Instrumental learning and relearning in individuals with psychopathy and in patients with lesions involving the amygdala or orbitofrontal cortex.

Previous work has shown that individuals with psychopathy are impaired on some forms of associative learning, particularly stimulus-reinforcement learning (Blair et al., 2004; Newman & Kosson, 1986). Animal work suggests that the acquisition of stimulus-reinforcement associations requires the amygdala (Baxter & Murray, 2002). Individuals with psychopathy also show impoverished reversal learning (Mitchell, Colledge, Leonard, & Blair, 2002). Reversal learning is supported by the ventrolateral and orbitofrontal cortex (Rolls, 2004). In this paper we present experiments investigating stimulus-reinforcement learning and relearning in patients with lesions of the orbitofrontal cortex or amygdala, and individuals with developmental psychopathy without known trauma. The results are interpreted with reference to current neurocognitive models of stimulus-reinforcement learning, relearning, and developmental psychopathy.

Social impairment in girls with ADHD: patterns, gender comparisons, and correlates.

OBJECTIVE: To investigate social impairment in girls with attention-deficit/hyperactivity disorder (ADHD), compare the social functioning of boys and girls with ADHD, and explore the association between social dysfunction and conditions comorbid with ADHD. METHOD: Four groups of index children were studied: 267 children (127 girls) with ADHD and 234 non-ADHD comparison children (114 girls). Groups were compared on social functioning, psychopathology, and demographic characteristics. RESULTS: Girls with ADHD manifested significant deficits in interpersonal functioning compared with girls without ADHD and evidenced a similar degree of social impairment compared with boys with ADHD. ADHD and associated comorbid disorders were significant correlates of specific domains of social dysfunction in boys and girls with ADHD. CONCLUSIONS: Interpersonal deficits are a major correlate of ADHD, irrespective of gender, and appear to stem from the behaviors associated with ADHD as well as behaviors characteristic of conditions comorbid with ADHD.

Requirements for viral-mediated autoimmune diabetes: beta-cell damage and immune infiltration.

The induction of autoimmunity by viruses has been attributed to numerous mechanisms. Coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) in mice resembling the final step of disease progression in humans. Following viral infection, autoreactive lymphocytes are activated through exposure to damaged islets consequently precipitating IDDM. However, the viral and host requirements leading up to this final step have yet to be elucidated. We provide evidence that disease induction requires a pre-existing accumulation of beta-cell specific autoreactive T cells within the pancreas, as well as the infection of islet beta-cells. Therefore, the primary role of CB4 in the development of IDDM is to infect tissue, resulting in the presentation of sequestered islet antigen, the stimulation of preexisting autoreactive T cells, and the initiation of disease.

The wreathing protocol: the imbrication of hypnosis and EMDR in the treatment of dissociative identity disorder and other dissociative responses. Eye Movement Desensitization Reprocessing.

Dissociative Identity Disorder (DID), a chronic childhood onset posttraumatic stress disorder, is currently recognized as a treatable condition. It is considered the paradigmatic dissociative condition and carries with it extreme posttraumatic symptomatology. Therapists skilled in the treatment of DID are typically fluent in the uses of hypnosis for stabilization, affect management, building a safe place and grounding to name of few. EMDR, which has come to the forefront of clinical awareness in the last ten years, seems aptly suited for the treatment of trauma, but can be destabilizing. This paper proposes a protocol, called Wreathing Protocol, for the imbricated use of EMDR and hypnosis in the treatment of not only DID (though this will be the primary focus of the paper), but also Dissociative Disorder Not Otherwise Specified (DDNOS) and chronic Posttraumatic Stress Disorder (PTSD). This protocol is useful to advanced clinicians skilled in both modalities independently. The sequential steps of the Wreathing Protocol will be described and illustrated by a clinical vignette on DID. The clinical implications of the use of the Wreathing Protocol will be discussed in DID as well as the chronic post traumatic spectrum.

Dissociation between 'theory of mind' and executive functions in a patient with early left amygdala damage.

There have been recent suggestions that the amygdala may be involved in the development or mediation of 'theory of mind'. We report a patient, B.M., with early or congenital left amygdala damage who, by adulthood, had received the psychiatric diagnoses of schizophrenia and Asperger's syndrome. We conducted a series of experimental investigations to determine B.M.'s cognitive functioning. In line with his diagnoses, B.M. was found to be severely impaired in his ability to represent mental states. Following this, we conducted a second series of studies to determine B.M.'s executive functioning. In the literature, there have been frequent claims that theory of mind is mediated by general executive functioning. B.M. showed no indication of executive function impairment, passing 16 tests assessing his ability to inhibit dominant responses, create and maintain goal-related behaviours, and temporally sequence behaviour. The findings are discussed with reference to models regarding the role of the amygdala in the development of theory of mind and the degree of dissociation between theory of mind and executive functioning. We conclude that theory of mind is not simply a function of more general executive functions, and that executive functions can develop and function on-line, independently of theory of mind. Moreover, we conclude that the amygdala may play some role in the development of the circuitry mediating theory of mind.

Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis.

Cardiovascular disease is one of the leading causes of death worldwide, and has been associated with many environmental risk factors. Recent evidence has indicated the involvement of pathogens such as viruses as causative agents, and specifically identified the coxsackievirus B serogroup as the leading culprit. Not only has coxsackievirus B3 (CB3) been identified from patients with cardiovascular disease, but also infection of mice with CB3 strains can reproduce human clinical heart disease in rodents. Several mechanisms have been proposed in an attempt to distinguish between pathology mediated by direct viral destruction of cardiac muscle cells or by the virus-induced immune response directed at infected myocytes or at 'mimicked' epitopes shared between viral and cardiac antigens. To distinguish between these mechanisms, we infected a unique mouse that diminishes the extent of infection and spread of the virus, but allows complete immunity to the virus. Transgenic mice expressing interferon-gamma in their pancreatic beta cells failed to develop CB-3-induced myocarditis. This work challenges the idea of the function of the immune response and 'molecular mimicry' in the CB-3-induced autoimmune myocarditis model, and instead favors the idea of virus-mediated damage. These results emphasize the benefit of reducing the level of viremia early during infection, thereby reducing the incidence of virus-mediated heart damage and autoimmunity.

The tactical-integration model for the treatment of dissociative identity disorder and allied dissociative disorders.

The ebb and flow of the diagnosis of Dissociative Identity Disorder (DID) and other dissociative conditions has led to the evolution of theories and treatment modalities to resolve the fluctuating and ephemerous symptoms of these conditions. This paper summarizes the structured cognitive-behavioral-based treatment of dissociative disorders that will foster not only symptom relief but also an integration of the personalities and/or ego states into one mainstream of consciousness. This model of DID therapy is called the tactical integration model; it promotes proficiency over posttraumatic and dissociative symptoms, is collaborative and exploratory, and conveys a consistent message of empowerment to the patient.

A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of cholinergic agents for ADHD. To this end, the authors completed a controlled study of ABT-418, a novel cholinergic activating agent, for the treatment of adults with ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, crossover trial that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated by 1 week of washout. RESULTS: Of the 32 subjects enrolled in the study (88% were men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of each active arm (last observation carried forward), a significantly higher proportion of subjects was considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%). Similarly, at endpoint there was a significantly greater reduction in ADHD symptom checklist scores (28% versus 15%). Symptoms reflective of attention, and subjects with less severe ADHD, responded more robustly to ABT-418. Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were the most frequently reported adverse effects. CONCLUSIONS: The results of this investigation indicate that ABT-418, a nicotinic analog, may be a potentially useful agent for the treatment of ADHD.

Absence of cardiovascular adverse effects of sertraline in children and adolescents.

OBJECTIVE: In a 12 week, placebo-controlled, parallel-design, multicenter study of sertraline for obsessive-compulsive disorder in 107 children and 80 adolescents, the authors prospectively assessed cardiovascular effects to doses of sertraline of < or = 200 mg/day. METHOD: Vital signs (blood pressure and heart rate) and electrocardiograph parameters (ECGs) were systematically evaluated at baseline and again throughout treatment. RESULTS: There were no clinically significant cardiovascular adverse events in any of the subjects enrolled in the study. Moreover, compared with baseline and placebo, sertraline treatment at an average dose of 167 mg did not result in any clinically meaningful changes in any ECG indices (PR, QRS, and QTc intervals), cardiac rhythm, blood pressure, or heart rate. CONCLUSIONS: These prospectively derived results support the cardiovascular safety of sertraline at doses up to 200 mg in children and adolescents.

Protection from lethal coxsackievirus-induced pancreatitis by expression of gamma interferon.

Coxsackievirus infection causes severe pancreatitis and myocarditis in humans, often leading to death in young or immunocompromised individuals. In susceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglycemia. To investigate the potential of gamma interferon (IFN-gamma) in protection and clearance of the viral infection, IFN-gamma knockout mice and transgenic (Tg) mice specifically expressing IFN-gamma in their pancreatic beta cells were infected with CB4. Lack of IFN-gamma in mice normally resistant to CB4-mediated disease resulted in hypoglycemia and rapid death. However, expression of IFN-gamma in the beta cells of Tg mice otherwise susceptible to lethal infection allowed for survival and protected them from developing the accompanying hypoglycemia. While all the mice had high levels of viral replication in their pancreata and comparable tissue pathology following viral infection, the Tg mice had significantly lower levels of virus at the peak of infection, significantly higher numbers of activated macrophages before and after infection, and less damage to their acinar tissue. Additionally, despite having increased levels of inducible nitric oxide synthetase (iNOS) expression, treatment of Tg mice with the iNOS inhibitor aminoguanidine did not alter the level of protection afforded by IFN-gamma expression. In conclusion, IFN-gamma protects from lethal coxsackievirus infection by activating macrophages in an iNOS-independent manner.

Diagnostic continuity between child and adolescent ADHD: findings from a longitudinal clinical sample.

OBJECTIVE: To determine whether there are differences in the clinical expression and correlates of attention-deficit hyperactivity disorder (ADHD) between children and adolescents. METHOD: Subjects were 6- to 17-year old Caucasian, non-Hispanic boys with and without ADHD. DSM-III-R structured diagnostic interviews, psychometric measures, and blind raters assessed psychiatric diagnoses, intellectual performance, social disability, school failure, and family functioning. RESULTS: Children and adolescents with ADHD had an almost identical pattern of correlates in multiple domains of assessment including psychosocial adversity and comorbidity with conduct, mood, and anxiety disorders. Although the rate of substance abuse differed in comparison between child and adolescent subjects, this was independent of ADHD status. CONCLUSIONS: These findings document the diagnostic continuity of ADHD between childhood and adolescence and support the inclusion of adolescent samples in ADHD research protocols.

Use of maltose hydrolysis measurements to characterize the interaction between the aqueous diffusion barrier and the epithelium in the rat jejunum.

Rates of intestinal absorption and surface hydrolysis are determined by the interaction of two barriers: poorly stirred fluid adjacent to the mucosa, and the epithelial cell. These two barriers commonly are modeled as a fixed, flat layer of epithelium covered by a fixed thickness of unstirred fluid. To more accurately simulate these barriers in a villous mucosa, maltase activity (measured in vitro) was distributed over an anatomically correct model of rat jejunal villi. We then determined what interaction of the aqueous and epithelial barriers best predicted in vivo maltose hydrolysis rates measured over a broad range of infusate concentrations. Hydrolysis was accurately predicted by a model in which unstirred fluid extended from 20 microm over the villous tips throughout the intervillous space. In this model, the depth of diffusion into the intervillous space is inversely proportional to the efficiency of epithelial handling of the solute. As a result, both the aqueous barrier and the functional surface area are variables rather than constants. Some implications of our findings (relative to the conventional model) include: higher predicted Vmax, efficient handling of low concentrations of a solute at the villous tips while high concentrations must penetrate thick aqueous barriers, and sensitive regulation of transport rates via ease of access to the intervillous space.

Measurements of the jejunal unstirred layer in normal subjects and patients with celiac disease.

Normal intestinal absorption of nutrients requires efficient luminal mixing to deliver solute to the brush border. Lacking such mixing, the buildup of thick unstirred layers over the mucosa markedly retards absorption of rapidly transported compounds. Using a technique based on the kinetics of maltose hydrolysis, we measured the unstirred layer thickness of the jejunum of normal subjects and patients with celiac disease, as well as that of the normal rat. The jejunum of humans and rats was perfused with varying maltose concentrations, and the apparent Michaelis constant (Km) and maximal velocity (Vmax) of maltose hydrolysis were determined from double-reciprocal plots. The true Km of intestinal maltase was determined on mucosal biopsies. Unstirred layer thickness was calculated from the in vivo Vmax and apparent Km and the in vitro Km of maltase. The average unstirred layer thickness of 11 celiac patients (170 micron) was seven times greater than that of 3 controls (25 micron). The unstirred layer of each celiac exceeded that of the controls. A variety of factors could account for the less efficient luminal stirring observed in celiacs. Although speculative, villous contractility could be an important stirring mechanism that would be absent in celiacs with villous atrophy. This speculation was supported by the finding of a relatively thick unstirred layer (mean: 106 micron) in rats, an animal that lacks villous contractility. Because any increase in unstirred layer slows transport of rapidly absorbed compounds, poor stirring appears to represent a previously unrecognized defect that could contribute to malabsorption in celiac disease and, perhaps, in other intestinal disorders.

A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin "add-back" regimens for women with leiomyomata uteri.

Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will result in profound hypoestrogenism, a significant but temporary reduction in uterine volume, and menstrual suppression. Long-term (i.e. > 6 months) treatment with a GnRH-a is not recommended because of accelerated bone resorption and the presence of hypoestrogenic symptoms. In this 2-yr study, women with myomas were treated with GnRH-a plus one of two steroid "add-back" regimens to minimize adverse sequelae of chronic hypoestrogenism. Fifty-one premenopausal women with large, symptomatic uterine myomas all received the GnRH-a, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks at which time the women were randomized to receive LAD plus either an estrogen-progestin or progestin-only add-back regimen for an additional 92 weeks. Efficacy parameters assessed included serial uterine volumes, hemoglobin concentrations, and hematocrits; safety parameters evaluated included serial bone mineral density measurements, lipid profiles, and medication-related symptoms. This report analyzes the first 52 weeks of study data. Mean uterine volume decreased to 64% of pretreatment size at 12 weeks of LAD treatment in both groups. The estrogen-progestin add-back group had no significant regrowth of uterine volume, which was 75% of pretreatment size at treatment week 52; in contrast, the progestin add-back group had a mean uterine volume of 92% of pretreatment size by treatment week 52. Both groups demonstrated significant improvements in mean hemoglobin concentrations and hematocrits. The progestin add-back group had a significant decline in mean high density lipoprotein-cholesterol concentration, which was not seen in the estrogen-progestin add-back group. Finally, after a significant 3% bone loss during the first 12 weeks of treatment, bone mineral density stabilized in both add-back regimen groups. GnRH-a/steroid add-back regimens provide a useful long-term treatment strategy in women with large, symptomatic uterine myomas and may obviate the need for surgical intervention in selected cases. The estrogen-progestin add-back regimen was superior or equal to the progestin add-back regimen in all efficacy and safety parameters assessed.

Recurrence of myomas after myomectomy in women pretreated with leuprolide acetate depot or placebo.

The recurrence of myomas and myoma-related symptoms was evaluated in women participating in a randomized, double-blind, P-controlled study of the efficacy of LA depot before myomectomy. After 27 to 38 months of follow-up, the recurrence of myomas was found to be greater when at least four myomas were resected. Myoma recurrence was not associated with pretreatment or preoperative uterine volume, resected myoma mass, or preoperative medical therapy.

Treatment stabilization and crisis prevention. Pacing the therapy of the multiple personality disorder patient.

This article briefly reviews the tactical integrationist's perspective in the work with multiple personality disorder patients. Its foundation is a cognitively based treatment paradigm geared toward controlled abreactions with cognitive restructuring throughout therapy. It is a suppression-dilution-of-affect model that focuses on the achievement of control and mastery for patient and therapist alike.

Accuracy of the MMPI in identifying multiple personality disorder.

A number of previous studies have delineated Minnesota Multiphasic Personality Inventory (MMPI) characteristics in patients with multiple personality. To test the accuracy of the MMPI in identifying such patients, the authors blindly rated 63 MMPIs as being either multiple personality or not. The over-all hit rate for the entire sample was 71.4%, with a 68% hit rate for correctly identified patients with multiple personality. These hit rates compare favorably with the hit rates in similar studies of other psychiatric disorders and further demonstrate the clinical usefulness of the MMPI in the diagnosis of multiple personality.

Cyclic GMP: a potential mediator of neurally- and drug-induced relaxation of opossum lower esophageal sphincter.

Electrical field stimulation (EFS) of isolated strips of opossum lower esophageal sphincter (LES) produced a relaxation that was accompanied by an elevation of intracellular cyclic GMP content. In order to compare the time dependence of the EFS-induced relaxation with that of the elevation of cyclic GMP, the ability of EFS to produce relaxation and increase cyclic GMP was measured. The results of these experiments showed that cyclic GMP content increased before the onset of relaxation. Cumulative addition of atriopeptin II, an activator of particulate guanylate cyclase, produced a concentration-dependent relaxation of this tissue and increased cyclic GMP content. In other experiments, zaprinast, an inhibitor of a cyclic GMP selective-phosphodiesterase, produced a concentration-related relaxation of opossum LES and increased cyclic GMP content. However, pretreatment with zaprinast (3 microM) did not potentiate the EFS-induced relaxation or the increase in cyclic GMP content. At this concentration, however, zaprinast increased the basal content of cyclic GMP. Finally, 8-Br-cyclic GMP, a membrane-permeable analog of cyclic GMP, produced a concentration-dependent relaxation of isolated strips of opossum LES. In conclusion, these data extend the initial findings that an elevation in cyclic GMP content is associated with relaxation and suggest that cyclic GMP is a potential intracellular messenger of neurally- and drug-induced relaxation of opossum LES.

Sonographic diagnosis of partial hydatidiform mole.

We undertook a study to determine whether partial hydatidiform mole could be distinguished from other cases of first-trimester missed abortion using ultrasound. Scans from 22 cases of pathologically proved partial hydatidiform mole and 33 cases of first-trimester missed abortion were independently reviewed by three radiologists, each unaware of the final pathologic diagnosis. Using a standard data form, each radiologist recorded the dimensions, shape, and contents of the gestational sac, the sonographic appearance of the decidual reaction/placenta and myometrium, and the presence or absence of adnexal cysts. The following two criteria were found to be significantly associated (P less than .05) with the diagnosis of partial mole: 1) ratio of transverse to anteroposterior dimension of the gestational sac greater than 1.5, and 2) cystic changes, irregularity, or increased echogenicity in the decidual reaction/placenta or myometrium. There was high interobserver correlation for both criteria, as measured by the kappa statistic. In 50% of the cases, either both or neither of these criteria were met. When both criteria were met, the frequency of partial mole was 87%; when neither criterion was met, the frequency of missed abortion was 90%. These results indicate that ultrasound can be of value in predicting a high likelihood of partial mole prior to curettage.