Oral findings in paediatric patients with severe heart, liver, and kidney failure prior to organ transplantation.

PURPOSE: Organ transplantation is an effective treatment for children with severe heart, liver, and kidney diseases. These patient groups may have more oral and dental diseases than healthy controls. It is important to eliminate oral infection foci before transplantation and to maintain good oral health to avoid potential post-transplant complications. The aim of this study was to describe and compare oral health in Finnish paediatric heart, liver, and kidney transplant recipients prior to organ transplantation. METHODS: Eighty-six children who received a heart (n = 21), liver (n = 19), or kidney (n = 46) transplant in Finland during the years 2014-2018 were included in this study. The inclusion criterion was a pre-transplantation oral examination. Oral hygiene, enamel anomalies, and the number of decayed, missing, and filled teeth (dmft/DMFT) were analyzed retrospectively from medical and dental records and compared between the three patient groups. RESULTS: Children with liver (p = 0.043) or heart (p = 0.047) disease had higher combined primary and permanent dentition dmft/DMFT scores compared to children with kidney disease. A higher combined dmft/DMFT score was associated with poor oral hygiene (p = 0.005). No significant differences in oral hygiene between the patient groups were found. Furthermore, all patient groups had a high prevalence of developmental dental defects. CONCLUSION: Children with liver or heart disease seem to have a higher combined dmft/DMFT score, indicating a higher prevalence of caries compared to children with kidney disease. Prevention of dental caries, along with promoting a good oral hygiene routine and regular check-ups, is suggested in these patient groups.

Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort.

BACKGROUND: The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT) density in vivo with positron emission tomography (PET) in healthy individuals with high or low HA scores using an 'oversampling' study design. Method Subjects consistently in either upper or lower quartiles for the HA trait were selected from a population-based cohort in Finland (n = 2075) with pre-existing Temperament and Character Inventory (TCI) scores. A total of 22 subjects free of psychiatric and somatic disorders were included in the matched high- and low-HA groups. The main outcome measure was regional 5-HTT binding potential (BPND) in high- and low-HA groups estimated with PET and [11C]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ([11C]MADAM). In secondary analyses, 5-HTT BPND was correlated with other TCI dimensions. RESULTS: 5-HTT BPND did not differ between high- and low-HA groups in the midbrain or any other brain region. This result remained the same even after adjusting for other relevant TCI dimensions. Higher 5-HTT BPND in the raphe nucleus predicted higher scores in 'self-directedness'. CONCLUSIONS: This study does not support an association between the temperament dimension HA and serotonin transporter density in healthy subjects. However, we found a link between high serotonin transporter density and high 'self-directedness' (ability to adapt and control one's behaviour to fit situations in accord with chosen goals and values). We suggest that biological factors are more important in explaining variability in character than previously thought.

Increased infection risk postliver transplant without pretransplant dental treatment.

OBJECTIVE: Infections cause considerable morbidity after liver transplantation (LT). Acute liver failure is a rapidly progressing life-threatening condition where pretransplant dental evaluation is not always possible. We investigated how missing pretransplant dental treatment in acute or subacute liver failure correlates with post-transplant infectious complications. SUBJECTS AND METHODS: Medical and dental data came from hospital records and infection data from the Finnish LT registry. The follow-up was until February 2011. Of 51 patients (LT during 2000-2006), 16 had and 35 did not have dental treatment pretransplant. RESULTS: Univariate Cox regression analysis demonstrated a 2.46-fold (95% CI 1.06-5.69) infection risk among the patients omitted from dental treatment. After adjustment for either pretransplant factors alone or both pre- and post-transplant factors, the corresponding infection risk increased, respectively, to 8.17-fold (95% CI 2.19-30.6) and 8.54-fold (95% CI 1.82-40.1). This increased risk involved a variety of bacterial, viral, and fungal infections of various sources both < 6 and > 6 months after transplantation. CONCLUSION: High risk of infections was noticed in acute liver failure patients without pretransplant dental treatment, but a more severe medical condition might have influenced the results. We encourage eradication of dental infection foci whenever clinical condition allows.

No association between serotonin 5-HT 1A receptors and spirituality among patients with major depressive disorders or healthy volunteers.

An earlier study (Borg et al., Am J Psychiatry 2003) found an inverse correlation between [carbonyl-(11)C]WAY-100635 ligand binding to 5-HT(1A) receptors and scores for self-transcendence, but no other of the six dimensions of the Temperament and Character Inventory, in a group of healthy males. The aim of this study was to investigate if the finding of an inverse correlation between spirituality and 5-HT(1A) could be seen in patients suffering from major depressive disorder or replicated among healthy volunteers. A total of 23 patients with major depressive disorder and 20 healthy volunteers were examined with PET using [carbonyl-(11)C]WAY-100635 as the radioligand. The personality traits were measured using the Finnish version of the Temperament and Character Inventory and correlated with ligand binding (BP). No significant correlations were found between the different Temperament and Character Inventory subscales and BP in any of the studied brain regions (amygdala, anterior cingulate cortex, dorsal raphe nuclei, dorsolateral prefrontal cortex, angular gyrus, inferior, middle, and superior temporal gyri, medial prefrontal cortex orbitofrontal cortex, hippocampus, insular cortex, subgenual anterior cingulate cortex, supramarginal gyrus, ventrolateral prefrontal cortex, and posterior cingulate cortex). These results do not support the idea that the serotonin system forms the biological basis of spiritual experiences among patients suffering from major depressive disorder or among healthy volunteers.

Observation of the h(c)(1P) Using e+ e- collisions above the DD threshold.

Using 586 pb(-1) of e+ e- collision data at E(c.m.) = 4170 MeV, produced at the Cornell Electron Storage Ring collider and collected with the CLEO-c detector, we observe the process e+ e- → π+ π- h(c)(1P). We measure its cross section to be 15.6±2.3±1.9±3.0 pb, where the third error is due to the external uncertainty on the branching fraction of ψ(2S) → π0 h(c)(1P), which we use for normalization. We also find evidence for e+ e- → ηh(c)(1P) at 4170 MeV at the 3σ level and see hints of a rise in the e+ e- → π+ π- h(c)(1P) cross section at 4260 MeV.

Effect of childhood physical abuse on social anxiety is mediated via reduced frontal lobe and amygdala-hippocampus complex volume in adult clinical high-risk subjects.

BACKGROUND: Childhood adverse experiences (CAE) are associated with clinical psychiatric disorders and symptoms, and with volumetric abnormalities in the amygdala-hippocampus complex (AmHiC) and frontal lobe (FroL) in adulthood. AIM: To study whether CAE are associated with reduced AmHiC and FroL and whether these structures mediate the effect of CAE on social anxiety and depression. METHOD: In seven European centres, 374 patients with recent onset of psychosis (n = 127), clinical high-risk to psychosis (n = 119) or recent onset of depression (n = 128) were scanned with MRI and their FroL and AmHiC volumes were measured. They all completed self-report scales for assessment of CAE, social anxiety and depression. RESULTS: Of the CAE domains, physical abuse was associated specifically with reduced grey and white matter volumes of FroL and AmHiC in psychotic and high-risk patients. After controlling intracranial volume, PhyAb associated significantly with FroL and its grey matter volume in high-risk patients only. In mediation analyses, the effect of physical abuse on social anxiety was mediated via reduced FroL grey mater volume in high-risk patients. In them, when the effects of AmHiC and depression were controlled, the effect of physical abuse on social anxiety was mediated via FroL grey matter volume reduction. CONCLUSIONS: Childhood physical abuse is associated with reduced frontal lobe and amygdala-hippocampus complex volume in adult subjects with psychotic symptoms. Reduced frontal lobe and amygdala-hippocampus complex volume mediate the effect of physical abuse on social anxiety in high-risk patients. The effect of physical abuse on depression-independent social anxiety is mediated via reduced frontal lobe.

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain. OBJECTIVES: To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief. METHODS: We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and µ-opioid receptors using a randomized, sham-controlled, double-blinded crossover study design and 3D-positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E-field navigated device. Dopamine D2 and µ-receptor availabilities were assessed with PET radiotracers [11 C]raclopride and [11 C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans. RESULTS: µ-Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long-lasting measurable dopamine release. Active rTMS potentiated the dopamine-regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS. CONCLUSIONS: rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top-down opioid-mediated inhibition may partly explain the clinical analgesic effects of rTMS. SIGNIFICANCE: Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11 C-carfentanyl-PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top-down opioid-mediated inhibition but not change the sensory discrimination of painful stimuli.

Cigarette smoking in long-term schizophrenia.

PURPOSE: Cigarette smoking is a great health problem and prevalent among subjects with schizophrenia. Our aim was to investigate the prevalence and associations of cigarette smoking in patients with long-term schizophrenia. METHODS: Seven hundred and sixty schizophrenia patients were interviewed and their cigarette smoking was recorded. RESULTS: Smoking was more prevalent men than in women patients. In logistic regression analysis, male gender, duration of illness (DUI) from 10 to 19 years, being divorced or separated, lower education and high daily doses of neuroleptics (DDN) associated significantly with regular smoking. Heavy smoking associated, in men, with hospital treatment. CONCLUSIONS: In schizophrenia patients, smoking is associated with long DUI, high DDN and institutional care. Interventions for cessation and/or reduction of cigarette smoking should be a part of the treatment for patients with schizophrenia.

Dopamine D1 receptor antagonism in schizophrenia: is there reduced risk of extrapyramidal side-effects?

The first selective D1 dopamine receptor antagonist, SCH23390, has been reported to be active in preclinical tests that predict antipsychotic activity in schizophrenic patients. This is particularly exciting because it has been claimed that this compound is 'atypical', in that it has a reduced propensity to induce extrapyramidal side-effects. However, in considering the evidence from preclinical screening tests for antipsychotic activity and extrapyramidal side-effects of potential neuroleptic drugs, Jarmo Hietala and colleagues conclude that the majority of available data is not compatible with the postulated atypical profile of SCH23390.

Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography.

BACKGROUND: According to the D2 dopamine receptor hypothesis of schizophrenia, there is an increased number of D2 receptors in the brains of schizophrenic patients than in those of healthy controls. We tested this hypothesis in 13 newly admitted neuroleptic-naive schizophrenic patients and 10 healthy volunteers using positron emission tomography. METHOD: The quantification of striatal D2 dopamine receptor density (Bmax) and affinity (Kd) was done using an equilibrium model described for raclopride labeled with carbon 11. RESULTS: No statistically significant alterations were found in D2 receptor densities or affinities between the patient and control groups. However, a subgroup of four patients with a relatively high striatal D2 dopamine density was identified. Two patients, especially, had D2 dopamine densities almost twice as high as the mean control Bmax value. The Kd values also tended to be higher in this subset of patients than in the controls. No consistent striatal D2 dopamine receptor laterality was observed in schizophrenic patients or controls. However, an association of high D2 dopamine density in the left striatum and the mass of raclopride injected in the scan with low-specific radioactivity was observed in patients but not in controls. CONCLUSIONS: There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.

Long-term use of benzodiazepines: Definitions, prevalence and usage patterns - a systematic review of register-based studies.

BACKGROUND: Numerous treatment guidelines recommend that long-term use of benzodiazepines (BZD) should be avoided primarily due to development of tolerance and a risk for BZD dependence. Despite this, long-term BZD use remains a controversial subject in clinical patient care with "for and against" debates. However, there is no explicit understanding of what is meant by long-term BZD use in real world. The aim of this study was to assess different definitions, usage patterns, prevalence and other characteristics of long-term BZD use based on published register-based studies. Synthesis of these characteristics is essential to derive a meaningful definition of long-term BZD. METHODS: Systematic review of register-based studies on long-term BZD use published in 1994-2014. RESULTS: Fourty-one studies met our predetermined inclusion criteria. The length of BZD use defined as "long-term" varied in these studies ranging from one month to several years. The most common definition was six months or longer during a year. The prevalence of long-term BZD use in the general population was estimated to be about 3%. The relative proportion of long-term BZD users (all definitions) in adult BZD users ranged from 6% to 76% (mean 24%; 95% CL 13-36%). The estimates were higher in studies only on the elderly (47%; 95% CL 31-64%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found. CONCLUSIONS: Long-term BZD use is common and a clinical reality. Uniform definitions for "long-term", which is in line with population-based evidence, is needed to have more comparable results between studies. Our systematic review suggests that duration of BZD treatment over six months, the most common definition for long-term BZD use in the included studies. As also recommended previously, it is a useful starting point for further analyses on disadvantages but also potential advantages associated with long-term BZD use.

The dopamine D2 receptor 5'-flanking variant, -141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo.

The Del allele of the -141C (Ins/Del) polymorphism located in the immediate 5'-flanking region of the human dopamine D2 receptor gene has been reported to be associated with reduced promoter activity in vitro. However, genetic association studies of the -141C (Ins/Del) polymorphism with schizophrenia and alcoholism have yielded conflicting results. In this report, we explored the effect of the Del allele on the D2 receptor binding characteristics in vivo in healthy volunteers using positron emission tomography and D2 receptor antagonist, [11C]raclopride. No difference in D2 receptor density was observed between the Del allele carriers compared to the individuals with the Ins/Ins genotype, indicating that the genetic variation at the -141C (Ins/Del) site does not affect D2 receptor expression level in vivo.

Measurement of cortical dopamine d1 receptor binding with 11C[SCH23390]: a test-retest analysis.

[11C]SCH 23390 is a standard ligand for positron emission tomography (PET) studies on striatal dopamine D1 receptors. Its usefulness for cortical D1 receptor quantification in human PET studies has been questioned but has not been addressed previously. The authors tested the reproducibility of [11C]SCH 23390 binding potential (BP) in cortical areas in five healthy volunteers using three-dimensional PET. Measurement of D1 receptor BP was reproducible in basal ganglia, as well as in all cortical areas studied (intraclass correlation coefficients between 0.81 and 0.92). The absolute variability in cortical areas was 9.21% +/- 0.07%. The reproducibility of cortical D1 receptor BP measurement with [11C]SCH 23390 is equal to that observed with a more recent D1-ligand, [11C]NNC 112. [11C]NNC 112 produces slightly higher specific-to-nonspecific binding ratios but has markedly slower kinetics resulting in a need for a longer scan time. These aspects should be considered when designing studies on the cortical D1-like receptors.

Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: a test-retest analysis.

Subacute and long-term stability of measurements of D2 dopamine receptor density (Bmax), affinity (Kd) was studied with positron emission tomography in eight healthy male volunteers. [11C]-Raclopride and the transient equilibrium method were used to measure D2 receptor characteristics. The interval between measurements (scan pairs) was 3 to 7 weeks (subacute) for four subjects and 6 to 11 months (long-term) for four subjects. A test-retest analysis of quantitative measurements of D2 receptor Bmax and Kd was compared with that done on binding potential (BP, Bmax/Kd) measures. In addition, the effect of error in defining the transient equilibrium time (tmax) in the parameter estimation procedure was explored with simulations. The subacute test-retest indicates good reproducibility of D2 receptor density, affinity, and BP ratio measurements with intraclass correlation coefficients of 0.90, 0.96, and 0.86, respectively. The variability of the measurements after 6 to 11 months was slightly higher than that seen in a subacute testing for Kd and more clearly so for binding potential and Bmax. The absolute variability in Bmax (14.5%) measurements was consistently higher than that of Kd (8.4%) or BP (7.9%) both in subacute and long-term measurements. Simulations indicated that the Bmax and Kd estimation procedure is more sensitive to error in the tmax than that for the BP. The results indicate a good overall stability of the equilibrium method with [11C]raclopride for measuring dopamine D2 receptor binding characteristics in the striatum. The BP approach is more stable than Kd and especially Bmax measurements. Error in defining the tmax in particular in the low specific radioactivity scan may be one source of greater variability in Bmax versus BP. However, a higher intraindividual variability in measurements of the D2 receptor Bmax also may include a component of continuous regulation of this parameter over time. These methodologic aspects should be considered in the design and interpretation of longitudinal studies on D2 dopamine receptor characteristics with [11C]-raclopride.

Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding.

Several approaches have been applied for quantification of D2 dopamine receptors in positron emission tomography studies using [11C]raclopride. Initial approaches were based on analyses of data obtained after rapid bolus injection of [11C]raclopride. A continuous infusion paradigm has more recently been applied. The current study compares these approaches in healthy men. Two positron emission tomography measurements were performed in each of six healthy men, the first with rapid bolus injection and the second with continuous infusion of [11C]raclopride. In rapid bolus injection, the binding potential was calculated by the following methods. One approach is the kinetic analysis using the standard three-compartment model. Another is to define a transient equilibrium at the moment when the specific binding reaches its maximum. In continuous infusion, binding potential was calculated by using time-activity data at equilibrium condition. All methods gave almost identical binding potential, representing cross-validation of these methods. The continuous infusion method can provide "true" equilibrium condition. The kinetic analysis is a sophisticated approach but requires determination of an arterial input function. The transient equilibrium method thus is suitable for routine clinical research, since it does not require determination of an arterial input function.

Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain.

Loss of dopamine D2-like receptors in the striatum has been associated with both normal human aging and impairment of cognitive and motor functions in the elderly. To investigate whether there are age-associated changes in dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the striatum, a D2/3R selective high-affinity radioligand [11C]FLB 457 was used in positron emission tomography (PET) examinations for 24 normal healthy male subjects (age range 19-74 years). Significant age-related declines of D2/3Rs were detected in all the brain regions studied: the anterior cingulate cortex (decline of 13% per increase of a decade in age, P < 0.001). the frontal cortex (11%, P < 0.001), the lateral temporal cortex (10%, P < 0.001), the hippocampus (10%, P < 0.01), the medial temporal cortex (9%, P < 0.001), the amygdala (7%, P < 0.01), the medial thalamus (6%, P < 0.001) and the lateral thalamus (5%, P < 0.01). The rate of D2/3R decline was significantly faster in the frontal cortex as compared to the medial temporal cortex (P < 0.05, Bonferroni corrected) and as compared to the medial thalamus (P < 0.05, Bonferroni corrected). These results indicate that the previously demonstrated age-related decline in striatal dopamine D2 receptors extends to several extrastriatal regions in normal human males. Further, the rate of D2/3R decline may be faster in the frontal cortex as compared to the temporal and thalamic regions.

Noradrenergic and dopaminergic effects of nomifensine in healthy volunteers.

Intravenous doses (100 mg in 20 minutes) of the antidepressant drug nomifensine, administered to male volunteers, increased heart rate and blood pressure, elevated the plasma levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and powerfully stimulated growth hormone release and inhibited the secretion of prolactin. Oral nomifensine, either as a single 100 mg dose or as a similar dose after 2 weeks' treatment with the drug (150 mg/day), caused none of the above effects. This was in line with the limited (less than 30%) oral bioavailability of the active, unconjugated form of the drug, estimated in the same subjects. MHPG in plasma was slightly but consistently reduced by the 2 weeks' treatment, suggesting reduced turnover of norepinephrine. The observed clinical effects of nomifensine are compatible with uptake inhibition and augmented release of norepinephrine and dopamine and possibly direct agonistic effects on dopamine receptors. Although nomifensine was withdrawn from the market because of immunologic complications, it serves as a model compound of a new pharmacologic class of antidepressants, devoid of many of the disturbing side effects of the tricyclic drugs.

Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo.

OBJECTIVE: The authors investigated whether striatal dopamine D2 receptor binding characteristics in vivo are similar in men and women and whether there are sex-related differences in the decline in D2 receptor density due to aging. METHOD: Striatal D2 receptor density (Bmax), affinity (Kd), and binding potential (Bmax/Kd) were measured with positron emission tomography and [11C]raclopride in 54 healthy subjects (33 men and 21 women). RESULTS: Women had generally lower D2 receptor affinity than men, and this difference was statistically significant in the left striatum. Bmax and Bmax/Kd tended to decline with age twice as fast in men as in women, but the difference did not reach statistical significance. CONCLUSIONS: These results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo. The lower D2 receptor affinity suggests an increased endogenous striatal dopamine concentration in women. This may have implications for the differential vulnerability of men and women to psychiatric disorders like schizophrenia and alcohol and substance dependence.