Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia.

BACKGROUND: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. METHOD: The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. RESULTS: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. CONCLUSIONS: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy.

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

Reference values of fetal aortic flow velocity waveforms and associated intra-observer reliability in normal pregnancies.

OBJECTIVES: It was the aim of the present study to calculate new Doppler reference ranges for blood flow velocities (Vmax, Vmean, Vmin) and resistance indices (PI, RI) for the fetal descending aorta by automatic waveform analysis. DESIGN: Cross-sectional prospective study. SUBJECTS: Nine hundred and twenty-six low-risk pregnancies at 18-41 weeks' gestation. METHODS: Aortic blood flow velocities were derived with pulsed-wave color Doppler. Measurements were carried out at the level of the diaphragm. Reference ranges for the individual measuring parameters were constructed based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. Further investigated were intra-observer reliability and the influence exerted by different measuring sites (aortic arch, diaphragm, below the renal vessels) on the aortic Doppler flow spectrum. RESULTS: Although a significant increase in aortic blood flow velocity was observed at 18-41 weeks' gestation (Vmax = 48.2 cm/s to 110.3 cm/s (P < 0.001), Vmean = 20 cm/s to 47.5 cm/s (P < 0.001) and Vmin = 7.6 cm/s to 18.6 cm/s (P < 0.001)), there were no significant changes in the pulsatility or resistance indices. The resistance indices PI and RI as well as absolute blood flow velocities (Vmax, Vmin) were significantly lower with increasing distance from the heart. Initial decreases were measured between the aortic arch and the diaphragm: PI, 2.34 to 1.87 (P < 0.0001); RI, 0.87 to 0.79 (P < 0.0001); Vmin: 8.5 cm/s to 15.0 cm/s (P < 0.0001). Furthermore, systolic blood flow velocities (Vmax) were decreased below the renal vessels from 97 cm/s to 64 cm/s (P < 0.0007). No significant changes were recorded in intensity-weighted mean flow velocities (Vmean). The intra-observer reliability was low, but of no clinical relevance. CONCLUSIONS: At constant measuring conditions, the reference ranges for blood flow velocities and resistance indices in the fetal aorta calculated by the authors serve as the basis for Doppler ultrasound antenatal examinations in a normal patient population and enable the early diagnosis of fetal risk.

Reference values of ductus venosus flow velocities and calculated waveform indices.

In recent years, investigations of the venous vascular system have become increasingly important in the assessment of fetal myocardial function. The aim of the present Doppler ultrasound study was to establish both new reference ranges for blood flow velocity during the different phases of the cardiac cycle (S, SD, D, a) and various calculated indices ((S-a)/S, (S-a)/V(mean), (S-a)D, S/D, a/S, S/a) for the ductus venosus. Pulsed-wave colour Doppler was used in this prospective cross-sectional study to examine 696 women with low-risk pregnancies during the period from 14 to 41 weeks' gestation. Reference curves were constructed for the individual measuring parameters based on a growth function from a four-parameter class of monotonic continuous functions according to the smallest square principle. A significant increase in blood flow velocity from 48 cm/s to 65.8 cm/s was observed during ventricular systole (=S) from 14 to 41 week's gestation. Similarly, increases in blood flow velocity were recorded during the endsystolic phase (=SD) (35.5 cm/s to 50.7 cm/s during early ventricular diastole (=D) (41.7 cm/s to 58 cm/s, p=0.0001) and atrial contraction (=a) (11.2 cm/s to 35 cm/s, p=0.0001), as well as for intensity-weighted mean velocity (30 cm/s to 48.3 cm/s). The venous indices were associated with significant decreases in the individual parameters with increasing gestational age: (S-a)/S from 0.77 to 0.47, (S-a)/V(mean) from 1.21 to 0.67, (S-a)/D from 0.89 to 0.54, S/a from 4.5 to 1.99. A significant increase from 0.23 to 0.53 was observed only for the quotient a/S. There were no changes in the S/D quotient (from 1.15 to 1.13). Regarding intra-observer reliability, more favourable results were obtained for calculated indices than for measurements of absolute blood flow velocities. At constant measuring conditions, the reference ranges established by this study for blood flow velocities and calculated indices in the ductus venosus may serve as the basis for Doppler ultrasound follow-up in a normal patient population as well as for the diagnosis of fetal myocardial insufficiency of hypoxic and congestive origin.

HTLV-I/II as a common etiology of myelopathies in Bahia, Brazil.

Infection by human T-cell lymphotrophic virus type I (HTLV-I) is associated with a myelopathy known as tropical spastic paraparesis (TSP). The prevalence of HTLV-I infection was found to be high in a pilot study in Bahia, Brazil. In the present study, among patients with myelopathy of unclear etiology, 27% (17/62) were immunoblot reactive to HTLV-I/II (serum and CSF), but none of 40 consecutive patients seen at the neurological clinic and having a well-established neurological diagnosis had detectable antibodies against those viruses (discrimination between HTLV-I and HTLV-II was not possible with the tests we used). The clinical syndrome of typical TSP with upper limb hyperreflexia was found to be a significant feature among the HTLV-I/II-seropositive patients compared to seronegative individuals. The 17 HTLV-I/II-reactive individuals had negative tests for syphilis, toxoplasmosis and schistosomiasis. TSP was also associated with female gender (P = 0.001). We conclude that TSP is strongly associated with HTLV-I/II infection in women in Bahia.

HTLV-I/II as a common etiology of myelopathies in Bahia, Brazil

Infection by human T-cell lymphotrophic virus type I (HTLV-I) is associated with a myelopathy known as tropical spastic paraparesis (TSP). The prevalence of HTLV-I infection was found to be high in a pilot study in Bahia, Brazil. In the present study, among patients with myleopathy of unclear etiology, 27 per cent (17/62) were immunoblot reactive to HTLV-I/II (serum and CSF), but none of 40 consecutive patients seen at the neurological clinic and having a well-established neurological diagnosis had detectable antibodies against those viruses (discrimination between HTLV-I and HTLV-II was not possible with the tests we used). The clinical syndrome of typical TSP with upper limb hyperreflexia was found to be a significant feature among the HTLV-I/II-seropositive patients compared to seronegative individuals. The 17 HTLV-I/II-reactive individuals had negative tests for syphilis, toxoplasmosis and schistosomiasis. TSP was also associated with female gender (P=0.001). We conclude that TSP is strongly associated with HTLV-I/II infection in women in Bahia.

Viscosity of duodenal juice examined in patients with excretory pancreas insufficiency by the pancreocymin secretin test compared to a control group and patients with cholelithiasis.

The viscosity of duodenal juice obtained during the pancreocymin secretin test from patients with excretory pancreas insufficiency was significantly higher compared to the viscosity of duodenal secretions from a control group or from patients with gall bladder stones. Since the viscosity was inversely related to the total volume as well as the bicarbonate and trypsin concentrations, it is concluded that the increased viscosity is due to a reduction in the secretory activity of the pancreas. The viscosity measurements found for patients with cholelithiasis reflects merely the higher viscosity of the gall bladder bile.

Erythrocyte deformability in a red cell ageing model.

The authors studied the effect of a period of storage on erythrocyte deformability in blood samples collected from 31 healthy subjects. A significant reduction in erythrocyte deformability was recorded over the course of time. The study was designed to determine whether pentoxifylline produces a dose-dependent increase in erythrocyte deformability in red cells from ageing blood. The effect of theophylline and prednisolone on this parameter was also studied. A dose-dependent increase in erythrocyte deformability was established for pentoxifylline and was measurable immediately after addition of the substance. Theophylline increased erythrocyte deformability but not to a degree which differed significantly from the controls. Prednisolone elicited a slight reduction in erythrocyte deformability, but again the change was not significant by comparison with the controls. None of the substances brought about any change in the rate of red cell ageing.

[Methodical investigations concerning the measurement of red cell deformability dependent on plasma viscosity, plasma proteins, hematokrit, filtration pressure as well as osmolarity (author's transl)]. / Methodische Untersuchungen zur Messug der Erythrozytenverformbarkeit (Filtrabilität, Flexibilität Fluidität) in Abhängigkeit der Plasmaviskosität, der Plasma-Proteine, der Hämatokrits, des Filtrationsdruckes sowied der Osmolarität

The measurement of red cell deformability (flexibility or fluidity) according to the method of filtration strongly depends on the suspension medium, the hematokrit, filtration pressure as well as osmolarity and is hard to differentiate over the influence of red cell aggregation. Therefore, data concerning the flexibility of red cells have to be established under standardized conditions, e.g. suspension medium, such as albumin, stabilized hematokrit, constant osmolarity and pressure.