Spreading Cerebral Oligemia in Classical- and Normal Cerebral Blood Flow in Common Migraine

SYNOPSIS
Regional cerebral blood flow was studied with intra-arterial ¹³³Xenon technique in 254 areas of a hemisphere during the development of classical migraine attacks in seven patients. We describe a gradual spread of reduced cerebral blood flow starting at the posterior pole of the hemisphere and advancing in a mode quite similar to the spreading depression phenomenon of Leao. In three patients the oligemia was preceeded by focal or perifocal hyperemia. Functional activation by speech etc. was usually impaired or abolished during prodromes or accompaniments. Headache was found concommitantly with cerebral blood flow reduction and cannot be caused by reactive hyperemia in these patients. Similar findings were made in two patients studied with tomographic ¹³³Xenon technique. During induced common migraine attacks repeated cerebral blood flow studies with stationary detectors (N =3) and with tomographic technique (N =4) revealed no alterations of global or cerebral blood flow. Also tomographic determination of spontaneous common migraine attacks in four patients was normal. It is concluded that the two forms of migraine are different with respect to cerebral blood flow abnormalities and that they should be studied separately in the future. Greater interest should be directed towards the phenomenon of spreading depression as a possible model of the classical migraine attack.     

Clinical trial of Nimodipine for single attacks of classic migraine

In a randomized, double-blind cross-over study, 43 patients with classic migraine received 40 mg Nimodipine and placebo as sublingual capsules. There was no significant effect on patients' preference, development of headache, need for escape medicine, duration of headache, severity of headache or headache index. Considerable methodological problems were encountered. Only 54% of the 79 patients selected for the trial could be evaluated. Suggestions for future trials are made.     

Aberrant expression of the polarity complex atypical PKC and non-muscle myosin IIA in active and inactive inflammatory bowel disease

Epithelial barrier function is contingent on appropriate polarization of key protein components. Work in intestinal epithelial cell cultures and animal models of bowel inflammation suggested that atypical PKC (aPKC), the kinase component of the Par3–Par6 polarity complex, is downregulated by pro-inflammatory signaling. Data from other laboratories showed the participation of myosin light chain kinase in intestinal inflammation, but there is paucity of evidence for assembly of its major target, non-muscle myosin II, in inflammatory bowel disease (IBD). In addition, we showed before that non-muscle myosin IIA (nmMyoIIA) is upregulated in intestinal inflammation in mice and TNFα-treated Caco-2 cells. Thus far, it is unknown if a similar phenomena occur in patients with IBD. Moreover, it is unclear whether aPKC downregulation is directly correlated with local mucosal inflammation or occurs in uninvolved areas. Frozen sections from colonoscopy material were stained for immunofluorescence with extensively validated specific antibodies against phosphorylated aPKC turn motif (active form) and nmMyoIIA. Inflammation was scored for the local area from where the material was obtained. We found a significant negative correlation between the expression of active aPKC and local inflammation, and a significant increase in the apical expression of nmMyoIIA in surface colon epithelia in inflamed areas, but not in non-inflamed mucosa even in the same patients. Changes in aPKC and nmMyoIIA expression are likely to participate in the pathogenesis of epithelial barrier function in response to local pro-inflammatory signals. These results provide a rationale for pursuing mechanistic studies on the regulation of these proteins.     

The TASK background K2P channels: chemo- and nutrient sensors

Specialized chemo- and nutrient-sensing cells share a common electrophysiological mechanism by transducing low O(2), high CO(2) and low glucose stimuli into a compensatory cellular response: the closing of background K(+) channels encoded by the K(2P) subunits. Inhibition of the TASK K(2P) channels by extracellular acidosis leads to an increased excitability of brainstem respiratory neurons. Moreover, hypoxic down-modulation of TASK channels is implicated in the activation of glomus cells in the carotid body. Stimulation of both types of cell leads to an enhanced ventilation and to cardiocirculatory adjustments. Differential modulation of TASK channels by acidosis and high glucose alters excitability of the hypothalamic orexin neurons, which influence arousal, food seeking and breathing. These recent results shed light on the role of TASK channels in sensing physiological stimuli.     

Intensive treatment models and coercion

Little evidence exists concerning the optimal treatment for patients with first-episode schizophrenia-spectrum disorders and the effect on traditional outcomes. The aim was to investigate whether optimal treatment models have an effect on the level of use of coercion and on traditional outcomes. Hospital-based Rehabilitation, an intensified inpatient treatment model, Integrated Treatment, an intensified model of Assertive Community Treatment, and standard treatment were compared for patients with first-episode schizophrenia-spectrum disorders. Ninety-four patients with first-episode schizophrenia-spectrum disorders estimated to benefit from long-term hospitalization were included consecutively from the Copenhagen OPUS-trial and randomized to the three treatment models. At 1-year follow-up, Hospital-based Rehabilitation and Integrated Treatment had better scores on symptoms in the negative dimension and on client satisfaction. Integrated Treatment had fewer bed-days, more patients living in non-supervised accommodation, and better score on quality of life. No differences were found as to the use of coercion. This study adds to the evidence that intensified treatment models are superior to standard treatment. A higher number of bed-days in Hospital-based Rehabilitation did not influence the effect on the outcomes measured.     

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood-brain-barrier

Bone morphogenetic protein (BMP) signaling is involved in differentiation of neural precursor cells into astrocytes, but its contribution to angiogenesis is not well characterized. This study examines the role of BMP signaling through BMP type IA receptor (BMPRIA) in early neural development using a conditional knockout mouse model, in which Bmpr1a is selectively disrupted in telencephalic neural stem cells. The conditional mutant mice show a significant increase in the number of cerebral blood vessels and the level of vascular endothelial growth factor (VEGF) is significantly upregulated in the mutant astrocytes. The mutant mice also show leakage of immunoglobulin around cerebral microvessels in neonatal mice, suggesting a defect in formation of the blood–brain-barrier. In addition, astrocytic endfeet fail to encircle cortical blood vessels in the mutant mice. These results suggest that BMPRIA signaling in astrocytes regulates the expression of VEGF for proper cerebrovascular angiogenesis and has a role on in the formation of the blood–brain-barrier.