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Despite high heritability of schizophrenia, genome-wide association studies (GWAS) have not yet revealed distinct combinations of single-nucleotide polymorphisms (SNPs), relevant for mental disease-related, quantifiable behavioral phenotypes. Here we propose an individual-based model to use genome-wide significant markers for extracting first genetic signatures of such behavioral continua. ‘OTTO’ (old Germanic=heritage) marks an individual characterized by a prominent phenotype and a particular load of phenotype-associated risk SNPs derived from GWAS that likely contributed to the development of his personal mental illness. This load of risk SNPs is shared by a small squad of ‘similars’ scattered under the genetically and phenotypically extremely heterogeneous umbrella of a schizophrenia end point diagnosis and to a variable degree also by healthy subjects. In a discovery sample of >1000 deeply phenotyped schizophrenia patients and several independent replication samples, including the general population, a gradual increase in the severity of ‘OTTO’s phenotype’ expression is observed with an increasing share of ‘OTTO’s risk SNPs’, as exemplified here by autistic and affective phenotypes. These data suggest a model in which the genetic contribution to dimensional behavioral traits can be extracted from combinations of GWAS SNPs derived from individuals with prominent phenotypes. Even though still in the ‘model phase’ owing to a world-wide lack of sufficiently powered, deeply phenotyped replication samples, the OTTO approach constitutes a conceptually novel strategy to delineate biological subcategories of mental diseases starting from GWAS findings and individual subjects.

Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood–brain–barrier permeability.

Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a 15N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated 15N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.

Abstract.: Endothelin-1 plays an important role as a paracrine factor in the regulation of regional blood flow. Plasma levels may represent the net result of spill-over from local stimulation/release and elimination of endothelin-1. In order to compare changes in the concentration of endothelin-1 in the plasma of subjects performing different types of sports exercises we measured immunoreactive endothelin-1 in healthy volunteers (n=20) performing in random order jogging on a treadmill and cycling on a bicycle ergometer, for 30 min each. Plasma immunoreactive endothelin-1 increased significantly after jogging (2.13±0.8 pg/ml versus 2.6±0.8 pg/ml, before and after exercise, respectively, P<0.03), whereas it decreased after cycling (2.45±0.76 pg/ml versus 2.25±0.9 pg/ml, before and after exercise, respectively, P<0.03). We suggest that microtraumatizing effects on the endothelial lining are more pronounced during jogging than during cycling, resulting in a greater increase in plasma endothelin-1, which is too high to be immediately eliminated by the lung despite exercise-induced enhanced pulmonary perfusion. In contrast, similarly enhanced lung perfusion together with a relatively lower stimulation of endothelin-1 compared with jogging, may explain the net decrease in plasma after cycling.

Single voxel proton magnetic resonance spectroscopy (MRS) provides a rapid non-invasive fingerprint of tissue chemistry. A case history is presented in which a B cell lymphoma with antecedent demyelinating lesions of the CNS was suspected by MRS and confirmed by neuropathological examination and immunoglobulin gene rearrangement.

Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). We studied prothrombin concentration in lumbar CSF (L-CSF) in patients with AD (n = 25), neurologic disease controls (NDC; n = 33) covering a wide range of neurologic disorders, and subjects with Guillain-Barré syndrome (GBS; n = 4) as well as in samples of non-pathological ventricular CSF (V-CSF; n = 4). The results were evaluated with respect to CSF flow rate, as indicated by the albumin quotient (QAlb). The concentrations of prothrombin in L-CSF in NDC (mean: 0.46 mg/l, range: 0.21–0.96), and AD (mean: 0.6 mg/l, range: 0.19–1.2) were in the normal range reported previously. Expectedly, prothrombin concentration in L-CSF of GBS was increased (mean: 6.3 mg/l, range: 2.3–9.7) corresponding to the increased QAlbin this group (mean 54.6 × 10−3, range: 17–88.1). The concentrations of both prothrombin and albumin were 5.5-fold higher in L-CSF than in V-CSF (mean QAlb: 1.1 × 10−3, mean concentration of prothrombin: 0.088 mg/l). In conclusion, CSF prothrombin in all conditions evaluated here is exclusively derived from blood.

The frequencies of structural chromosomal aberrations were analyzed in peripheral blood lymphocytes of 31 chronic alcoholics at the beginning of an intensive outpatient treatment program at a neuro‐psychiatric clinic and were compared with 31 controls matched for gender, age, smoking habits, and nondrinkers. A statistically significant difference was observed in the level of chromosomal aberrations in somatic cells from alcoholics when compared with controls (3.01 % vs. 1.28%, p < 0.001). A follow‐up study was carried out for a subset of the patients after 3 months (8 subjects) and 12 months (14 subjects) of controlled abstinence. A statistically significant increase in the mean frequency of cells with aberrations was observed in the group of 14 subjects reinvestigated after 12 months of abstinence when compared with the mean value of the first blood samples immediately after hospitalization (4.61% vs. 3.01%; p< 0.001). An excessive increase in cigarette consumption during alcohol abstinence, reflected by a dramatic elevation of CO‐hemoglobin levels, may, at least in part, account for this finding. In conclusion, chronic alcoholism leads to genotoxic effects that, instead of recovering after 1 year of alcohol abstinence, are even enhanced, most likely due to the “shift in addictive behavior.”

Abstract: Quantitative calculations are reported of both band-to band Auger and radiative recombination lifetimes in thin-layered type II InxGa1−x Sb/InAs superlattices with energy gaps in the 5–17 μm range, using accurate band structure and numerical techniques. Results for an 11 μm superlattice are compared with similar calculations for bulk HgCdTe and a HgTe/CdTe superlattice having the same energy gap. The results show the n-type Auger rates to be comparable and the p-type rates to be suppressed by three orders of magnitude in some experimentally realizable structures. Thus, well fabricated III–V superlattices appear to be excellent candidates as a new class of infrarer detectors.

In spite of the fact that prothrombin is produced by cells within the central nervous system, its presence in the cerebrospinal fluid (CSF) has not been investigated. We determined the concentration of prothrombin in CSF with reference to the concentration in plasma in paired samples from 18 “normal” control patients and 4 patients with relapsing-remitting type of multiple sclerosis (MS). The newly developed ELISA was very specific (no cross-reactivity with thrombin) and sensitive (detection limit—0.7 ng/ml) with an imprecision of CV = 8.3% (intraseries) and 7.0% (interassay). The mean prothrombin concentration in normal CSF was 0.55 mg/l (CV ± 33%, range: 0.28–0.93 mg/l), in normal plasma 121.8 mg/l ± 21%, resulting in a mean CSF/plasma concentration quotient (QProth)—4.5 · 10−3(CV ± 35%, range: 2.1–8.3 · 10−3) corresponding to a mean albumin quotient in this group of subjects of QAlb= 5.8 · 10−3. Due to the QProthand the molecular weight of prothrombin (72 kDa)—similar to that of albumin—we conclude that prothrombin in normal human CSF originates predominantly (>95%) from blood. The enzymatic activity in CSF is conserved. Comparable results obtained in MS patients with only few small MRI lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the CSF if the blood-CSF barrier function is normal.

An exact procedure is derived for inverting the cohesive energy of an isostructural one-component system as a function of volume to find the radial pair potential that will reproduce the cohesive energy function. Pair potentials for K, Cu and Mo constructed in this way are compared with standard pair potentials from the literature, and used to calculate elastic properties.

Three ab initio calculations of the theoretical tensile strength of an ideal crystalline metal (f.c.c. Cu) are presented. The first two employ a full band-theoretic approach to compute the cohesive energy as a function of uniaxial lattice deformation. One of these is based on non-self-consistent KKR calculations using the muffin-tin approximation. The other uses the self-consistent augmented spherical wave (ASW) method. The third calculation is based on a new, non-empirical pair potential φ that can be expressed formally in terms of the cohesive energy E and can be evaluated if E is known as a function of the nearest-neighbour distance r1. The theoretical tensile strengths obtained using these three approaches differ by about 40%, but all are consistent with available measurements.

We determined the precise genetic location of the human endothelin-1 gene (EDN1), which encodes a peptide with extremely potent vasoactive properties and is apparently involved in a spectrum of diseases ranging from hypertension to asthma. Analyzing the segregation of a four-allele EDN1 polymorphism in 40 CEPH families including 480 individuals, we detected significant linkage of EDN1 to DNA markers spanning the telomeric half of chromosome arm 6p. EDN1 was closest to the highly polymorphic nucleotide-repeat marker D6S89 at a theta = 0.06 with the highest pairwise LOD score Zmax = 31.2. Subsequent multipoint analysis placed EDN1 at 8 cM distal to D6S89; EDN1 was flanked at its telomeric site at a 13-cM distance by the gene encoding the A subunit of blood clotting factor XIII (F13A1). Furthermore, EDN1 was located at approximately 34–36 cM distal to the HLA region defined by HLA-A, -B, and -DRB1, and 31 cM proximal to the most telomeric marker D6S7. This location of EDN1 on the primary genetic map is strongly supported with odds of 2.7 × 1012:1 against the next best alternative.

In ring segments from rat basilar artery (BA) the endothelin (ET) peptides ET-1, ET-2, and ET-3 induced concentration-related contractions. The order of potency was ET-1 = ET-2 > ET-3, while no differences occurred in the maximum contraction. The selective ETAreceptor antagonist, BQ-123 (10−10-10−4M) alone elicited a small contraction only at 10−4M. In the presence of BQ-123 (10−7-10−5M), the concentration-response curve for ET-1 was shifted to the right without any decrease in maximum contraction, indicating competitive inhibition of ET-1 binding to the ETAreceptor by BQ-123. The pA2value calculated for BQ-123 was 6.935; the slope of the regression curve was 0.734. In contrast to ET-1, the contractile action of ET-3 was abolished by 10−5MBQ-123. In segments precontracted with 10−6Mserotonin, ET-3, but not ET-1, induced relaxation at low concentrations (10−11-10−8M), with maximum relaxation amounting to 17.8 ± 14.7% of precontraction (mean ± SD; n = 16). The relaxant action of ET-3 was abolished in vessels incubated with NG-nitro-l-arginine (10−5M), an inhibitor of nitric oxide synthase. These results indicate that the ET-induced contraction of the isolated rat BA involves activation of the ETAreceptor. The ET-3-induced relaxation of precontracted rat BA is apparently mediated by release of nitric oxide from the endothelium.

The endothelin (ET) receptor mediating relaxation of cerebral arteries was characterized using ring segments obtained from the rat basilar artery. Under resting tension, ET-3 (>10−8M) but not the specific ETBreceptor agonist IRL 1620 induced contraction. In ring segments precontracted with 3 × 10−6Mprostaglandin (PG) F2α, ET-3 (10−12–10−8M) and IRL 1620 (10−14–10−6M) induced concentration-related relaxation. IRL 1620 was more potent than ET-3, the pD2(-log10EC50) values being 10.002 ± 0.751 (mean ± SD) for IRL 1620 and 8.836 ± 0.415 for ET-3. Relaxation was abolished after preincubation with the nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine (10−5M) as well as in segments devoid of a functionally intact endothelium. At a concentration above 10−8M, ET-3 resulted in a further increase of PGF2α-induced contraction that was not observed with IRL 1620. The presumably specific ETBreceptor antagonist IRL 1038 (10−7–3 × 10−6M) diminished or even abolished (3 × 10−6M) the relaxation induced by ET-3 or IRL 1620. IRL 1038 did not exert any vasomotor effect by itself, and it did not significantly affect ET-3-induced contraction. These results indicate that in the rat isolated basilar artery, the ET-3-induced relaxation is probably due to activation of an ETB-type receptor located on the endothelial cells and mediated by release of nitric oxide.

Endothelins are peptides, originally isolated from endothelial cells, with potent vasoactive and mitogenic properties. In this study, we demonstrate that human macrophages synthesize and secrete endothelins. Cultured human macrophages were found by immunocytochemistry to stain positively for endothelin 1 and endothelin 3. Their capability to produce and release these peptides was confirmed by a combination of reverse-phase high-performance liquid chromatography and radioimmunoassays, specific for endothelin 1 and 3, respectively. Immunoreactive peptides were identified both in cellular extracts and in macrophage-conditioned medium. The secretion of endothelin 1, but not of endothelin 3, from macrophages could be stimulated 6-10-fold by lipopolysaccharide or phorbol myristate acetate (PMA). Northern blot analysis of total macrophage RNA using an endothelin 1 cDNA probe revealed induction of endothelin mRNA in PMA-treated macrophages. Furthermore, immunoreactive endothelin 1 and 3 were found in U937 cells, a human promonocytic line, and in freshly isolated human monocytes. In contrast, no immunoreactive endothelin was detected in cell extracts from human neutrophils and lymphocytes. The expression of endothelins in tissue macrophages was demonstrated in paraffin sections of human lung using immunohistochemistry. In conclusion, the finding that human macrophages produce endothelins suggests an important role for these peptides in the microenvironment of tissue macrophages. Macrophage-derived endothelins may have an essential function in blood vessel physiology, and aberrant production may contribute to vessel pathology.

Recent developments in the multiple scattering theory of disordered substitutional alloys are reviewed. In view of experimental advances in alloy spectroscopy, the approaches involving the most realistic single particle Hamiltonians are emphasized. Specifically, we focus on the application of the average t-matrix approximation to the muffin tin model of the alloy. It is shown that the electronic structures of a phase CuZn and paramagnetic CuNi alloys can be characterized in terms of their respective complex energy bands. The interpretations of several experiments, bearing on the real as well as the imaginary parts of the complex bands, are discussed.

1In addition to its well established neuroendocrine and neurotransmitter effects, corticotropin releasing factor (CRF) exerts a potent vasorelaxant action. Recently, a CRF‐related peptide, urocortin, has been identified in the mammalian brain. In the present study, the cerebral vasomotor action of this peptide and the mechanism underlying its relaxant effect are characterized.2Ring segments obtained from the rat basilar artery were used for measurement of isometric force. The relaxant action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium.3In segments precontracted with prostaglandin F2α, urocortin, CRF and sauvagine induced concentration‐related relaxation. The order of potency was as follows (pD2±s.e.m. given in brackets): urocortin (9.32±0.07) > sauvagine (9.08±0.08) > CRF (7.50±0.07). Complete relaxation was achieved with each agonist. Relaxation was not affected by removal of the endothelium but was markedly attenuated in segments precontracted with 50 mmK+Krebs solution. The relaxant effect of urocortin was inhibited by astressin in an apparently competitive manner. A pA2value of 7.52 was estimated for astressin. Inhibition of urocortin‐induced relaxation was also observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD2in the presence of 300 μmSQ22536, 9.36±0.05) and the K+channel blockers tetraethylammonium (10 mm; pD2, 8.65±0.07), iberiotoxin (100 nm; pD2, 8.88±0.08) and apamin (10 nm; pD2, 8.94±0.07). However, the inhibitory actions of SQ22536 and apamin or iberiotoxin were not additive.4The results suggest that urocortin induces relaxation of cerebral arteries by activating CRF‐R2receptors present in the vascular wall. Relaxation appears to be mediated by adenylate cyclase stimulation and activation of Ca2+‐dependent K+channels.

Summary In an attempt to find a non-invasive method yielding a comprehensive insight into a patient's intestinal activity, continuous multichannel registration and analysis of acustic phenomena as produced by the intestines were performed. Previous work, described by others, was further developed with respect to topographical interpretation of the data obtained, and to the possible introduction into general clinical use by installing different methods of artifact detection and reduction.

Summary Administration of synthetic human corticotropin-releasing factor (hCRF, 2 µg/kg body weight) during simultaneous application of the opioid antagonist naloxone (1.6 mg i.v. bolus, followed by an infusion at a rate of 1.2 mg/h) produced a significant increase in plasma C-peptide levels of six male Type 2 diabetic patients which even exceeded the postprandial values. This stimulatory effect of hCRF/naloxone on plasma C-peptide was less pronounced in six healthy men. hCRF alone did not provoke any reaction of plasma C-peptide in either group.

Endothelin-1 is a recently identified cytokine with potent vasoconstrictor activity which is associated with various diseases involving blood vessels. HIV-1 related retinal microangiopathic syndrome is a frequent finding in patients with AIDS or AIDS-related complex, presenting predominantly with retinal cotton-wool spots. We investigated 55 HIV-1 infected patients by ophthalmoscopy and for endothelin-I immunoreactivity in plasma and an additional 76 HIV-1 infected patients only for endothelin-1 levels. For reference values 13 age-matched healthy subjects were studied. In 18 of 55 patients (33%) investigated ophthalmoscopically we found evidence of microangiopathic syndrome. Overall, the mean endothelin-1 immunoreactivity in plasma of HIV-1 infected patients was significantly elevated as compared to controls (4.28 ± 3.62 versus 2.72 ± 0.67 fmol/ml, P < 0.0001). HIV-1 infected patients with retinal microangiopathic syndrome had significantly higher plasma levels of endothelin-1 immunoreactivity (4.59 ± 1.38 fmol/ ml) compared to HIV-1 infected patients without microangiopathic syndrome (3.18 ± 1.64 fmol/ml, P = 0.003). Correlation analysis revealed that endothelin-1 immunoreactivity in plasma had no significant association with disease progression, CD4 cell count, ß2-mi-croglobulin, neopterin, or age. Endothelin-1 immunoreactivity in plasma was correlated exclusively with retinal microangiopathic syndrome in one or both eyes (r = 0.45, P = 0.0006) and with the number of cotton-wool spots (r = 0.50, P = 0.0001). In conlusion, HIV-1 related retinal microangiopathic syndrome is associated with elevated plasma levels of endothelin-1. By virtue of its potent vasoconstrictor activity endothelin-1 may be involved in the pathogenesis of HIV-1 related vascular disease.

Summary The human gastrointestinal tract, important for body salt and water balance, was investigated by endoscopic biopsy for the presence of atrial natriuretic peptide (ANP). Using immunohistochemistry, ANP-immunoreactive cells were identified in the lamina epithelialis mucosae of stomach, duodenum, jejunum, colon, and rectum. The findings indicate that ANP plays a role in intestinal salt and water regulation in man. ANP measurements in tissue specimens reached by endoscopic biopsy may be of major interest for future investigations on (patho-)physiological and pharmacological aspects of ANP.

Abstract: An easy, reproducible and semi-quantitative, non-radioactive method for the analysis of mRNA expression for various cytokines, (i.e., Interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor (TNF)-α, lymphotoxin (LT), transforming growth factor (TGF)-β, interferon (IFN)-γ and endothelin-1 (ET-1)) in cells from cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) has been established. By means of polymerase chain reaction primers that cover a splice junction, amplification of contaminating DNA was omitted. Densitometric scanning of ethidium bromide-stained agarose gels proved to be very sensitive for semiquantitative analysis of PCR products. Serial tenfold dilutions of cDNA revealed a log-linear regression from 106 to 102 cells under optimal cycle conditions. The intra- and inter-assay variability of the method was below 10%. With this assay, the cytokine expression pattern of as few as 104 mononuclear cells from blood or CSF was determined. This method made it possible to detect differences in the cytokine gene expression pattern of mononuclear cells from patients with different neurological diseases. CSF cells from 43 patients with various neurological diseases were analyzed. TNF-α, LT, and IL-1 mRNA were prominent in the CSF cells of most patients with bacterial meningitis. TNF-α, LT, IFN-γ and IL-6 mRNAs were detected in patients with active multiple sclerosis, whereas TNF-α, IL-6, and endothelin-1 mRNA expression was found frequently in patients with HIV encephalitis. Pro-inflammatory cytokines were rarely detected in CSF cells from patients with non-inflammatory diseases of the central nervous system. In blood mononuclear cells from patients with multiple sclerosis, TNF-α mRNA expression was associated with disease activity. The sensitivity, specificity, velocity and reliability of this assay considerably facilitates the analysis of cytokine production in mononuclear cells even in conditions where only a limited number of cells is available for analysis.

Abstract: The vasomotor effects of the endothelins (ETs) are mediated by activation of receptor subtypes termed ETA and ETB. The present study aimed to characterize the interaction of ETA and ETB receptor activation in the cerebral circulation. Ring segments obtained from rat basilar artery were used for measurement of isometric force under resting tension or following precontraction with prostaglandin F2α. In some segments, the endothelium was removed mechanically. In precontracted arteries, ET-1 elicited contraction only. In the presence of the ETA receptor antagonist, BQ-123 (10−5 M), however, ET-1 induced a concentration-related relaxation with a pD2 value of 8.930.16 (meanSEM,n=15). The relaxant action was abolished following princubation with an ETB receptor antagonist, IRL-1038 (310−6 M), or with a nitric oxide synthase inhibitor,N G-nitro-l-arginine (10−5 M). These results indicate that the relaxation was mediated by ETB receptor activation coupled to the release of nitric oxide. Under resting tension, ET-1 elicited concentration-related contraction (pD2: 8.030.04,n=37). In arteries devoid of a functional endothelium, the concentration-effect curve was shifted to the left yielding a pD2 value of 8.880.11 (n=31). Similarly, in endotheliumintact arteries contraction to ET-1 was augmented following nitric oxide synthase inhibition or ETB receptor blockade with 310−6 M BQ-788 (pD2: 8.940.18,n=19). The results suggested that, in the isolated rat basilar artery, ET-1 induced coactivation of the contraction-mediating ETA receptor and the relaxation-mediating ETB receptor. The coactivation resulted in opposing vasomotor effects, but the contraction covered relaxation under normal conditions. However, force development by ET-1 was suppressed by its endothelium-dependent relaxant action.

Summary Administration of synthetic human corticotropin-releasing factor (hCRF; 2 µg/kg body weight) to six normal male subjects produced a significant rise in plasma ACTH, followed by an increase in circulating cortisol. Simultaneous treatment with the opioid antagonist naloxone (1.6 mg i.v. bolus, followed by an infusion at a rate of 1.2 mg/h) significantly potentiated the hCRF-induced rise in ACTH and enhanced the cortisol response to hCRF. It is suggested that naloxone acts by antagonizing an inhibitory ultra-short-loop feedback effect of coreleased ß-endorphin on pituitary corticotrophs, thereby amplifying the net effect of hCRF, i.e., the release of ACTH.

A case of complete bilateral internal ophthalmoplegia as the sole clinical sign of botulism is reported. Diagnosis was immediately confirmed by single-fibre electromyography (SFEMG), which revealed abnormally high blocking (14.3%), contrasting with moderately increased jitter (mean consecutive difference in the extensor digitorum communis muscle, 43.9 µs). After giving equine botulinum antitoxin and simultaneous forced emptying of the bowels, ocular symptoms completely disappeared within 2 days. Six days, 5 weeks and 6 months after the first SFEMG study, the jitter was still abnormal, even becoming more so with time. Blocking, however, was only rarely observed in the follow-up studies. It is concluded that SFEMG may serve as a useful and sensitive method for the rapid diagnosis of botulinum intoxication, even in cases where no clinical signs of general muscular weakness are apparent.