Downregulation of cyclic adenosine monophosphate levels in leukocytes of hibernating captive black bears is similar to reported cyclic adenosine monophosphate findings in major depressive disorder.

Introduction: Cyclic adenosine monophosphate (cAMP) levels in the lymphoblasts and leukocytes of patients with major depressive disorder (MDD) have been reported to be downregulated compared to in controls. cAMP is a derivative of adenosine triphosphate (ATP), and low ATP turnover has been reported in the state of hypometabolism associated with human MDD and with mammalian hibernation due to suppression of mitochondrial metabolism. Similarities have been noted between many state-dependent neurobiological changes associated with MDD in humans and with mammalian hibernation. Methods: To compare cAMP levels between human MDD and mammalian hibernation and to investigate whether cAMP downregulation is another state-dependent neurobiological finding, we measured cAMP concentrations in lysed leukocytes, plasma, and serum in serial blood specimens from nine female captive black bears (Ursus americanus; CBBs), and cortisol levels in serum from 10 CBBs. Results: Cortisol levels were significantly higher during hibernation in CBBs, confirming previous findings in hibernating black bears and similar to findings in humans with MDD. cAMP levels were significantly lower during hibernation versus active states (pre-hibernation and exit from hibernation) and were similar to the cAMP downregulation reported in MDD patients versus euthymic patients or controls. cAMP level changes during the different states (hibernation, pre-hibernation, active) confirm their state-dependent status. Discussion: These findings are similar to the neurobiological findings associated with the hypometabolism (metabolic depression) observed during mammalian hibernation and reported during MDD. A sudden increase in cAMP levels was observed before entrance into pre-hibernation and during exit from hibernation. Further investigation is suggested into the possible role of elevated cAMP levels in initiation of the chain reaction of changes in gene expression, proteins, and enzymes leading to the suppression of mitochondrial metabolism and to low ATP turnover. This process leads to hypometabolism, the old adaptive mechanism that is used by organisms for energy preservation and is associated with both mammalian hibernation and human MDD.

Triggers of Aggressive Behaviors in Intellectually Disabled Adults and Their Association with Autism, Medical Conditions, Psychiatric Disorders, Age and Sex: A Large-Scale Study.

Aggressive behaviors in those with intellectual disability (ID) and autism (ASD) have been linked to a variety of factors including ID level, age, sex, psychiatric disorders, and medical conditions but these factors have not been studied, in large samples, in terms of how they affect the stimuli that trigger aggression. In this survey of 2243 adults, four triggers of aggression associated with frustration, discomfort, change in the physical/social environment, and defensive reactions were analyzed for their relation to ID level, ASD, age, sex, number of psychiatric diagnoses, sleeping problems, seizures, visual impairment, ear infections and gastrointestinal problems. All four triggers were associated with increasing number of psychiatric disorders, with frustration, discomfort, and change intolerance commonly linked to sleeping problems and ASD. Implications for assessment and intervention are discussed.

Melanoma central nervous system metastases: current approaches, challenges, and opportunities.

Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

Effects of antidepressants on longevity and dementia onset among adults with Down syndrome: a retrospective study.

OBJECTIVE: To investigate the effects of antidepressants on longevity, age at dementia onset, and survival after onset among adults with Down syndrome, controlling for late-onset seizures, trisomy 21 mosaicism, and cholinesterase inhibitor use. METHOD: The charts of 357 adults with Down syndrome (mean age at first visit = 46.3 years, SD = 9.0) evaluated in a metropolitan diagnostic and research clinic between 1990 and 2008 were reviewed. Seventeen patients had trisomy 21 mosaicism; 155 patients were diagnosed with depressive disorders using DSM-III-R and IV criteria, 78 of whom received antidepressants for over 90 days. Of 160 patients who developed dementia, the estimated mean age at onset was 52.8 years. Fifty-six patients (demented and nondemented) had late-onset seizures. Longevity and age at estimated onset among those receiving and not receiving antidepressants were compared. Cox proportional hazards models examined risks for dementia onset and death. RESULTS: The mean age at dementia onset among those receiving antidepressants before onset was 53.75 years versus 52.44 years among others. Proportional hazards models showed a significant delay of onset among those taking antidepressants (hazard ratio = 0.69; 95% CI, 0.48-0.98; P = .038). Mean age at death or at end of study for those receiving antidepressants was 54.71 years; among others, it was 52.60 years (hazard ratio = 0.63; 95% CI, 0.42-0.94; P = .024). Among the 35 adults with late-onset seizures and dementia who died, mean survival after seizure onset was 4.23 years. CONCLUSIONS: The findings in this retrospective study revealed that antidepressant use was associated with delayed dementia onset and increased longevity in adults with Down syndrome; mean survival after late-onset seizures was longer than previously reported. Further studies, however, are needed to confirm these associations, optimally in a clinical trial to confirm causality.

Prevalence of psychotropic drug use in adults with intellectual disability: positive and negative findings from a large scale study.

The use of psychotropics by categories and the reason for their prescription was investigated in a large scale study of 4,069 adults with ID, including those with autism spectrum disorder, in New York State. Similar to other studies it was found that 58 % (2,361/4,069) received one or more psychotropics. Six percent received typical, while 39 % received atypical antipsychotics [corrected]. There was greater use of antidepressants (23 %), mood stabilizers (19 %), and antianxiety agents (16 %) relative to other studies. The use of anti-impulsives, stimulants and hypnotics was rare (1-2 %). Half of the psychotropics were prescribed for treatment of major psychiatric disorders, 13 % for control of challenging behaviors, and 38 % for both. Results indicated that the major psychiatric disorders, except anxiety disorder and autism, influenced the use of psychotropics and the number of medication used. These findings imply that although practitioners still rely too heavily on the use of antipsychotics in this population, there is a welcome shift in the prescription patterns relative to other studies. The practitioners appeared to use psychotropics primarily to treat diagnosed psychiatric disorders and not just to control aggressive behavior which suggests that evidence-based practice of psychiatry is playing an increasing role in the ID population.

Volumetric classification of pituitary macroadenomas predicts outcome and morbidity following endoscopic endonasal transsphenoidal surgery.

Endoscopy in combination with extended approaches allow for resection of large pituitary adenomas via a transsphenoidal route. The objective of the current study was to determine a volumetric threshold for lesions with high perioperative morbidity and high rate of subtotal resection following endonasal endoscopic surgery. Thus, we analyzed a prospectively collected database of 71 patients who underwent endoscopic transsphenoidal approaches for macroadenomas (diameter >1 cm). Extend of resection (EOR) was calculated based on volumetric analysis of pre-and post-operative contrast-enhanced MRI. Average EOR was 97.8% and a gross total resection (GTR) was achieved in 76.1% of all patients. GTR was accomplished in 92.0% versus 38.1% of adenomas either without or with CS invasion, respectively. Likewise, GTR was accomplished in 90.2% versus 40.0% of lesions less than or greater then 10 cm(3) respectively. However, even if only subtotal resection was achieved, 90.3% of tumor volume was removed. At 17 months follow-up, visual field defects improved in 80.8% of patients. Complications included permanent diabetes insipidus (5 patients), panhypopituitarism (4 patients), injury to the ophthalmic artery (1 patient) and CSF leak (1 patient). On multivariate logistic regression, two factors negatively predicted GTR: invasion of the CS and volume greater than 10 cm(3). A 10 cm(3) threshold was a stronger predictor of EOR and complication risk than diameter-based measurements. A volume greater than 10 cm(3) and CS invasion may help to identify pituitary lesions associated with a higher likelihood of subtotal resection and post-operative morbidity.

A large scale study of the psychometric characteristics of the IBR Modified Overt Aggression Scale: findings and evidence for increased self-destructive behaviors in adult females with autism spectrum disorder.

The psychometric characteristics of the IBR Modified Overt Aggression Scale were studied in over 2,000 people with Intellectual Disability (ID). Reliability ranged from good to excellent. Aggression toward others and objects was highest in the youngest adults, in those in the moderate to severe range of ID, and in those with an autism spectrum diagnosis. Self-injury was highest in those in the severe to profound range of ID and in those with autism, particularly the females. Females with autism were also more likely to make the most self-deprecating statements. Our data suggest that adult females with autism are a unique group and support the notion that mood and anxiety disorders play a role in self-destructive behaviors in this population.

Psychotic manifestations in a patient with mental retardation and a 6.2 megabase deletion at the distal short arm of chromosome 12.

Genetic factors are known to contribute to the development of schizophrenia and related psychoses. Cytogenetic abnormalities have been occasionally found in patients with psychotic disorders and, thus, have helped identify candidate gene contributors for these conditions. The individual described here first presented with mental retardation and anxiety disorder in his mid-childhood. In his early 20s, the patient started exhibiting various psychotic manifestations, including delusions and hallucinations. His psychotic symptoms were difficult to control with psychotropic medications. The family history was negative for psychiatric disorders. This patient was found to have a 6.2 megabase deletion of the terminal portion of the short arm of chromosome 12 that was characterized using fluorescence in situ hybridization and microarray comparative genomic hybridization analysis. The maternal chromosomes were normal, but the paternal chromosomes could not be tested. To-date such a chromosomal abnormality has not been described in association with schizophrenia/psychosis. This case suggests that psychosis-associated gene(s) may be located in the terminal region of the short arm of chromosome 12.

Pearson syndrome in an infant heterozygous for C282Y allele of HFE gene.

BACKGROUND: Pearson syndrome is a rare mitochondrial disorder characterized by sideroblastic anemia, liver disease, renal tubulopathy and exocrine pancreas deficiency. OBSERVATIONS: We describe a female infant suffering from anemia since birth who gradually developed the complete picture of Pearson syndrome by 13 months. Iron overload was disproportionate to blood transfusions. The patient was heterozygous for HFE gene C282Y mutation (type I hemochromatosis). After an initial response to deferoxamine she presented with cutaneous zygomycosis and died after metabolic derangement and Pneumocystis jiroveci pneumonia. CONCLUSION: This is the second case of a Pearson syndrome individual who was also heterozygous for HFE gene mutation C282Y published. It is also the second case report of a Pearson patient suffering from severe iron overload and liver disease that responded to therapy with deferoxamine.

Maternal recurrent mood disorders and high-functioning autism.

A quantitative examination was made of the association of parental mood and anxiety disorders with severity of disability within a large sample of young children with Pervasive Developmental Disorder (PDD). Maternal recurrent mood disorders were associated with elevated cognitive and adaptive functioning in their affected children, parent reports of increased behavior problems and teacher reports of an internalizing behavioral style. Maternal histories of anxiety disorders and paternal depression or anxiety disorders were not associated with levels of adaptive/cognitive functioning or levels of maladaptive behaviors in the children. Various genetic models are discussed. It is hypothesized that genes associated with recurrent depression in women may exert a "protective" effect on cognition and adaptive functioning in children with PDD.

Metabolic depression in hibernation and major depression: an explanatory theory and an animal model of depression.

Metabolic depression, an adaptive biological process for energy preservation, is responsible for torpor, hibernation and estivation. We propose that a form of metabolic depression, and not mitochondrial dysfunction, is the process underlying the observed hypometabolism, state-dependent neurobiological changes and vegetative symptoms of major depression in humans. The process of metabolic depression is reactivated via differential gene expression in response to perceived adverse stimuli in predisposed persons. Behavior inhibition by temperament, anxiety disorders, genetic vulnerabilities, and early traumatic experiences predispose persons to depression. The proposed theory is supported by similarities in the presentation and neurobiology of hibernation in bears and major depression and explains the yet unexplained neurobiological changes of depression. Although, gene expression is suppressed in other hibernators by deep hypothermia, bears were chosen because they hibernate with mild hypothermia. Pre-hibernation in bears and major depression with atypical features are both characterized by fat storage through overeating, oversleeping, and decreased mobility. Hibernation in bears and major depression with melancholic features are characterized by withdrawal from the environment, lack of energy, loss of weight from not eating and burning stored fat, changes in sleep pattern, and the following similar neurobiological findings: reversible subclinical hypothyroidism; increased concentration of serum cortisol; acute phase protein response; low respiratory quotient; oxidative stress response; decreased neurotransmitter levels; and changes in cyclic-adenosine monophosphate-binding activity. Signaling systems associated with protein phosphorylation, transcription factors, and gene expression are responsible for the metabolic depression process during pre-hibernation and hibernation. Antidepressants and mood stabilizers interfere with the hibernation process and produce their therapeutic effects by normalizing the fluctuation of activities in the different signaling systems, which are down-regulated during hibernation and depression and up-regulated during exodus from hibernation and the hypomanic or manic phase of mood disorders. The ways individuals cognitively perceive, understand, communicate, and react to the vegetative symptoms of depression, from downregulation in energy production, and in the absence of known medical causes, produce the other characteristics of depression including guilt, helplessness, hopelessness, suicidal phenomena, agitation, panic attacks, psychotic symptoms, and sudden switch to hypomanic or manic episodes. The presence of one or more of these characteristics depends on the person's neuropsychological function, its social status between the others, and the other's response to the person. Neurobiological changes associated with metabolic depression during entrance, maintenance, and exodus from hibernation in bears is suggested as a natural animal model of human depression and mood disorders.

Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy.

Fragile X syndrome is the leading inherited form of mental retardation, and second only to Down's syndrome as a cause of mental retardation attributable to an identifiable genetic abnormality. Fragile X syndrome is caused by a defect in the fragile X mental retardation 1 gene (FMR1), located near the end of the long arm of the X chromosome. FMR1 normally synthesises the fragile X protein (FMRP), but mutations in FMR1 lead to a lack of FMRP synthesis, resulting in fragile X syndrome. While the specific function of FMRP is not yet fully understood, the protein is known to be important for normal brain development. The physical, cognitive and behavioural features of individuals with fragile X syndrome depend on gender (females have two X chromosomes, one active and one inactive) and the molecular status of the mutation (premutation, full mutation or mosaic). Features of the behavioural profile of individuals with fragile X syndrome include hypersensitivity to stimuli, overarousability, inattention, hyperactivity and (mostly in men) explosive and aggressive behaviour to others or self. Social anxiety, other anxiety disorders, depression, impulse control disorder and mood disorders are the most common psychiatric disorders diagnosed in individuals with fragile X syndrome, although no formal studies have been undertaken. There have been very few psychopharmacological studies of the treatment of behaviours associated with fragile X syndrome. These limited studies and surveys of psychotropic drugs used in individuals with fragile X syndrome suggest that stimulants are helpful for hyperactivity, that alpha(2)-adrenoceptor agonists and beta-adrenoceptor antagonists help to control overarousability, impulsivity and aggressiveness, and that SSRIs can control anxiety, impulsivity and irritability, alleviate depressive symptoms and decrease aggressive and self-injurious behaviour. Typical and atypical antipsychotics in combination with other psychotropics have been used for control of psychotic disorders and severe aggressive behaviours. Mood stabilisers have been found to be useful when mood dysregulation or mood disorders are present with or without aggressive behaviour. Folic acid and L-acetylcarnitine (levacecarnine) have not been found to improve deficits or behaviours. As there is no specific psychotropic drug for any of the deficits or behaviours associated with fragile X syndrome, clinicians are advised to diagnose any psychiatric syndromes or disorders present and treat them with the appropriate psychotropic drug. If no psychiatric disorder can be diagnosed and the patient's challenging behaviours cannot be controlled with environmental manipulation or behaviour modification techniques, the most benign psychotropic drug should be used. Antipsychotics should be reserved for psychotic disorders, for impulse control disorders (used in combination with other psychotropics), or when challenging behaviours constitute an emergency. In the future, new medications targeting molecules implicated in the modulation of anxiety, fear and fear responding will be useful for treating the social anxiety and overarousability exhibited by individuals with fragile X syndrome.

Evaluation of screening tools for dementia in older adults with mental retardation.

We compared groups with and without diagnosed dementia matched on IQ, age, and presence of Down syndrome. The Dementia Scale for Down Syndrome and Dementia Questionnaire for Mentally Retarded Persons were used to assess participants. We developed two performance tasks to determine whether they were useful in separating subjects with and without dementia and also used the Reiss Screen. Both dementia scales and both performance tasks discriminated between groups. The dementia scales were not related to premorbid IQ, age, or gender, whereas performance tasks were related to dementia and IQ but not age or gender. Various Reiss Screen subscales also discriminated between groups. Subscales of the screening instruments and performance tasks were significantly related, indicating congruent validity. Logistic regression was conducted to assess which combination of tests discriminated best between groups.

Elevated levels of serum alpha(2) macroglobulin in wild black bears during hibernation.

Bear serum alpha(2) macroglobulin (alpha(2)M) was purified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and partially characterized by tryptic digestion of alpha(2)M and analysis of the peptides by peptide mass fingerprinting. The molecular weight of bear serum alpha(2)M was 181 kDa, same as for human serum alpha(2)M, on SDS-PAGE. However, the MALDI mass spectrum of the tryptic digested bear serum alpha(2)M showed that it is different from human alpha(2)M or other data bank proteins. Liquid chromatography (LC)/mass spectrometry (MS)/MS of the proteolytic products of bear serum alpha(2)M showed eight peptides that had similarities to human alpha(2)M suggesting that the protein of interest was indeed alpha(2)M of bear. The polyclonal antibody against bear serum alpha(2)M recognized only one protein from the western blot of bear serum proteins. It also recognized human alpha(2)M. The levels of serum alpha(2)M were significantly increased during hibernating state as compared to active state of bears indicating its protective role from the consequences of the metabolic depression during hibernation.

Treatment of previously undiagnosed psychiatric disorders in persons with developmental disabilities decreased or eliminated self-injurious behavior.

BACKGROUND: Self-injurious behavior (SIB) is one of the most common challenging behaviors in persons with autistic disorder or severe/profound mental retardation. Many psychotropic drugs have been evaluated for their effectiveness in SIB. Results have varied, and no one psychotropic drug has been indicated for SIB. In this prospective, open clinical study, psychotropic drugs were used to treat the previously undiagnosed psychiatric disorder in persons exhibiting SIB. METHOD: Data were collected from 26 individuals with mental retardation (14 males, 12 females), 7 to 45 years of age (mean = 30.3 years), who exhibited SIB. Psychiatric diagnosis was made according to DSM-III-R and DSM-IV criteria. The Behavior Problem Inventory, Yudofsky's Overt Aggression Scale, repeated direct observation, and information on use of protective devices and Likert scales from log books were used to evaluate degree of SIB. Most of the patients were treated with different psychotropic drugs and behavior modification before they were evaluated for this study, but only 7 of them carried a psychiatric diagnosis. Data were collected between 1987 and 1997. RESULTS: Depressive disorders, impulse-control disorder, and anxiety disorder were the most common final diagnoses. Neuroleptics were discontinued in 5 patients and tapered by 50% to 75% in 14 patients. Antidepressants were added in 12 patients. Treatment of psychiatric disorders produced significant (p < .001) decrease in the severity of SIB in the 26 patients, and SIB was eliminated in 12 patients. The severity of SIB decreased to mild from a moderate, severe, or extreme degree in 11 patients and from an extreme to a severe degree in 3 patients. CONCLUSION: The most effective treatment for SIB that is resistant to environment changes and behavior modification in persons with developmental disabilities is the treatment of their psychiatric disorders with the appropriate psychotropics.

Changes during hibernation in different phospholipid and free and esterified cholesterol serum levels in black bears.

During hibernation, fat is known to be the preferred source of energy. A detailed analysis of different phospholipids, as well as free and esterified cholesterol, was conducted to investigate lipid abnormalities during hibernation. The levels of total phospholipids and total cholesterol in the serum of black bears were found to increase significantly in hibernation as compared with the active state. Both free and esterified cholesterol were increased in the hibernating state in comparison with the active state (P < 0.05). The percentage increase during hibernation was more in free cholesterol (57%) than in esterified cholesterol (27%). Analysis of subclasses of serum phospholipids showed that choline containing phospholipids, i.e., sphingomyelin (SPG) (14%) and phosphatidylcholine (PC) (76%), are the major phospholipids in the serum of bear. The minor phospholipids included 8% of phosphatidylserine (PS) + phosphatidylinositol (PI), while phosphatidylethanolamine (PE) was only 2% of the total phospholipids. A comparison of phospholipid subclasses showed that PC, PS + PI and SPG were significantly increased, while PE was significantly decreased (P < 0.05) in the hibernating state as compared with the active state in black bears. These results suggest that the catabolism of phospholipids and cholesterol is decreased during hibernation in black bears, leading to their increased levels in the hibernating state as compared with the active state. In summary, our results indicate that serum cholesterol and phospholipid fractions (except PE) are increased during hibernation in bears. It is proposed that the increase of these lipids may be due to the altered metabolism of lipoproteins that are responsible for the clearance of the lipids.