Neuroinflammatory and morphological changes in late-life depression: the NIMROD study.

We studied neuroinflammation in individuals with late-life depression, as a risk factor for dementia, using [11C]PK11195 positron emission tomography (PET). Five older participants with major depression and 13 controls underwent PET and multimodal 3T magnetic resonance imaging (MRI), with blood taken to measure C-reactive protein (CRP). We found significantly higher CRP levels in those with late-life depression and raised [11C]PK11195 binding compared with controls in brain regions associated with depression, including subgenual anterior cingulate cortex, and significant hippocampal subfield atrophy in cornu ammonis 1 and subiculum. Our findings suggest neuroinflammation requires further investigation in late-life depression, both as a possible aetiological factor and a potential therapeutic target.

Cyclooxygenase-1 and -2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning.

BACKGROUND: The purpose of this study was to examine the effects of cyclooxygenase (COX) deficiency on baseline functional characteristics and on recovery of left ventricular developed pressure (LVDP) after 20 minutes of global ischemia and 40 minutes of reperfusion in untreated and preconditioned hearts. METHODS AND RESULTS: Compared with hearts from wild-type (WT) and COX-2(-/-) mice, baseline cardiac prostaglandin (PG) E(2) and 6-keto-PGF(1alpha) levels were significantly decreased in hearts from COX-1(-/-) mice. After ischemia, cardiac PGE(2) levels increased in WT, COX-1(-/-), and COX-2(-/-) mice (P<0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1(-/-) and COX-2(-/-) mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia significantly decreased LVDP recovery; however, perfusion of WT hearts with indomethacin for 40 minutes before ischemia did not significantly alter LVDP recovery. Postischemic recovery of LVDP in COX-1(-/-) and COX-2(-/-) was unchanged by perfusion with 5 micromol/L PGE(2), PGD(2), PGF(2alpha), or carboprostacyclin. Hearts from COX-2(-/-) mice showed an increase in ischemic contracture compared with hearts from WT and COX-1(-/-) mice; however, hearts did not differ in intracellular pH, ATP, or inorganic phosphate during ischemia. Ischemic preconditioning significantly improved postischemic LVDP recovery in COX-1(-/-), COX-2(-/-), and WT mice. CONCLUSIONS: Genetic disruption or 2-day chemical inhibition of COX-1 and COX-2 decreases recovery of LVDP after ischemia; however, acute perfusion with indomethacin is not detrimental. These data are consistent with protection due to the altered expression of some protein that is modulated by COX or its metabolites.

Dopamine-beta-hydroxylase in behaviorally disturbed youth. Relationship between teacher and parent ratings.

A series of neurotransmitters, metabolites, and enzymes considered relevant to emotional and behavioral disorders was studied in blood samples obtained from boys admitted to a residential setting because of disruptive or unmanageable behavior in their home environments. The youth were categorized into mainly prepubertal (under 12.0 years) and pubertal/post pubertal (12.0 years and over) groups. Behavior ratings of the younger group completed by parents revealed significant inverse correlations between several behavioral factors and dopamine-beta-hydroxylase (DBH) activity levels, notably in the aggressive behavior and antisocial domains. Teacher ratings completed after about 1 month of living in the residential setting also showed numerous significant, but positive, correlations between several behavior factors and DBH activity levels. Furthermore, teacher and parent ratings themselves often were significantly and inversely correlated. The findings related to DBH activity levels were strongest in the younger group of boys. The results are discussed in terms of the possibility that low DBH activity in boys reflects a vulnerability towards behavioral disorder, which in certain environments becomes manifested by conduct problems and antisocial behavior.

ATP, ADP, and magnesium mixed solutions: in vitro 31P NMR characterization and in vivo application to lens.

The difference between the 31P NMR resonance position of the beta-peak of ADP and the gamma-peak of ATP at a fixed monovalent ion concentration level and pH is shown in vitro to depend only on free magnesium concentration. This difference can vary by more than 1 ppm depending on the pH of the solution and free magnesium concentration. Using 31P NMR and ion-selective electrodes we have constructed experimental curves to show how calibration of experimental results can be achieved. Theoretical calculations can be used to predict the functional dependence of the chemical shift difference on the above parameters. However, using the reported ion dissociation constants the fit was not exact and the discrepancy increased at higher pH values. To demonstrate that this technique can yield valid in vivo results and to analyze a previously unreported system where free magnesium levels vary, sample spectra from lenses and enucleated eyes are given. The data show a disagreement between the present methods and the more conventional ATP method. The reason for this difference is not known although some possible reasons are suggested.

Aggressive behavior in youth: characteristics, outcome, and psychiatric diagnoses.

This study evaluated the characteristics and outcome of a group of children and adolescents treated in day hospital and inpatient settings. Severe aggressive/destructive behavior was present in about one-third of the sample and was more common in boys, in children and adolescents with history of parental substance abuse, and in those with a concurrent diagnosis of conduct disorder. Although both an admission diagnosis of conduct disorder and aggressive/destructive behavior as a preadmission variable predicted poor outcome, aggressive/destructive behavior was the more important of the two. Aggressive/destructive behavior in association with conduct disorder seems to confer an especially poor prognosis in hospital-treated youth.

Parental substance abuse and suspected child abuse/maltreatment predict outcome in children's inpatient treatment.

There has been relatively little empirical study of outcome for school aged children treated in psychiatric hospitals. In earlier studies, four preadmission variables were operationally defined and studied as hypothesized predictors of poor outcome in psychiatric day treatment by the criterion of recommended in-home or out-of-home placements on discharge. The preadmission variables are recent histories of severe aggression and suicidal ideation/behavior in the child and histories of parental substance abuse and reported suspicions of child abuse/maltreatment. In this study, the work has been extended to determine if these four preadmission factors relate to outcome of children treated in inpatient hospitalization. The findings indicate that the parent/family related variables, and not the child variables (nor child diagnosis), are significantly related to out-of-home recommended placements.

Sensation seeking in psychiatrically disturbed youth: relationship to biochemical parameters and behavior problems.

OBJECTIVE: Relatively little research has been conducted on the relationship of personality traits or behavioral tendencies with biological parameters in youth. This study was intended to determine whether relationships exist between self-reported sensation-seeking tendencies and biochemical parameters in boys. METHOD: Twenty-five male youth aged 8 to 15 years admitted to a residential diagnostic center because of noncompliant, disruptive, and/or antisocial behavior were studied. Biochemical parameters associated with sensation seeking in adults or antisocial behavior were measured along with diagnoses, behavior ratings, and self-reported sensation seeking. RESULTS: High sensation seeking, as assessed on a newly developed sensation-seeking scale for children, was inversely correlated with 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in the older youth (> or = 12.0 years) but not in the younger boys (< 12.0 years) in the group. Elevations on the sensation seeking scale also correlated marginally in these older youth with parent-reported problems on a behavior rating scale, reflecting "delinquent" behavioral tendencies. CONCLUSIONS: The findings support hypothesized noradrenergic dysregulation in some sensation-seeking persons (including youth > or = 12.0 years) and the relationship between high sensation-seeking tendencies and antisocial or disruptive behavioral disorder.

Dynamic frequency shifts of complexed ligands: An NMR study of D--1-13C,1-2H-glucose complexed to the Escherichia coli periplasmic glucose/galactose receptor.

The 13C multiplet structure of D--1-13C,1-2H-glucose complexed to the Escherichia coli periplasmic glucose/galactose receptor has been studied as a function of temperature. Asymmetric multiplet patterns observed are shown to arise from dynamic frequency shifts. Multiplet asymmetry contributions resulting from shift anisotropy-dipolar cross correlations were found to be small, with optimal fits of the data corresponding to small, negative values of the correlation factor, chiCD-CSA. Additional broadening at higher temperatures most probably results from ligand exchange between free and complexed states. Effects of internal motion are also considered theoretically, and indicate that the order parameter for the bound glucose is >/=0.9.

Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride.

An understanding of the distribution of manganese ions in the brain is of interest in connection with the development of an understanding of the neurotoxicity of this element. Information about the time dependent biodistribution of manganese ions in the brains of intact rats subsequent to single IP injections of MnCl2 has been obtained from magnetic resonance imaging (MRI) studies. The enhanced MRI contrast is based on the reduction in the spin lattice relaxation time (T1) of water protons which exchange into the coordination sphere of the manganese ions. These studies indicate rapid and significant accumulations of water accessible manganese in the ventricles, the pineal gland, and the pituitary gland. The rapid appearance of high levels of manganese in the ventricular cerebrospinal fluid indicates that manganese readily crosses the filtration barrier of the choroid plexus and is thereafter apparently absorbed by the ependymal surfaces of the ventricles and transported to the subarachnoid space.

Homovanillic acid and monoamine oxidase in sons of substance-abusing fathers: relationship to conduct disorder.

OBJECTIVE: Children of substance-abusing (SA) fathers have been found to have increased rates of conduct disorder (CD). Substance abuse and antisocial behavior have been linked to alterations in dopaminergic regulation and to monoamine oxidase (MAO) in adults. This study assessed the relationship between homovanillic acid (HVA), the metabolite of dopamine (DA), and MAO, the enzyme facilitating the conversion of DA to HVA, with CD in boys of SA and non-SA fathers. METHOD: Male youths (N = 65), between the ages of 6 and 15 years, admitted to a residential setting because of behavior problems, were studied through peripheral blood samples and structured interviews. RESULTS: The findings indicated that MAO activity was significantly higher in boys of SA fathers with CD than (1) in boys of non-SA fathers with CD and (2) in boys of SA fathers without CD. HVA levels did not differ significantly among the groups. CONCLUSIONS: In the context of previous studies, the findings support the concept of dopaminergic dysregulation in sons of SA fathers, manifested by alterations in MAO activity levels in those youths with CD.

Interrelationship between protein phosphatase-2A and cytoskeletal architecture during the endothelial cell response to soluble products produced by human head and neck cancer.

Tumor neovascularization is necessary for the progressive development of all solid tumors, including head and neck squamous cell carcinomas (HNSCCs). The angiogenic process includes increased endothelial cell motility. Our prior studies have shown the importance of protein phosphatase-2A (PP-2A) in restricting endothelial cell motility. Because motility is regulated by the polymerization/depolymerization of the cellular cytoskeleton, the present study defined the interrelationship between PP-2A and the cytoskeleton during endothelial cell responses to HNSCC-derived angiogenic factors. PP-2A was shown to colocalize with microtubules of unstimulated endothelial cells. However, exposure to HNSCC-derived products resulted in a more diffuse distribution of PP-2A staining and a loss of filamentous tubulin. The feasibility of pharmacologically preventing this cytoskeletal disorganization as a means of blocking tumor-induced angiogenesis was tested. This was accomplished by use of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and all-trans -retinoic acid to indirectly stimulate PP-2A activity through their capacity to elevated intracellular levels of the second messenger ceramide. Pretreatment of endothelial cells with either 1,25(OH)(2)D(3) or retinoic acid prevented the cytoskeletal disorganization that otherwise occurs in endothelial cells on exposure to HNSCC-derived products. These studies support the feasibility of using elevation of PP-2A to prevent the morphogenic component of the angiogenic process that is stimulated by HNSCC-derived factors.

Protein phosphatases 1 and 2A maintain endothelial cells in a resting state, limiting the motility that is needed for the morphogenic process of angiogenesis.

Angiogenesis that is induced by cancers, including those of the head and neck, requires endothelial cells to shift from a nonmotile resting state to an increased level of motility. Using a human microvascular endothelial cell line, this study shows the importance of the serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) in restricting endothelial cell motility. Treatment of endothelial cells with increasing concentrations of the PP1 and PP2A inhibitor okadaic acid resulted in cell rounding and increased motility, which was accompanied by cytoskeletal disorganization involving a loss of filamentous beta-tubulin and F-actin. These effects occurred at okadaic acid levels that selectively inhibit PP2A and became more prominent with higher levels that inhibit both PP2A and PP1. This study shows the importance of PP1 and PP2A in maintaining cytoskeletal organization, thereby limiting endothelial cell motility, and suggests that pharmacologic approaches to enhance PP1 and PP2A activities may be useful in preventing key events of the angiogenic process.

Behavioral ratings and outcome of medical treatment for encopresis.

The relationship between behavior problems and encopresis remains controversial. Recent research suggests that children with encopresis do have numerous behavior problems, but that these problems are generally not as severe as the behavior problems found in children referred for mental health services. This study explores the relationship between baseline behavior ratings of encopretic boys, ages 6-11, on a standardized rating form, the Child Behavior Checklist (CBCL), and outcome of medical treatment for their encopresis. A strong correlation between the product of the sum of the factors on the internalizing scales and the sum of the factors on the externalizing scales and their interaction on the CBCL was associated with outcome. Specifically, moderate elevations of this function predicted good outcome at 3, 6, and 12 months. Very high elevations and minimal or no elevation predicted poor outcome at 3, 6, and 12 months. Possible reasons for these somewhat surprising results are discussed.

Prevalence of behavior problems and mental health utilization among encopretic children: implications for behavioral pediatrics.

The psychiatric literature traditionally has viewed encopretic children as having severe and characteristic behavior problems. Current psychiatric views as expressed in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III), and in the pediatric literature, however, tend to regard the behavior problems of encopretic children as being rather mild or secondary to the consequences of the encopresis itself. Using a behavioral checklist with empirically derived factors (the Child Behavior Checklist), 55 children presenting for medical treatment of their encopresis have been assessed. Numerous behavior problems are reported on parental ratings, but the overall severity of behavior problems in this group of children falls below that found in children with behavior problems who are referred for mental health services. Most children presenting for medical management of encopresis have not been seen or evaluated by mental health services. Encopresis is a disorder in which psychological evaluation and intervention by the pediatrician may be advisable.

Neuropsychological functioning in children with immunodeficiency disorders.

A small group of children with various types of immunodeficiency disorders, examined on a battery of neuropsychological and intellectual tests, was found to be impaired on perceptual speed, visuospatial sequencing, and visual attention span capacities when compared to a control group of closest aged siblings and normal children matched for age, education, and IQ. The results suggest that cerebral dysfunction may be associated with immunodeficiency disorders in children, although these findings are tentative since other factors, such as the effects of chronic illness, could not be excluded in this small cohort of patients.

Mental health providers confronting organizational change: process, problems, and strategies.

Under the influence of managed care and diminished funding, the mental health field is undergoing a major transformation. Existing mental health programs, departments, and agencies are downsizing and restructuring to develop new types of service delivery systems. Organizations must change to survive; yet necessary and adaptive change may be resisted in numerous ways by providers whose reactions and behaviors may reduce the viability of their own programs and agencies. This paper explores various characteristics and reactions of mental health care professionals as they face great stress, professional devaluation, and necessary organizational change and restructuring. Adaptive and maladaptive patterns in response to potential organizational change are explored. The role of the leader in guiding and implementing programmatic changes and in dealing with denial and resistance is highlighted. Strategies to enhance the prospects for adaptive organizational change are offered.

Aggressive children in a day treatment program: changed outcome and possible explanations.

An earlier study (Gabel, Finn & Ahmad, 1988) of severely disturbed children treated in a day hospital program, found that outcome was particularly poor for children with preadmission histories of severe aggressive/destructive behavior. The study reported here compares the outcome in a more recent group of children treated in the same setting with the earlier group's outcome. The recent group of children, like the earlier one, was made up of youngsters who were often from dysfunctional and abusive families. Outcome for aggressive children, including aggressive children with histories of suspected child abuse/maltreatment, was significantly improved. Possible reasons for this improvement in outcome in terms of programmatic changes that had occurred are discussed.

Neglected rupture of the Achilles tendon.

Delayed treatment of a rupture of the Achilles tendon is a challenge. Operative treatment is generally recommended, with a variety of techniques being described to appose the tendinous ends and augment the repair.

Excrescent lesion: a diagnosis of lateral talar exostosis in chronically symptomatic sprained ankles.

The excrescent lesion is a symptomatic anterolateral exostosis at the insertion of the anterior talofibular ligament. It is found in patients with chronic ankle pain after inversion injuries. It is most reliably diagnosed by computed tomography scan, but physical examination and oblique radiographs are suggestive in most cases. A technique for surgical excision and, in some cases, repair of the anterior talofibular ligament is described. Five patients having a history of inversion sprains of the ankle, without significant symptomatic improvement for a mean of 21 months after the injury, were evaluated. None had significant instability in the ankle or subtalar joints, clinically or with stress radiographs. The diagnosis of excrescent lesion was confirmed with computed tomography scan in all five patients. Each underwent excision of the exostosis. Removal of the exostosis produced laxity of the anterior talofibular ligament in four of the patients and required an additional modified Broström procedure to tighten the anterior talofibular ligament. Clinical results were evaluated at a mean of 33 months postoperatively, using the Ankle-Hindfoot scale from the American Orthopaedic Foot and Ankle Society. The three patients without pending claims for Workers' Compensation or related litigation all had excellent results (mean score, 93 points). Two patients with active legal claims had fair and poor results (mean score, 53 points).

Primary repair without augmentation for early neglected Achilles tendon ruptures in the recreational athlete.

From 1987 to 1994, the senior author performed 41 Achilles tendon repairs. We identified 11 patients during this period (age, 35.3 years; range, 26-60 years) who fit the criterion for neglected Achilles tendon rupture (repair > or = 4 weeks and < or = 12 weeks from injury). All patients underwent proximal release of the gastrocsoleus complex, imbrication of the early fibrous scar without excision of any local tissue, and primary repair of the tendinous ends with two No. 5 Ticron sutures (5R, 6L). Several (three to five) No. 0 Vicryl sutures were used to augment the repair. The ankle was placed in a 20 degree plantarflexion nonweightbearing short leg cast for 3 weeks. All skin closures were primary. At 3 weeks, weightbearing as tolerated was initiated in a short leg cast. The cast was discontinued at 6 weeks, and physical therapy was initiated, consisting of range of motion exercises and closed kinetic exercises, progressing to functional exercises as swelling, strength, and pain allowed. Minimal follow-up was 18 months (mean, 3.5 years; range, 1.5-5.8 years). There have been no subsequent ruptures to date. All patients returned to a preinjury level of activity at a mean of 5.8 months (range, 2.5-9 months). Total range of motion was not different (P > 0.05) between the involved (67 degree) and uninvolved (74 degree) ankle. Plantarflexion loss of strength in the involved ankle was the same (98.4%, 88.1%, and 87.6% respectively, involved to uninvolved) as that seen after acute repair at all speeds tested. Visual analog pain scale (0 to 10) revealed a mean score of 0.7 (range 0-2) during activities of daily living and 1.0 (range, 0-3) during sports activity. The subjective and objective outcome was similar (P > 0.05) to that seen after an acute repair by the same surgeon. There were no complications including skin sloughs or nerve damage. We believe this is the first article to report the results after primary repair without augmentation for the neglected Achilles tendon rupture. We conclude that this approach can result in excellent clinical and functional outcome, a low rate of subsequent rupture, and a high rate of return to sports in the recreational athlete whose repair is performed between 4 and 12 weeks after injury.