Low-flow perfusion via the innominate artery during aortic arch operations provides only limited somatic circulatory support.

BACKGROUND: Aortic arch operations in pediatric patients using low-flow perfusion techniques have been standardized to a certain degree, but some of the often-stated beneficial effects have never been proven. Especially, the existence or efficacy of any subdiaphragmal perfusion still remains unclear. METHODS: Twenty-six newborn male piglets (10-15 kg) underwent aortic arch surgery under general anesthesia using either low-flow perfusion via the innominate artery (LF, 30 ml/(kg min), 25 degrees C, n=12) or conventional deep hypothermic circulatory arrest (DHCA, 20 degrees C, n=14). Cortical somatosensory-evoked potentials (SSEPs), carotid, and subdiaphragmal blood flows were measured. The animals of both groups have been randomized to either pH-stat or alpha-stat management on cardiopulmonary bypass (CPB). RESULTS: During low-flow perfusion via the innominate artery only negligible flows of maximum 1-3 ml/min in the femoral arteries were detected, whereas the right carotid artery flow doubled. During reperfusion, serum-lactate and aspartate amino-transferase (AST) levels were significantly higher compared to the circulatory arrest group, whereas alanine amino-transferase (ALT), gamma-glutamyl transpeptidase (gamma-GT), AP, and creatinine did not show any significant differences. Cortical SSEP returned to preoperative values in all but two low-flow animals. There was no return of SSEP in all piglets operated under deep hypothermic circulatory arrest (p<0.01). CONCLUSION: Compared to DHCA, low-flow perfusion via the innominate artery provides superior neuroprotection despite higher tissue temperatures. Although collateral blood flow via the subclavian artery and the circulus arteriosus willisii has often been presumed, only 'trickle-flow' with some protective potential was detectable in the femoral arteries during low-flow perfusion. Origin of elevated lactate and AST levels seems to be the lower limbs.     

Sumatriptan nasal spray in the acute treatment of migraine in adolescents and children

About 4-10% of children and adolescents suffer from migraine. In the last few years, several studies have been performed to assess the efficacy and safety of triptans for the acute treatment of migraine in children and adolescents. Only sumatriptan nasal spray has been approved for the treatment of acute migraine with or without aura in adolescents aged 12-17 years in Europe. This review describes the results of the studies with sumatriptan nasal spray that have been performed in children and adolescents, including a study performed in the Netherlands.     

Effect of Ethanol and Stress on Plasma Catecholamines and Their Relation to Changes in Emotional State and Performance

The "tension reduction hypothesis" of ethanol was investigated with respect to stress- and ethanol-induced changes of plasma catecholamines and their relations to changes in emotional state and performance. Twenty-two healthy male volunteers were tested under the influence of 0.8 g/kg ethanol and compared to 22 matched controls receiving a placebo drink. Stress was induced by mental arithmetic applied prior to and 45 min after fluid consumption. Plasma epinephrine (E) and norepinephrine (NE) obtained from an indwelling cannula inserted 50 min prior to stress application were determined prior to and after each stress session. Percentage changes were compared within and between groups and correlated with respective changes of emotional states and performance in mental arithmetic. While ethanol decreased performance and stress-related emotional arousal, it did not affect stress-induced changes in plasma catecholamines. Rather, the fluid (ethanol as well as placebo) increased NE levels. Emotional tension reduction was associated with low resting or average levels of E in the placebo group but this relationship was disrupted by ethanol. High NE resting levels and drink induced increases predicted emotional tension reduction with placebo but an increase in stress induced depression with alcohol. "Biochemical tension reduction" (represented by both reduced E and NE stress response) may be predicted from generally lower levels of activation and elation by alcohol but not with the placebo condition. Although performance was positively related to low NE resting levels and stress responses, no influence of alcohol on this relationship was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli

Substitution therapies for orphan genetic diseases, including enzyme replacement methods, are frequently hampered by the limited availability of the required therapeutic substance. We describe the isolation of a pterin intermediate from bacteria that was successfully used for the therapy of a hitherto incurable and lethal disease. Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder characterized by the loss of the molybdenum-dependent enzymes sulphite oxidase, xanthine oxidoreductase and aldehyde oxidase due to mutations in Moco biosynthesis genes. An intermediate of this pathway-'precursor Z'-is more stable than the cofactor itself and has an identical structure in all phyla. Thus, it was overproduced in the bacterium Escherichia coli, purified and used to inject precursor Z-deficient knockout mice that display a phenotype which resembles that of the human deficiency state. Precursor Z-substituted mice reach adulthood and fertility. Biochemical analyses further suggest that the described treatment can lead to the alleviation of most symptoms associated with human Moco deficiency.     

Behavioural strategies used by the hookworms Necator americanus and Ancylostoma duodenale to find, recognize and invade the human host

The infective third-stage larvae of the hookworms Necator americanus and Ancylostoma duodenale infect their human hosts by active skin invasion, but A. duodenale is in addition capable of oral infection. The behaviour of the larvae when crawling on surfaces has already been described. Here we analyse in various in vitro systems the other behavioural invasion phases: activation, penetration, and orientation within the host. The larvae normally remained in a motionless, energy-saving, resting posture. An activation to sinusoidal locomotion was stimulated in both species by similar cues such as touch, vibration, water currents, heat, light, and chemicals. Human breath in addition stimulated searching and waving (nictating) behaviour, which facilitates a change-over to the host. Activating cues in air streams were warmth and moisture; CO₂ activated only in combination with warmth and/or moisture. Penetration behaviour in both species was stimulated by warmth and skin extracts. The stimulating components of skin extracts were fatty acids, but their stimulating characteristics differed from those inducing schistosome cercarial skin penetration. After penetration into agar substrates, both species showed thermo-orientation, but only A. duodenale followed gradients of serum. The directing serum cues were not amino acids and glucose (the supposed cues for schistosome blood vessel localization), but Ringers solution attracted the larvae. The host-finding and host-invasion behaviour of both hookworm species is well adapted to the invasion of the human skin, and there seems to be no particular adaptation of A. duodenale behaviour to the oral infection mode. Hookworm host-finding behaviour is not as complex as that of schistosome cercariae but seems well adapted to the ecological conditions in the transmission sites.     

The influence of surface roughness of titanium on beta1- and beta3-integrin adhesion and the organization of fibronectin in human osteoblastic cells

Mechanisms of cell adhesion and extracellular matrix formation are primary processes in the interaction with the material surface of an implant which are controlled by integrin receptors. The aim of our study was to find out whether beta1- and beta3-integrins of osteoblastic cells sense the surface topography of titanium, and if structural alterations of integrin adhesions were involved in the organization of fibronectin. Pure titanium surfaces were modified by polishing (P), machining (NT), blasting with glass spheres (GB), and blasting with corundum particles (CB) resulting in increasing roughness. Confocal microscopic investigations revealed fibrillar adhesions of beta1- and alpha5-integrins on P, NT, and GB, but on CB with its sharp edges these integrin subunits did not form fibrillar adhesions. beta3 generally appeared in focal adhesions. We observed aligned fibrillar structures of fibronectin on NT not only on the basal site but interestingly, also on the apical cell surface. In contrast, on CB, fibronectin appeared apically clustered. We suggest that this alignment of fibronectin fibrils depends on the directed actin cytoskeleton and in particular, on the capability of the beta1-integrins to form fibrillar adhesions, which is affected by the surface roughness of titanium.     

LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway

The transmembrane form of tumor necrosis factor (mTNF), expressed on activated monocytes (MO) and macrophages (MPhi), is able to induce apoptosis in human endothelial cells (EC). Apoptosis is mediated by two distinct mechanisms: direct cell contact and a yet-unidentified soluble protein, death factor X. In addition, mTNF acts as a receptor that transduces a "reverse signal" into MO/MPhi when bound to the TNF receptor on EC. Reverse signaling by mTNF confers resistance to bacterial lipopolysaccharide (LPS). Stimulation of reverse signaling by mTNF blocks the ability of MO/MPhi to produce death factor X and proinflammatory cytokines. We have investigated which signaling pathways are used by mTNF acting as receptor. Reverse signaling triggers two independent pathways that can be distinguished by protein kinase C (PKC) inhibitors. The suppression of LPS-induced death factor X is dependent on PKC, whereas the suppression of LPS-mediated cytokine release is not. LPS and reverse signaling stimulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. It is interesting that the activation of reverse signaling by mTNF renders MO/MPhi refractory to a subsequent activation of the MAPK/ERK pathway by LPS. Thus, reverse signaling achieves LPS resistance in monocytic cells through interference with key signal-transduction pathways.     

Antigen discovery and delivery of subunit vaccines by nonliving bacterial ghost vectors

The bacterial ghost (BG) platform system is a novel vaccine delivery system endowed with intrinsic adjuvant properties. BGs are nonliving Gram-negative bacterial cell envelopes which are devoid of their cytoplasmic contents, yet maintain their cellular morphology and antigenic structures, including bioadhesive properties. The main advantages of BGs as carriers of subunit vaccines include their ability to stimulate a high immune response and to target the carrier itself to primary antigen-presenting cells. The intrinsic adjuvant properties of BGs enhance the immune response to target antigens, including T-cell activation and mucosal immunity. Since native and foreign antigens can be carried in the envelope complex of BGs, combination vaccines with multiple antigens of diverse origin can be presented to the immune system simultaneously. Beside the capacity of BGs to function as carriers of protein antigens, they also have a high loading capacity for DNA. Thus, loading BGs with recombinant DNA takes advantage of the excellent bioavailability for DNA-based vaccines and the high expression rates of the DNA-encoded antigens in target cell types such as macrophages and dendritic cells. There are many spaces within BGs including the inner and outer membranes, the periplasmic space and the internal lumen which can carry antigens, DNA or mediators of the immune response. All can be used for subunit antigen to design new vaccine candidates with particle presentation technology. In addition, the fact that BGs can also carry piggyback large-size foreign antigen particles, increases the technologic usefulness of BGs as combination vaccines against viral and bacterial pathogens. Furthermore, the BG antigen carriers can be stored as freeze-dried preparations at room temperature for extended periods without loss of efficacy. The potency, safety and relatively low production cost of BGs offer a significant technical advantage over currently utilized vaccine technologies.