Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation

The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), APP/Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction, extensive microspongiosis in the white matter, and apoptotic neurons in select areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pronounced amyloid deposition in APP/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.     

An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions

Perioperative immediate hypersensitivity reactions are rare. Subsequent allergy investigation is complicated by multiple simultaneous drug exposures, the use of drugs with potent effects and the many differential diagnoses to hypersensitivity in the perioperative setting. The approach to the investigation of these complex reactions is not standardized, and it is becoming increasingly apparent that collaboration between experts in the field of allergy/immunology/dermatology and anaesthesiology is needed to provide the best possible care for these patients. The EAACI task force behind this position paper has therefore combined the expertise of allergists, immunologists and anaesthesiologists. The aims of this position paper were to provide recommendations for the investigation of immediate‐type perioperative hypersensitivity reactions and to provide practical information that can assist clinicians in planning and carrying out investigations.     

Analgesic anesthesia with fentanyl (F) and sufentanil (SF) in coronary surgery. A double blind study.

The study includes 54 unselected coronary patients. Fifty underwent one or several aortocoronary bypass associated with left ventricular resection (3 times), mitral valve replacement (twice), aortic valve replacement (twice). Four patients underwent left ventricular resection alone. The operations were performed under analgesic anesthesia with sufentanil (SF) or fentanyl (F) with a double blind protocol. The ratio of concentrations of the two analgesics was SF/F = 1/10. Flunitrazepam induced and maintained sleep. After having reached by increments the total dose of 1.5 mg F/M2 or 0.15 mg SF/M2, droperidol was then added in small amounts of 3.75 mg/M2, alternating with the analgesic both being given as needed to maintain blood pressure between 100 and 120 mm Hg, in order to potentiate the level of analgesia reached and prevent vasoconstriction. Under this setting tachycardia (heart rate greater than 100 beats/min. and less than 120 beaths/min.) was observed before ECC in only 7.4% of cases with both analgesics and brief episodes of hypertension (mean maximum systolic blood pressure 140.7 +/- 20.3 mm Hg seen with SF exclusively). There was neither postoperative hypertension (except with 6 out of the 7 known hypertensive patients) nor low cardiac output, nor arbythmia. No patients remained in intensive care unit more than 24 hour. No difference attribuable to the used analgesic was detectable in the early and late follow-up in both series. On an average, the patients were discharged on postoperative day 10 in a valid condition.     

Value of skin tests for the choice of a neuromuscular blocking agent after an anaphylactic reaction

We report a grade III allergic hypersensitivity reaction occurring in a 72-year-old patient immediately after anaesthesia induction. Anaphylaxis to cisatracurium was diagnosed on clinical symptoms, biological tests and positivity of the cutaneous tests to this neuromuscular blocking agent. Five days after this allergological assessment, rocuronium, a muscle relaxant for which skin tests appeared negative was used during surgery without adverse effects. The authors underline the value of a detailed allergological assessment to identify the pathophysiologic mechanism, the culprit drug and to propose a safer alternate drug that might be used.     

Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice

Evidence is accumulating for a role for amyloid peptides in impaired synaptic plasticity and cognition, while the underlying mechanisms remain unclear. We here analyzed the effects of amyloid peptides on NMDA-receptor function in vitro and in vivo. A synthetic amyloid peptide preparation containing monomeric and oligomeric A beta (1-42) peptides was used and demonstrated to bind to synapses expressing NMDA-receptors in cultured hippocampal and cortical neurons. Pre-incubation of primary neuronal cultures with A beta peptides significantly inhibited NMDA-receptor function, albeit not by a direct pharmacological inhibition of NMDA-receptors, since acute application of A beta peptides did not change NMDA-receptor currents in autaptic hippocampal cultures nor in xenopus oocytes expressing recombinant NMDA-receptors. Pre-incubation of primary neuronal cultures with A beta peptides however decreased NR2B-immunoreactive synaptic spines and surface expression of NR2B containing NMDA-receptors. Furthermore, we extended these findings for the first time in vivo, demonstrating decreased concentrations of NMDA-receptor subunit NR2B and PSD-95 as well as activated alpha-CaMKII in postsynaptic density preparations of APP[V717I] transgenic mice. This was associated with impaired NMDA-dependent LTP and decreased NMDA- and AMPA-receptor currents in hippocampal CA1 region in APP[V717I] transgenic mice. In addition, induction of c-Fos following cued and contextual fear conditioning was significantly impaired in the basolateral amygdala and hippocampus of APP[V717I] transgenic mice. Our data demonstrate defects in NMDA-receptor function and learning dependent signaling cascades in vivo in APP[V717I] transgenic mice and point to decreased surface expression of NMDA-receptors as a mechanism involved in early synaptic defects in APP[V717I] transgenic mice in vivo.     

Previous safe administrations of neuromuscular blocking agents do not exonerate from the risk of anaphylactic shock

We describe a grade IV anaphylactic shock to atracurium. A 34-year-old woman was scheduled for her ninth abdominal surgery. Within the last 10 months, for previous abdominal procedures she had received atracurium, cisatracurium or suxamethonium. No adverse event was reported. In the present case, a cardiac arrest occurred within 1 min after atracurium injection. Anaphylaxis was immediately evoked and treatment started. The diagnosis of anaphylaxis to atracurium was confirmed by the allergological assessment. This case report highlights the fact that patients without any previous adverse events to neuromuscular blocking agents are never exempt from risk of anaphylactic shock, even with a designated low-risk agent of sensitization.