Adult metachromatic leukodystrophy: neurophysiologic findings

The visual and somatosensory evoked potentials were delayed in two cases of the adult form of metachromatic leukodystrophy. Brainstem auditory evoked potentials were normal. The conduction velocity along peripheral nerves was 50% slowed in one case and near normal in the other. The findings are compatible with demyelination in the central and peripheral nervous systems. The diagnosis of metachromatic leukodystrophy should be considered in cases of early dementia, with or without psychosis or other neurologic deficits, in which evoked potentials are delayed and peripheral nerve conduction is slowed.     

Painful legs and moving toes

3 patients with the condition of "painful legs and moving toes" are reported. The etiology was unknown in 2 of them, but in 1 patient the symptoms were temporarily relieved by surgery for a lumbar herniated disc. The movements restarted 6 months after surgery. EMG studies showed near rhythmical muscle action potentials in the involved muscles of the foot at rates of 3.0, 2.5 and 0.5 cps respectively with a maintained reciprocal innervation. These spontaneous movements could only be suppressed for seconds. The EEG, nerve conduction studies and somatosensory evoked potentials were normal.     

Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight

OBJECTIVE: This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight. METHODS: The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed to antagonize the effect of the H3 receptor agonist R-alpha-methylhistamine on isoprenaline-induced accumulation of cAMP. The affinity of NNC 38-1049 for a number of variants of the histamine receptor was also determined. Following single dosing of normal rats with NNC 38-1049, hypothalamic histamine levels were assessed by means of microdialysis. Plasma and brain levels of NNC 38-1049 and acute effects on food intake and energy expenditure were followed after oral doses of 3-60 mg/kg. Potential side effects were examined with rat models of behaviour satiety sequence (BSS), pica behaviour and conditioned taste aversion (CTA). Intakes of food and water together with body weight were recorded for 15 days during daily dosing of dietary obese rats. RESULTS: NNC 38-1049 was found to be a highly specific and competitive antagonist towards both human and rat histamine H3 receptors, and measurable amounts of NNC 38-1049 were found in the plasma of rats following single oral doses of 3-60 mg/kg and in the brain after 15-60 mg/kg. Following single intraperitoneal injections of NNC 38-1049 (20 mg/kg), significant increases in extracellular histamine concentrations were observed. The same dose did not change BSS or pica behaviour acutely, nor did it induce CTA following repeated administration for 7 days. Reductions in food intake were seen very soon after administration, and occurred in a dose-dependent fashion. Energy expenditure was unchanged, but the respiratory quotient (RQ) tended to decrease at higher doses, indicating an increase in lipid oxidation. Twice daily administration of 20 mg/kg of NNC 38-1049 in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week study, and was associated with a highly significant (P<0.01) decrease in body weight compared with controls (-18.4+/-3.4 vs +0.4+/-2.7 g). The same dose of NNC 38-1049 produced an acute decrease of water intake, but 24 h intakes were not significantly changed. CONCLUSIONS: The results of this study strongly support the idea that an increase in the hypothalamic concentration of histamine produces a specific reduction of food intake and that this effect can be translated into a decrease in body weight.     

Visualizing reaction pathways in photoactive yellow protein from nanoseconds to seconds

Determining 3D intermediate structures during the biological action of proteins in real time under ambient conditions is essential for understanding how proteins function. Here we use time-resolved Laue crystallography to extract short-lived intermediate structures and thereby unveil signal transduction in the blue light photoreceptor photoactive yellow protein (PYP) from Halorhodospira halophila. By analyzing a comprehensive set of Laue data during the PYP photocycle (forty-seven time points from one nanosecond to one second), we track all atoms in PYP during its photocycle and directly observe how absorption of a blue light photon by its p-coumaric acid chromophore triggers a reversible photocycle. We identify a complex chemical mechanism characterized by five distinct structural intermediates. Structural changes at the chromophore in the early, red-shifted intermediates are transduced to the exterior of the protein in the late, blue-shifted intermediates through an initial "volume-conserving" isomerization of the chromophore and the progressive disruption of hydrogen bonds between the chromophore and its surrounding binding pocket. These results yield a comprehensive view of the PYP photocycle when seen in the light of previous biophysical studies on the system.     

Dissecting neural circuitry by combining genetics and pharmacology

In systems neuroscience, advances often come from lesioning and reversible inhibition of brain regions. Dissecting the circuitry of regions involves conceptually the same approach - stop a class of cell from firing action potentials, or make the cells fire more, then deduce how these components influence the performance of the circuit and animal behaviour. To perform such cell-type-specific and reversible fine-scale analysis of circuitry, and to do so on the fast signalling timescale of the brain (milliseconds to seconds), is challenging in mammals. Ingenious and diverse methods are being developed towards this goal. These new tools will encourage further synergy between molecular biologists, systems neuroscientists and electrophysiologists.     

Dexamethasone suppression test in borderline personality disorder--effects of posttraumatic stress disorder

BACKGROUND: Divergent findings of hypothalamic-pituitary-adrenal (HPA) axis functioning in borderline personality disorder (BPD) may be caused by a different degree of comorbid posttraumatic stress disorder (PTSD), in which alterations of the HPA axis are well known. Here we investigate alterations of the HPA axis in BPD patients with and without comorbid PTSD compared to healthy controls. Considering previous findings current major depression (MDD) was taken into account as a confounding variable. METHODS: Apart from clinical assessment the 0.5 mg dexamethasone suppression test (DST) was performed in 21 female borderline patients and 23 healthy controls. RESULTS: Twelve BPD patients suffered from comorbid PTSD. Relative suppression (%) did not differ between healthy controls and the total BPD group, but BPD patients with comorbid PTSD showed increased suppression compared to those without. Comorbid MDD was not associated with suppression. CONCLUSIONS: Our results do not indicate a dysfunction of the HPA axis in BPD. However, comorbid PTSD seems to be associated with a relative hypersuppression in the 0.5 mg DST.     

Observer variability in the evaluation of dual-isotope Tl-201/Tc-99m sestamibi rest/stress myocardial perfusion SPECT in men and women with known or suspected stable angina pectoris

BACKGROUND: Observer variability of dual-isotope myocardial perfusion imaging (MPI) with single photon emission computed tomography has rarely been investigated. The aim of our study was to evaluate the interpretive reproducibility with this technique. METHODS AND RESULTS: We report on 507 patients with known or suspected stable angina who were studied before coronary angiography. A 1-day thallium 201/technetium 99m sestamibi rest/stress MPI protocol was used. MPI was interpreted by 2 independent observers without knowledge of clinical data, using a 20-segment scoring model. By consensus, the overall rate of abnormal MPI was 49% (59% in men and 34% in women). The interobserver agreement for the whole group (kappa = 0.85) and for men and women separately (kappa = 0.86 and 0.82, respectively) was excellent with regard to the overall diagnosis (normal, reversible, or fixed defects) as well as left anterior descending and left circumflex artery vascular territories (kappa = 0.85 and 0.82, respectively). However, in the right coronary artery territory, agreement was excellent in men (kappa = 0.83) but moderate in women (kappa = 0.57). CONCLUSIONS: In a relatively large group of men and women with stable angina pectoris, interpretive reproducibility (overall and individual vessel diagnosis) was excellent, except in the right coronary artery territory of women, in which it was moderate.