Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 µm² in CA1 (mean ± SEM: MD = 9.2 ± 0.6 and BD = 8.4 ± 0.6) and subiculum (BD = 6.7 ± 0.4) when compared to control group (6.6 ± 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 ± 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development.

Opioidergic orofacial antinociception induced by electroacupuncture at acupoint St36

The participation of opioids in the antinociceptive effect of electroacupuncture was evaluated in terms of nociception produced by thermal stimuli applied to the face of male Wistar rats, weighing 180-230 g. Electrical stimulation (bipolar and asymmetric square wave with 0.5 mA intensity for 20 min) of acupoint St36, located in the anterior tibial muscle 10 mm distal to the knee joint, induced antinociception in the present model, which was maintained for 150 min. Acupoint LI4, located in the junction of the first and second metacarpal bones, did not achieve antinociception at any frequency studied (5 Hz: 1.7 ± 0.1; 30 Hz: 1.8 ± 0.1; 100 Hz: 1.7 ± 0.1 vs 1.4 ± 0.2). The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency 100 Hz (3.0 ± 0.2 vs 1.0 ± 0.1) was used, and not with 5 or 30 Hz (1.2 ± 0.2 and 0.7 ± 0.1 vs 1.0 ± 0.1). The antinociceptive effect of acupuncture occurred by opioid pathway activation, since naloxone (1 and 2 mg/kg, subcutaneously) antagonized it (1.8 ± 0.2 and 1.7 ± 0.2 vs 3.0 ± 0.1).

Genetics of homocysteine metabolism and associated disorders

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

Pain-related diseases and sleep disorders

Pain and sleep share mutual relations under the influence of cognitive and neuroendocrine changes. Sleep is an important homeostatic feature and, when impaired, contributes to the development or worsening of pain-related diseases. The aim of the present review is to provide a panoramic view for the generalist physician on sleep disorders that occur in pain-related diseases within the field of Internal Medicine, such as rheumatic diseases, acute coronary syndrome, digestive diseases, cancer, and headache.

Psychiatric disorders and cardiac anxiety in exercising and sedentary coronary artery disease patients: a case-control study

Regular physical exercise has been shown to favorably influence mood and anxiety; however, there are few studies regarding psychiatric aspects of physically active patients with coronary artery disease (CAD). The objective of the present study was to compare the prevalence of psychiatric disorders and cardiac anxiety in sedentary and exercising CAD patients. A total sample of 119 CAD patients (74 men) were enrolled in a case-control study. The subjects were interviewed to identify psychiatric disorders and responded to the Cardiac Anxiety Questionnaire. In the exercise group (N = 60), there was a lower prevalence (45 vs 81%; P < 0.001) of at least one psychiatric diagnosis, as well as multiple comorbidities, when compared to the sedentary group (N = 59). Considering the Cardiac Anxiety Questionnaire, sedentary patients presented higher scores compared to exercisers (mean ± SEM = 55.8 ± 1.9 vs 37.3 ± 1.6; P < 0.001). In a regression model, to be attending a medically supervised exercise program presented a relevant potential for a 35% reduction in cardiac anxiety. CAD patients regularly attending an exercise program presented less current psychiatric diagnoses and multiple mental-related comorbidities and lower scores of cardiac anxiety. These salutary mental effects add to the already known health benefits of exercise for CAD patients.

Expression of MMP-2 and MMP-9 in the rat trigeminal ganglion during the development of temporomandibular joint inflammation

Orofacial pain is a prevalent symptom in modern society. Some musculoskeletal orofacial pain is caused by temporomandibular disorders (TMDs). This condition has a multi-factorial etiology, including emotional factors and alteration of the masticator muscle and temporomandibular joints (TMJs). TMJ inflammation is considered to be a cause of pain in patients with TMD. Extracellular proteolytic enzymes, specifically the matrix metalloproteinases (MMPs), have been shown to modulate inflammation and pain. The purpose of this investigation was to determine whether the expression and level of gelatinolytic activity of MMP-2 and MMP-9 in the trigeminal ganglion are altered during different stages of temporomandibular inflammation, as determined by gelatin zymography. This study also evaluated whether mechanical allodynia and orofacial hyperalgesia, induced by the injection of complete Freund's adjuvant into the TMJ capsule, were altered by an MMP inhibitor (doxycycline, DOX). TMJ inflammation was measured by plasma extravasation in the periarticular tissue (Evans blue test) and infiltration of polymorphonuclear neutrophils into the synovial fluid (myeloperoxidase enzyme quantification). MMP expression in the trigeminal ganglion was shown to vary during the phases of the inflammatory process. MMP-9 regulated the early phase and MMP-2 participated in the late phase of this process. Furthermore, increases in plasma extravasation in periarticular tissue and myeloperoxidase activity in the joint tissue, which occurred throughout the inflammation process, were diminished by treatment with DOX, a nonspecific MMP inhibitor. Additionally, the increases of mechanical allodynia and orofacial hyperalgesia were attenuated by the same treatment.

Early detection of metabolic and energy disorders by thermal time series stochastic complexity analysis

Maintenance of thermal homeostasis in rats fed a high-fat diet (HFD) is associated with changes in their thermal balance. The thermodynamic relationship between heat dissipation and energy storage is altered by the ingestion of high-energy diet content. Observation of thermal registers of core temperature behavior, in humans and rodents, permits identification of some characteristics of time series, such as autoreference and stationarity that fit adequately to a stochastic analysis. To identify this change, we used, for the first time, a stochastic autoregressive model, the concepts of which match those associated with physiological systems involved and applied in male HFD rats compared with their appropriate standard food intake age-matched male controls (n=7 per group). By analyzing a recorded temperature time series, we were able to identify when thermal homeostasis would be affected by a new diet. The autoregressive time series model (AR model) was used to predict the occurrence of thermal homeostasis, and this model proved to be very effective in distinguishing such a physiological disorder. Thus, we infer from the results of our study that maximum entropy distribution as a means for stochastic characterization of temperature time series registers may be established as an important and early tool to aid in the diagnosis and prevention of metabolic diseases due to their ability to detect small variations in thermal profile.

Serum uric acid and disorders of glucose metabolism: the role of glycosuria

Hyperuricemia has been associated with hypertension, diabetes mellitus, and metabolic syndrome. We studied the association between hyperuricemia and glycemic status in a nonrandomized sample of primary care patients. This was a cross-sectional study of adults ≥20 years old who were members of a community-based health care program. Hyperuricemia was defined as a value >7.0 mg/dL for men and >6.0 mg/dL for women. The sample comprised 720 participants including controls (n=257) and patients who were hypertensive and euglycemic (n=118), prediabetic (n=222), or diabetic (n=123). The mean age was 42.4±12.5 years, 45% were male, and 30% were white. The prevalence of hyperuricemia increased from controls (3.9%) to euglycemic hypertension (7.6%) and prediabetic state (14.0%), with values in prediabetic patients being statistically different from controls. Overall, diabetic patients had an 11.4% prevalence of hyperuricemia, which was also statistically different from controls. Of note, diabetic subjects with glycosuria, who represented 24% of the diabetic participants, had a null prevalence of hyperuricemia, and statistically higher values for fractional excretion of uric acid, Na excretion index, and prevalence of microalbuminuria than those without glycosuria. Participants who were prediabetic or diabetic but without glycosuria had a similarly elevated prevalence of hyperuricemia. In contrast, diabetic patients with glycosuria had a null prevalence of hyperuricemia and excreted more uric acid and Na than diabetic subjects without glycosuria. The findings can be explained by enhanced proximal tubule reabsorption early in the course of dysglycemia that decreases with the ensuing glycosuria at the late stage of the disorder.

Gender, race and socioeconomic influence on diagnosis and treatment of thyroid disorders in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Thyroid diseases are common, and use of levothyroxine is increasing worldwide. We investigated the influence of gender, race and socioeconomic status on the diagnosis and treatment of thyroid disorders using data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multicenter cohort study of civil servants (35-74 years of age) from six Brazilian cities. Diagnosis of thyroid dysfunction was by thyrotropin (TSH), and free thyroxine (FT4) if TSH was altered, and the use of specific medications. Multivariate logistic regression models were constructed using overt hyperthyroidism/hypothyroidism and levothyroxine use as dependent variables and sociodemographic characteristics as independent variables. The frequencies of overt hyper- and hypothyroidism were 0.7 and 7.4%, respectively. Using whites as the reference ethnicity, brown, and black race were protective for overt hypothyroidism (OR=0.76, 95%CI=0.64-0.89, and OR=0.53, 95%CI=0.43-0.67, respectively, and black race was associated with overt hyperthyroidism (OR=1.82, 95%CI=1.06-3.11). Frequency of hypothyroidism treatment was higher in women, browns, highly educated participants and those with high net family incomes. After multivariate adjustment, levothyroxine use was associated with female gender (OR=6.06, 95%CI=3.19-11.49) and high net family income (OR=3.23, 95%CI=1.02-10.23). Frequency of hyperthyroidism treatment was higher in older than in younger individuals. Sociodemographic factors strongly influenced the diagnosis and treatment of thyroid disorders, including the use of levothyroxine.

Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion

Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise.

International adoption: Symptoms of attachment disorders and their associations with the child’s background and developmental outcome

Many internationally adopted children have lived their first years of life in an environment with limited opportunities for primary caregiving. The lack of consistent care increases the prevalence of attachment disorders among them. Less is known about the influences of attachment disorders on a child’s later course of life. This study is part of the Finnish Adoption Study. Parents of all Finnish children who had been internationally adopted by legal adoption organisations between 1985 and 2007 were sent questionnaires (N=1450). Parental evaluations of the children’s symptoms of reactive attachment disorder (RAD) at the time of adoption, their later learning or language problems using a screening scale, and children’s self-reported school bullying experiences were evaluated. Each child’s attachment-related behavioural problems were requested in a follow-up survey 1.9 and 3.8 years after adoption and compared with a Finnish reference group. This study indicated that Finnish internationally adopted children have at least three-fold prevalence of learning and language problems compared with their age-mates. A child’s symptoms of attachment disorders were associated with learning or language problems at school age as well as with his/her school bullying experiences. The adopted children had more attachment-related behavioural problems two years after adoption than their age-mates, but the difference was no longer evident four years after adoption. In conclusion, this study showed that the symptoms of attachment disorder indicate a risk for an adopted child’s later developmental outcome. The findings demonstrate the need for comprehensive clinical examinations and planning of treatment strategies for children with symptoms of RAD.

Gut Microbiota and Metabolic Disorders

Obesity and its co-morbidities, such as metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, have increased over the last few decades like an epidemic. So far the mechanisms of many metabolic diseases are not known in detail and currently there are not enough effective means to prevent and treat them. Several recent studies have shown that the unbalanced gut microbiota composition (GMC) and activity have an influence on the fat accumulation in the body. Further, it seems that the GMC of obese individuals differs from the lean. The aim of this study was to investigate whether there are differences between the GMC of metabolically impaired overweight/obese (MetS group), metabolically healthy overweight/obese and normal-weight individuals. In addition, the mechanisms by which the gut bacteria as well as their specific structures, such as flagellin (FLG) that stimulates the Toll-like receptor 5 (TLR5) affect metabolism, were investigated both in vivo and in vitro in human adipocytes and hepatocytes. The results of this study show that the abundance of certain gram-positive bacteria belonging to the Clostridial cluster XIV was higher in the MetS group subjects compared to their metabolically healthy overweight/obese and lean counterparts. Metabolically impaired subjects tended to also have a greater abundance of potentionally inflammatory Enterobacteria in their gut and thus seemed to have aberrant GMC. In addition, it was found that subjects with a high hepatic fat content (HHFC group) had less Faecalibacterium prausnitzii in their gut than individuals with low hepatic fat content. Further gene expression analysis revealed that the HHFC group also had increased inflammation cascades in their adipose tissue. Additionally, metabolically impaired individuals displayed an increased expression of FLG-recognizing TLR5 in adipose tissue, and the TLR5 expression levels associated positively both with liver fat content and insulin resistance in humans. These changes in the adipose tissue may further contribute to the impaired metabolism observed, such as insulin resistance and dyslipidemia. In vitro -studies showed that the FLG-induced TLR5 activation in adipocytes enhanced the hepatic fat accumulation by decreasing insulin signaling and mitochondrial functions and increasing triglyceride synthesis due to increased glycerol secretion from adipocytes. In conclusion, the findings of this study suggest that it may be possible that the novel prevention and personalized treatment strategies based on GM modulation will succesfully be developed for obesity and metabolic disorders in the future.

Adherence to Treatment in Psychotic Disorders - Development of user-centered mobile health intervention

The aim of this study was to explore adherence to treatment among people with psychotic disorders through the development of user-centered mobile technology (mHealth) intervention. More specifically, this study investigates treatment adherence as well as mHealth intervention and the factors related to its possible usability. The data were collected from 2010 to 2013. First, patients’ and professionals’ perceptions of adherence management and restrictive factors of adherence were described (n = 61). Second, objectives and methods of the intervention were defined based on focus group interviews and previously used methods. Third, views of patients and professionals about barriers and requirements of the intervention were described (n = 61). Fourth, mHealth intervention was evaluated based on a literature review (n = 2) and patients preferences regarding the intervention (n = 562). Adherence management required support in everyday activities, social networks and maintaining a positive outlook. The factors restricting adherence were related to illness, behavior and the environment. The objective of the intervention was to support the intention to follow the treatment guidelines and recommendations with mHealth technology. The barriers and requirements for the use of the mHealth were related to technology, organizational issues and the users themselves. During the course of the intervention, 33 (6%) out of 562 participants wanted to edit the content, timing or amount of the mHealth tool, and 23 (4%) quit the intervention or study before its conclusion. According to the review, mHealth interventions were ineffective in promoting adherence. Prior to the intervention, participants perceived that adherence could be supported, and the use of mHealth as a part of treatment was seen as an acceptable and efficient method for doing so. In conclusion, the use of mHealth may be feasible among people with psychotic disorders. However, clear evidence for its effectiveness in regards to adherence is still currently inconclusive.

Early detection and intervention for infants at risk of autism spectrum disorders

Autism is a developmental disorder that is characterized by abnonnal social interactions and communications as well as repetitive and restricted activities and interests. There is evidence of a genetic component, as 5% of younger siblings are diagnosed if their older sibling has been diagnosed. Autism is generally not diagnosed until age 3 at the earliest, yet it has been shown that early intervention for children with autism can greatly increase their functioning. Because of this, it is important that symptoms of autism are identified as early as possible so that diagnosis can occur as soon as possible to allow these children the earliest intervention. This thesis was divided into two parts. The first looked at the psychometrics of two proposed measures, the Parent Observation Checklist (POC), administered monthly, and the Infant Behavior Summary Evaluation (mSE), administered bimonthly, to see if they can be used with the infant population to identify autistic symptoms in infants who are at high risk for autism or related problems because they have an older sibling with autism. Study 1 reported acceptable psychometric properties of both the POC and IBSE in terms of test-retest reliability, internal consistency, construct validity and predictive validity. These results provide preliminary evidence that parent report measures can help to detect early symptoms of ASD in infants. The POC was shown to differentiate infants who were diagnosed from a matched group that was not diagnosed by 3 years of age. The second part of this thesis involved a telephone interview of parents who reported developmental and/or behavior problems in their high-risk infants that may be early signs of Autism Spectrum Disorder (ASD). During the interview, a service questionnaire was administered to see what interventions (including strategies recommended by the researchers) their at risk infants and affected older siblings were receiving, how satisfied the parents were with them and how effective they felt the interventions were. 3 Study 2 also yielded promising results. Parents utilized a variety of services for at risk infants and children with ASD. The interventions included empirically validated early intervention (e.g., ABA) to non-empirically validated treatments (e.g., diet therapy). The large number of nonempirically validated treatments parents used was surprising, yet parents reported being involved and satisfied, and thought that the services were effective. Parents' perceptions of their stress levels went down slightly and feelings of competence rose when they accessed services for their infants. Overall, the results of this thesis provide new evidence that parent-report methods hold promise as early detection instruments for ASD in at-risk infants. More research is needed to further validate these instruments as well as to understand the variables related to the parents' choice of early intervention for their at risk and affected children.