-GluR3B Ab's were found in 22/77 (29%) patients whose epilepsy is their main disease, but in none of the patients whose seizures accompany APS or SNS. Yet, all the APS and SNS patients harbored the characteristic anti-phospholipid Ab's (aPL), directed against cardiolipin and beta2-glycoprotein I, and had lupus anti-coagulant. Thus, anti-GluR3B Ab's are not crossreactive with aPL, and not produced as a non-specific consequence of seizures on the one hand, or autoimmune-diseases on the other. Taken together with new findings accumulated recently in our lab, we suggest that anti-GluR3B Ab's are produced primarily in the periphery due to specific/non-specific "irritation" of the immune system, and that once they reach the brain via a leaky blood-brain barrier they may cause neuronal/glial damage and facilitate the outburst of epilepsy and additional neurological abnormalities. In contrast, the presence of anti-GluR3B Ab's does not seem to increase the probability of developing APS, SNS or the seizures that often accompany these autoimmune-diseases. These findings may have important diagnostic and therapeutic implications.

National trends in the concurrence of tuberculosis and acquired immunodeficiency syndrome.

BACKGROUND: Elucidation of the relationship between tuberculosis (TB) and the acquired immunodeficiency syndrome (AIDS) is needed to help predict the future course of these two epidemics. We examined nationwide trends in TB and AIDS occurring in the same individual. METHODS: Health departments in the 50 states, District of Columbia, Puerto Rico, and Guam matched their TB and AIDS case registries to determine the number of persons diagnosed with both TB and AIDS. The number of AIDS cases, TB cases, AIDS cases that matched with a TB case on the TB registry, and TB cases that matched with an AIDS case on the AIDS registry were reported to the Centers for Disease Control and Prevention, Atlanta, Ga. Data were analyzed for the period from 1981 through 1991. The number of matched TB-AIDS cases was compared with a modeled estimate of excess TB cases during the period from 1985 through 1990. RESULTS: From 1981 through 1991 there were 11,299 AIDS cases that matched with a TB case on the TB registry, representing 5.1% (geographic variation, 0% to 9.3%) of AIDS cases. The TB cases that matched with an AIDS case on the AIDS registry represent 4.3% (geographic variation, 0% to 15.1%) of TB cases from 1981 through 1991. Since 1981, matched TB and AIDS cases increased yearly through 1990. When examined by year of AIDS report, the percentage of AIDS cases that matched with a TB case increased from 1981 to 1982 (1.9% to 5.1%), remained fairly constant from 1983 through 1987 (range, 4.0% to 4.7%), increased in 1988 (5.4%) after extrapulmonary TB was added to the AIDS case definition, and increased slightly through 1990 (5.8%). When examined by year of TB report, the percentage of TB cases that matched with an AIDS case increased steadily from 1981 through 1990 (0.1% to 9.5%). The calculated fraction of excess TB cases during the period from 1985 through 1990 that could be accounted for by identified TB-AIDS cases was 30%. CONCLUSION: The risk of TB or AIDS among persons already diagnosed with one disease is much higher than among the general population. The percentage of persons with TB who are also diagnosed with AIDS has been increasing rapidly. Human immunodeficiency virus-induced immunosuppression is an important contributor to the TB epidemic and probably accounts for a minimum of 30% of excess TB cases during the period from 1985 through 1990.