Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus.

Objectives Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10-3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10-3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10-6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10-5). Conclusions Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

Successful application of belimumab in two patients with systemic lupus erythematosus experiencing a flare during tocilizumab treatment.

This case report describes two female lupus patients who both received biological treatment with tocilizumab and with belimumab. The disease course was remarkably similar in both cases. Tocilizumab resulted in a transient improvement in pleurisy and arthritis but was then followed by a clinical flare accompanied by an increase in autoantibodies and a drop in complement levels. Alike, both patients experienced a rapid and sustained improvement after institution of belimumab. The clinical benefit obtained is currently stable under ongoing belimumab therapy.

Cortical activation to auditory mismatch elicited by frequency deviant and complex novel sounds: a PET study.

The analysis of auditory deviant events outside the focus of attention is a fundamental capacity of human information processing and has been studied in experiments on Mismatch Negativity (MMN) and the P3a component in evoked potential research. However, generators contributing to these components are still under discussion. Here we assessed cortical blood flow to auditory stimulation in three conditions. Six healthy subjects were presented with standard tones, frequency deviant tones (MMN condition), and complex novel sounds (Novelty condition), while attention was directed to a nondemanding visual task. Analysis of the MMN condition contrasted with thestandard condition revealed blood flow changes in the left and right superior temporal gyrus, right superior temporal sulcus and left inferior frontal gyrus. Complex novel sounds contrasted with the standard condition activated the left superior temporal gyrus and the left inferior and middle frontal gyrus. A small subcortical activation emerged in the left parahippocampal gyrus and an extended activation was found covering the right superior temporal gyrus. Novel sounds activated the right inferior frontal gyrus when controlling for deviance probability. In contrast to previous studies our results indicate a left hemisphere contribution to a frontotemporal network of auditory deviance processing. Our results provide further evidence for a contribution of the frontal cortex to the processing of auditory deviance outside the focus of directed attention.

[Delusional depression as differential dementia of the Alzheimer type diagnosis]. / Wahnhafte Depression als Differenzialdiagnose der Demenz vom Alzheimer-Typ.

For several years, a 68-year-old patient had been treated for a dementia of Alzheimer's type and finally admitted to a closed gerontopsychiatric nursing home. According to information from his relatives, he first developed psychotic symptoms 3 years prior to admission in our psychiatric department. Several months later, he developed a lack of drive, lack of interests, and reduced emotional reaction. After a standard diagnostic work-up (psychiatric, neurological, and general medical examination, CSF examination, laboratory analyses, cranial computerized tomography), we began electroconvulsive therapy (ECT) with a working hypothesis of major depression with psychotic symptoms. The ECT was able to ameliorate rapidly the psychiatric status of the patient. After 10 weeks of inpatient treatment, he could be discharged from the hospital and was able to take up his usual professional activities on a voluntary basis. This article describes the need for an early differential diagnosis of dementias. Standardized and differential diagnoses of dementias are necessary for an antidementive therapy as well as for the detection of potentially curable diseases.

Dorsolateral prefrontal cortex activation during automatic auditory duration-mismatch processing in humans: a positron emission tomography study.

This study aimed to identify the neural networks underlying automatic and active auditory deviant detection in six healthy subjects using positron emission tomography. Eight alternating blocks of standard and standard plus duration-deviant tones were presented while subjects performed a visual discrimination task. In an additional four blocks, the subjects then performed an auditory discrimination task on the deviant tones. Actively attending the deviant tones increased regional cerebral blood flow (rCBF) in the superior temporal and inferior frontal gyrus as well as in the superior and medio-frontal gyrus. When performing the visual task and presented with deviant tones, significant increase of rCBF was detected in the caudate nucleus, cerebellum, posterior cingulate, inferior frontal and pre-central gyrus thus indicating automatic extra-pyramidal processing of auditory duration deviants.

Involvement of the human cerebellum during habituation of the acoustic startle response: a PET study.

The present study investigated the involvement of the human cerebellum in the habituation of the acoustic startle response using PET. The startle response was elicited in seven young, healthy subjects by a tone presented via headphones. Startle responses were recorded from the right sternocleidomastoid muscle. Regional cerebral blood flow (rCBF) was assessed in nine scans and one startle stimulus was applied during each scan. The reduction of size of the sternocleidomastoid muscle response was correlated with changes in rCBF during the ongoing process of startle response habituation. A significant decrease of rCBF was found in the medial cerebellum. These data are consistent with an involvement of the medial parts of the human cerebellum in non-associative learning as proposed by previous animal studies.

Experimental cranial pain elicited by capsaicin: a PET study.

Using a positron emission tomography (PET) study it was shown recently that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so called 'migraine generator'. To test this hypothesis we performed an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as in the migraine patients. A small amount of capsaicin was administered subcutaneously in the right forehead to evoke a burning painful sensation in the first division of the trigeminal nerve. Increases of regional cerebral blood flow (rCBF) were found bilaterally in the insula, in the anterior cingulate cortex, the cavernous sinus and the cerebellum. Using the same stereotactic space limits as in the above mentioned migraine study no brain stem activation was found in the acute pain state compared to the pain free state. The increase of activation in the region of the cavernous sinus however, suggests that this structure is more likely to be involved in trigeminal transmitted pain as such, rather than in a specific type of headache as was suggested for cluster headache.

Emerging treatments in headache.

Recent PET studies performed in humans during migraine attacks revealed a 'spreading depression-like' oligemia in the occipital cortex during the aura phase and a region of increased blood flow in the brainstem during the headache phase. Animal models were established to test new migraine drugs. A number of 5-HT agonists, the so-called 'triptans', will be available in future besides sumatriptan to treat acute migraine attacks. Migraine prophylaxis is still hampered by the fact that we do not understand the action of drugs used for this purpose and do not have an animal model. Nevertheless, new substances were introduced recently into the prophylaxis of migraine.

Brain representation of active and passive movements.

During active and passive (driven by a torque motor) flexion and extension of the right elbow, regional cerebral blood flow (rCBF) was measured in six healthy, male volunteers using positron emission tomography and the standard H2(15)O injection technique. During active as well as during passive movements of the right elbow there were strong increases in rCBF, identical in location, amount, and extent in the contralateral sensorimotor cortex. There were activations during both conditions in the supplementary motor area (stronger and more inferior in the active condition) and inferior parietal cortex (on the convexity during active movements and in the depth of the central sulcus during passive movements). During active movements only, activations of the basal ganglia and the cingulate gyrus were found. Brain activations during motor tasks are largely related to the processing of afferent information.

Brain stem activation in spontaneous human migraine attacks.

Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.

[Pathological jaw opening reflex after whiplash injury]. / Pathologischer Kieferöffnungsreflex nach HWS-Beschleunigungsverletzung.

The brainstem mediated inhibitory reflex of the m. temporalis was investigated on average 3 days after the accident in 61 patients (f = 36; m = 25; mean age = 28 years +/- 9 SD) who presented an acute cervico-cephalic syndrome with posttraumatic headache and neck pain following acute whiplash injury but without neurological deficits, bone injury of the cervical spine or combined direct head trauma. We postulated a disturbed reflexive temporalis muscle inhibition in patients with 'whiplash cephalalgia', as has previously been reported for classical muscle tension headache. Latencies and durations of the early and late exteroceptive EMG suppression (ES1 and ES2) and the interposed EMG activity (IE) of the voluntarily contracted right temporalis muscle following ipsilateral stimulation of V/2 + 3 afferents were recorded. The reflex data were compared to a cohort of 69 age and sex matched normal subjects (f = 37; m = 32; mean age = 28 years +/- 7 SD). The following significant reflex changes were found in patients: a shortened duration of ES2 with delayed onset and premature ending, a slight prolongation of ES1 and IE, a delayed onset of IE and a diminished ratio of ES2:ES1 and ES2:IE. We conclude that the abnormality of the antinociceptive reflex is based on a transient dysfunction of the brainstem mediated reflex circuit following the acceleration trauma, which can be considered a neurophysiological correlate of the posttraumatic cervico-cephalic pain syndrome and may be useful as a 'biological marker' in monitoring the time course of recovery from pain.(ABSTRACT TRUNCATED AT 250 WORDS)

[Doppler and duplex sonography of the vertebral arteries]. / Die Doppler- und Duplexsonographie der Vertebralarterien.

In a prospective study 451 patients were examined with extracranial CW-Doppler sonography (mastoidal slope), suboccipital transcranial Doppler sonography and colour-coded duplex sonography to evaluate unusual vertebral arteries (hypoplasia, stenosis and occlusion). Colour duplex sonography was used as reference method. CW-Doppler sonography had a sensitivity of 100% and a specificity of 27% for the detection of an unusual vertebral artery. For transcranial Doppler sonography these values are 38% and 58%. Our study showed that CW-Doppler is a useful screening examination for identifying pathological findings of vertebral arteries. In case of abnormalities in CW-Doppler, duplex sonography, especially colour-coded duplex sonography, should be added.

Effects of ovariectomy and steroid replacement on GABAA receptor binding in female rat brain.

The specific binding of tritiated muscimol to gamma-aminobutyric acid (GABA) receptor sites was studied in distinct brain areas of female rats during different endocrine states. In diestrous rats with intact ovaries the highest receptor densities were found in the cortex (10.24 pmol/mg protein) and the lowest concentrations in the mediobasal hypothalamus (3.29 pmol/mg protein). Four weeks after removal of the ovaries, the number of binding sites was enhanced up to 2.4-fold in all brain areas investigated: the preoptic brain area, mediobasal hypothalamus, corticomedial amygdala, and cerebral cortex. The affinity of the binding sites remained unchanged. Substitution of estradiol and progesterone reduced the number of binding sites to values seen before ovariectomy. The induction of an afternoon surge of LH by estradiol that could be blocked by enhancing the GABAergic tone was accompanied by a distinct reduction in Bmax in the preoptic area in the morning. These results give evidence that ovarian hormones modulate GABAergic neurotransmission by regulation of GABAA receptor synthesis or degradation.

Evidence that 3 alpha-hydroxy-5 alpha-pregnan-20-one is a physiologically relevant modulator of GABA-ergic neurotransmission.

3 alpha-Hydroxy-5 alpha-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABAA receptor binding, by determining the allosteric properties of HPO on the in vitro binding of 3H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of 3H-muscimol to GABAA receptor sites by 52% and enhanced the number of accessible binding sites from 5.5 +/- 0.5 to 7.5 +/- 1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABAA receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.

Sex differences in GABAA receptor binding in rat brain measured by an improved in vitro binding assay.

The distribution of GABAA receptor sites was studied in female and male rat brain by an improved in vitro binding assay using 3H-muscimol and carefully washed membrane fractions. The binding studies revealed a single class of binding sites exhibiting the properties of GABAA receptors. The specific binding of 3H-muscimol was measured in four brain areas: the preoptic brain area, mediobasal hypothalamus, corticomedial amygdala and cerebral cortex. The equilibrium dissociation constants (KD) ranged from 11.2 to 23.3 nM in diestrous females and from 13.1 to 50.4 nM in males, the maximal number of binding sites (Bmax) from 3290 to 10240 fmol/mg protein in females and from 5495 to 17449 fmol/mg protein in males. In the preoptic area and mediobasal hypothalamus both, KD and Bmax, were significantly higher in males than in females. The sex differences in the binding of muscimol observed in vitro indicated sexually dimorphic GABAergic neurotransmission that is probably related to the control of gonadotropin secretion and/or sexual behavior.