Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [11C]PBR28 positron emission tomography.

Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [11C]PBR28. The outcome measure was total distribution volume (VT) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome VT or when normalizing VT to the lateral occipital cortex (p > 0.05). RA patients had numerically lower VT values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [11C]PBR28 VT in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [11C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.

OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity.

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study.

The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [11C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

[Comparing of Treatment Results of Monocanalicular and Bicanalicular Intubation in Inborn Lacrimal Duct Obstruction]. / Srovnání lécebných výsledku monokanalikulární a bikanalikulární intubace u vrozené nepruchodnosti slzovodu.

PURPOSE: To compare the success rate of monocanalicular (MI) and bicanalicular intubation (BI) in congenital nasolacrimal duct obstruction (CNLDO). METHODS: MI through the inferior canaliculus and BI were performed under general anaesthesia in children from 7 to 24 months old with CNLDO. Only children after unsuccessful conservative therapy and two and more probings were included in the study. The tubes were removed 3 months after intubation and the therapeutic success was evaluated 6 months after intubation. RESULTS: There were performed 139 MI in 114 children and 119 BI in 88 children. The success rate 6 months after intubation is 135/139 (97.1%) in MI, 114/119 (95.8%) in BI and the difference in therapeutic results between MI and BI is not significant (p = 0.737). CONCLUSION: Silicone intubation is an effective procedure for treating CNLDO without difference in therapeutic success between MI and BI.Key words: congenital nasolacrimal duct obstruction (CNLDO), monocanalicular intubation (MI), bicanalicular intubation (BI).

Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects.

PURPOSE: The PET radioligand [(11)C]PBR28 binds to the translocator protein (TSPO), a marker of brain immune activation. We examined the reproducibility of [(11)C]PBR28 binding in healthy subjects with quantification on a regional and voxel-by-voxel basis. In addition, we performed a preliminary analysis of diurnal changes in TSPO availability. METHODS: Twelve subjects were examined using a high-resolution research tomograph and [(11)C]PBR28, six in the morning and afternoon of the same day, and six in the morning on two separate days. Regional volumes of distribution (V T) were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. RESULTS: For the whole sample, the mean absolute variability in V T in the grey matter (GM) was 18.3 ± 12.7 %. Intraclass correlation coefficients in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 min yielded a variability of 16.9 ± 14.9 %. There was a strong correlation between the parametric and 2TCM-derived GM values (r = 0.99). A significant increase in GM V T was observed between the morning and afternoon examinations when using secondary methods of quantification (p = 0.028). In the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91-min 2TCM data. CONCLUSION: V T of [(11)C]PBR28 binding showed medium reproducibility and high reliability in GM regions. Our findings support the use of parametric approaches for determining [(11)C]PBR28 V T values, and indicate that the acquisition time could be shortened. Diurnal changes in TSPO binding in the brain may be a potential confounder in clinical studies and should be investigated further.

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder.

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [(11)C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSAS(anx) change on D2-R-binding potential (BP(ND)) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BP(ND) and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.

Revison endonasal dacryocystorhinostomies: analysis of 44 procedures.

PURPOSE: To determine the success rate of revision endoscopic dacryocystorhinostomies (DCR) and to analyse 44 revision DCRs. METHODS: The operative and postoperative data were collected in 44 revision DCRs. The corrections of associated structural anatomic alterations were performed during the surgery (resection of the scarr, the bone window creating, resection of the head of the middle turbinate, septoplasty, ethmoidectomy etc.) and the intubation was performed in all cases. RESULTS: The follow-up interval ranged from 12 to 36 months. The 44 ReEDCRs were performed in adults and there were only 5 children under the age of 15. The surgery was performed under local or general anaesthesia. The most frequent secondary procedures were scar resections, creating a wider bone window, and partial middle turbinate resection. Four patients were excluded for their follow-up periods had not been completed. An average time of the tubes removal was 5.6 months. The total success rate was 84.0%; the success rate was 85.7% in the group with closed rhinostomy and 1/2 in the group of canalicular and rhinostomy obstructions. CONCLUSIONS: The endonasal revision DCR is a safe and very effective surgical procedure following the failed DCRs. The correction of associated structural anatomic alterations that may be involved in the failure of previous surgeries can be easily performed.

[Bilateral simultaneous dacryocystorhinostomy and conjunctivocystorhinostomy]. / Oboustranná simultánni dakryocystorinostomie a konjunktivocystorinostomie.

In patients with bilateral symptoms of lacrimal pathways occlusion, the endonasal dacryocystorhinostomy (EDCR) and conjunctivo-dacryocystorhinostomy (CDCR) may be performed simultaneously or consequently. The simultaneous bilateral surgery does not worsen the surgery results. The advantages of this procedure are one anesthesia only, only unsubstantial extension of the surgery duration, and shorter sick leave as well. The authors performed during the period from 1995 to 2007 altogether 630 primary EDCRes and 117 CDCRes. In 92 patients, 184 simultaneous dacryocystorhinostomies were performed. Out of 164 evaluated surgeries, the good results were obtained in 150 cases (91.5 %). Out of 40 simultaneously performed CDCRes (20 patients), they were successful in 14 patients. Unsuccessful they were in 3 patients in whom the silicone drainage implant was used.

The triple classification of dry eye for practical clinical use.

PURPOSE: "Dry Eye is a condition produced by the inadequate interrelation between lacrimal film and ocular surface epithelium, and is caused by quantitative and qualitative deficits in one or both of them. It can be produced by one or combined etiologic causes, affecting one or several of the secretions of the glands serving the ocular surface, and producing secondary manifestations of different grades of severity". Clinicians need a practical classification to face diagnosis, prognosis and treatment. Dry eyes have many etiologies and pathogenesis, different affectation of the various dacryoglands and ocular surface epithelium, and diverse grades of severity. The specialists in xero-dacryology must know these three parameters to evaluate any case of dry eye, and to establish an adequate treatment. METHODS: To facilitate this, an open session in the 8th congress of the International Society of Dacryology and Dry Eye (Madrid, April, 2005) proposed modifying the Triple Classification of dry eye approved in the XIV congress of the European Society of Ophthalmology (Madrid, June, 2003). There was consensus of all conclusions. CONCLUSIONS: The following classification has been established: First, a classification of the etio-pathogenesis, distributed in ten groups: age-related, hormonal, pharmacologic, immunopathic, hyponutritional, dysgenic, infectious/inflammatory, traumatic, neurologic and tantalic. Second, a classification of the affected glands and tissues, which under the acronym of ALMEN includes the Aqueo-serousdeficient, Lipodeficient, Mucindeficient and Epitheliopatic dry eyes, and the Non dacryological affected exocrine glands (saliva, nasal secretion, tracheo-pharyngeal secretion, etc). And thirdly, a classification of severity, in three grades: Grade 1 or mild (symptoms without slitlamp signs), grade 2 or moderate (symptoms with reversible signs), and grade 3 or severe (symptoms with permanent signs).

[Conjunctivocystorhinostomy--seven years of experience--part I (Description of the surgery, groups of patients)]. / Konjunktivocystorinostomie--sedmileté zkusenosti I (Popis operace, sestava).

The principle of conjunctivocystorhinostomy according to Jones consists in creating new way (tunnel) between the conjunctival sac and the nasal cavity where the drainage of tears is possible through a hollow tube made from allogenic material implanted into the tunnel. The main indication for performing the conjunctivocystorhinostomy is the obliteration of the proximal part of both lacrimal canaliculi. The operation consists of two parts--dacryorhinostomy (DCR) and the insertion of the draining tube. DCR may be performed from an external access, or from an endonasal access, which is preferred by the authors. Authors present altogether 74 surgeries, which were performed during the period of 1996-2002 in 59 patients, (55 women, 19 men) mostly in the group of 51-60 years of age. During the surgery, they use the glass tubes only, because, in contrast to the silicone ones, they become not to be obstructed. In 11 cases the loss of the tubing occurred. To prevent the possibility of the loss and the migration of the tube, the authors fixate it always with a stitch to the lower eyelid.

[Conjunctivocystorhinostomy--seven years of experience--part II (Commentary)]. / Konjunktivocystorinostomie--sedmileté zkusenosti II (Komentár).

The authors answer the frequent questions concerning conjunctivo-cystorhinostomy (CDCR) according to Jones. The surgery is successful in 80-90%. The minimal age for the surgery is 10 years of age; patients 70 years old and older tolerate the operation less well. The basic prerequisite for its indication is good motivation of the patient. In the glass tube, the obstruction is not common, and there is the reason why the authors prefer them. The tube remains in situ during the whole life. In contrast to dacryocystorhinostomy, in CDCR the complication ratio is higher--up to 2/5 of patients. Fixation of the tube to the eyelid with a stitch lowers the number of commonest complications (loss and migration of the tube medially).

[Significance of the fluorescein dye disappearance test (FDDT) in the removal of the silicone cannula and prognosis in congenital lacrimal duct obstruction]. / Význam FDDT (fluorescein dye disappearance test) pro termín odstranení silikonové kanyly a prognózu vrozené nepruchodnosti slzných cest.

OBJECTIVE: Assessment of the prognostic value of the FDD test (fluorescein dye disappearance test) for treatment of congenital occlusion of the lacrimal pathways by means of silicone intubation and for assessment of the time of removal of the cannula. METHOD: The drainage function of the lacrimal pathways was evaluated perspectively in a group of 46 children with inborn occlusion of the lacrimal pathways, aged 1-3 years, treated by means of silicone intubation. The evaluation was made before insertion of the cannula, one week, one month after the operation, during removal of the cannula, one month and one year after its removal. The results of FDDT were compared with the clinical condition and the therapeutic results. RESULTS: In all instances (36 children) where shortly after surgery regression of the signs and symptoms of occlusion occurred and FDDT was 0-1 the long-term result (one year after removal of the cannula) of treatment was favourable. Nine of 11 cases where FDDT 2-3 and signs of occlusion persisted also when the cannula was removed after its removal marked improvement of the symptoms of occlusion occurred or they disappeared and the drainage of the lacrimal pathways was normal. If FDDT suggests during the period with the inserted cannula a satisfactory function of the lacrimal pathways, the prognosis of cure is good and the cannula can be removed already after 6-8 weeks. If during the time with the cannula the impaired drainage function of the lacrimal pathways persists, i.e. FDDT 2-3, it is better to remove the cannula not sooner than after 5-6 months. CONCLUSION: FDDT can serve as a prognostic factor in the treatment of congenital occlusion of the lacrimal pathways by means of a silicone cannula and for assessment of the time of its removal.

[Dacryolithiasis--analysis of 15 cases]. / Dakryolitiáza--rozbor 15 prípadu.

Dacryoliths are found in 15-20% patients subject to dacryocystorhinostomy. Dacryoliths are formed by proteins or calcium and phosphate salts. In the development or dacryolithiasis participates chronic inflammation of the sac, it is found more frequently in women where some part is played by the structure of the lacrimal duct, hormonal influence and the use of cosmetic preparations. A typical sign of the disease in the variability of complaints and results of clinical examinations. Assessment of the diagnosis before surgery can be facilitated by dacryocystography. The method of choice in dacryolithiasis is dacryocystorhinostomy. The authors present their own group of 16 dacryolithis which they observed 10x in women and 5x men. The concrements were examined by the method of infrared spectroscopy and gas chromatography. All were formed by proteins; calcium and phosphate salts were not found In all patients after dacryocystorhinostomy the complaints disappeared.