Mutational Insight into Allosteric Regulation of Kir Channel Activity.

Potassium (K+) channels are regulated in part by allosteric communication between the helical bundle crossing, or inner gate, and the selectivity filter, or outer gate. This network is triggered by gating stimuli. In concert, there is an allosteric network which is a conjugated set of interactions which correlate long-range structural rearrangements necessary for channel function. Inward-rectifier K+ (Kir) channels favor inward K+ conductance, are ligand-gated, and help establish resting membrane potentials. KirBac1.1 is a bacterial Kir (KirBac) channel homologous to human Kir (hKir) channels. Additionally, KirBac1.1 is gated by the anionic phospholipid ligand phosphatidylglycerol (PG). In this study, we use site-directed mutagenesis to investigate residues involved in the KirBac1.1 gating mechanism and allosteric network we previously proposed using detailed solid-state NMR (SSNMR) measurements. Using fluorescence-based K+ and sodium (Na+) flux assays, we identified channel mutants with impaired function that do not alter selectivity of the channel. In tandem, we performed coarse grain molecular dynamics simulations, observing changes in PG-KirBac1.1 interactions correlated with mutant channel activity and contacts between the two transmembrane helices and pore helix tied to this behavior. Lipid affinity is closely tied to the proximity of two tryptophan residues on neighboring subunits which lure anionic lipids to a cationic pocket formed by a cluster of arginine residues. Thus, these simulations establish a structural and functional basis for the role of each mutated site in the proposed allosteric network. The experimental and simulated data provide insight into key functional residues involved in gating and lipid allostery of K+ channels. Our findings also have direct implications on the physiology of hKir channels due to conservation of many of the residues identified in this work from KirBac1.1.

Human factors and environmental support in Alzheimer's disease.

Cognitive aging research suggests that environmental support can minimize memory failures in older adults. Similarly, designers of dwellings for frail and dementing older populations try to provide prosthetic environments to support greater independence. We review some of these research issues and design practices from a human factors perspective. Early in the disease process training approaches may be most effective, whereas later on there will need to be more reliance on effective design. We also suggest a framework for optimizing design across stakeholders and discuss some public policy issues.

Human factors and environmental support in Alzheimer's disease.

Cognitive aging research suggests that environmental support can minimize memory failures in older adults. Similarly, designers of dwellings for frail and dementing older populations try to provide prosthetic environments to support greater independence. We review some of these research issues and design practices from a human factors perspective. Early in the disease process training approaches may be most effective, whereas later on there will need to be more reliance on effective design. We also suggest a framework for optimizing design across stakeholders and discuss some public policy issues.

[Dissection of the intracranial arteries. Apropos of 10 cases]. / Dissections des artères intracrâniennes. A propos de 10 observations.

Ten cases of spontaneous dissection of the cerebral arteries are reported. 3 males and 7 females aged 6 to 60 years (mean age 30 years) were investigated in the Department of Neuroradiology of Toulouse between 1989 and 1994 with CT, angiography and MRI. In 5 cases the dissection involved the carotid artery, in 5 cases the vertebro-basilar system. The clinical presentation was of two types: ischaemic stroke (7 cases) or subarachnoid haemorrhage (3 cases). Their evolution is never lethal, contrary to the classical descriptions of the literature. In all cases an initial angiography then follow up has been performed showing an irregular located arterial stenosis. The diagnosis of intracranial dissection is sometimes made in front of a dissequant aneurysm. In case of doubt, magnetic resonance (MR) imaging is helpful showing a linear hypersignal parallel to an arterial segmental stenosis, and angiography MR an irregular aspect and stenosis of the endoluminal artery.

[The contribution of "time-of-flight" MRI-angiography in the study of neurovascular interactions (hemifacial spasm and trigeminal neuralgia)]. / Apport de l'angio-IRM "temps de vol" dans l'exploration des conflits neurovasculaires (hémispasme facial et névralgie du trijumeau).

The purpose of this study was to investigate capabilities of Magnetic Resonance Angiography (MRA) in delineating neurovascular compression which has emerged as the most frequent etiology in cases of Hemi-Facial Spasm and Trigeminal Neuralgia. MR investigations were carried out at 1.5 t unit (Magnetom Vision, Siemens). The examination consisted of 3D time-of-flight MRA (3d TOF) protocol, with a FISP sequence (Fast Imaging Steady Precession) and magnetization transfer. Imaging parameters were; TR 39 ms, TE 7 ms; MX 256-512; FOV 210-210 mm. Time acquisition is 10 mm 30 s. The axially acquired angiographic slices were reformatted with a multiplanar reconstruction program (MPR) along and across the plane of facial and trigeminal nerves. Then millimetric raw data images were postprocessed with a maximum intensity projection (MIP) technique. 58 patients presented either with hemifacial spasm (36 cases, 16 women, 20 men, mean age: 58.5 y) or trigeminal neuralgia (22 cases, 13 women, 8 men, mean age: 51 y) were compared with 17 patients (9 women, 8 men, mean age: 57.5 y) as references. MRA with MIP and MPR techniques reliably demonstrates neurovascular compression at the root entry zone (REZ), and allows recognition of the implicated vascular loop in 34 the cases of hemifacial spasm investigated. Raw data were post-processed in an axially oblique plane parallel to the acoustico-facial bundle and secondarily reconstructed in coronally obliques views. These reconstructed images clearly delineate the cross-compression of the emerging facial nerve. The neurovascular conflict was related to an arterial loop from the postero-inferior cerebellar artery (PICA, 21 cases, 61%) and the antero-inferior cerebellar artery (AICA, 8 cases, 23%). Vertebral artery is implicated in conflicts in 5 cases. In 2 cases MRA exploration was negative. In HFS group distance between Vth nerve emergency and neuro vascular contact was measured and compared with control group; there is a significative difference (p < 0.01). In case of trigeminal neuralgia, MRA demonstrates neurovascular compression at the root entry zone of the Vth nerve of 16 patients. In theses cases, oblique and coronally reconstructed images are crucial in demonstrating neurovascular contacts. The vessel implicated in conflict is always the superior cerebellar artery (SCA). A supero-medial loop of the superior cerebellar artery was depicted in these 16 cases. Although 3 patients had negative MRA and MR studies, a case of compression of the origin of the Vth nerve by a enlarged draining vein in a case of brainstem arterio-venous malformation, a petrous apex meningioma was incidentally discovered and thoroughly investigated with gadolinium T1 weighted sequences and 1 demyelinating plaques located along the intraaxial course of the Vth nerve were noticed. In control group on 34 explanations only there are only 4 contacts between Vth nerve and SCA. MRA with a 3D-TOF FISP sequence allows recognition of neurovascular conflicts in case of hemifacial spasm and trigeminal neuralgia while MIP helps to characterize the implicated vessel. Sources images need to be carefully assessed in order to depict unsuspected pathology.

Age effects in cued recall: sources from implicit and explicit memory.

In 2 experiments, young and old adults were compared on cued recall using direct and indirect test instructions. Participants studied words under an incidental orienting task of rating each word for concreteness. Test cues were meaningfully related to the targets, and participants used them either to recall the studied word (direct test) or to generate a related word (indirect test). Target words and test cues varied in the number of associates linked to them prior to the laboratory experience, and effects of the size of the sets of associates were used as indicators of implicit memory search. Age differences were observed in the effects of target and cue set size as well as in the effects of type of test instruction.

Ophthalmic manifestations of Rochalimaea species.

Rochalimaea henselae and R. quintana belong to the order Rickettsiales and are thought to be responsible for trench fever, bacillary angiomatosis, and cat scratch disease. We recently examined four patients with intraocular inflammation of unknown origin. Each patient had either unilateral or bilateral moderate loss of visual acuity ranging from 20/25 to counting fingers. Bilateral intraocular inflammation manifested by anterior and posterior segment cells, retinal lesions, macular exudate, and optic nerve head swelling was present to varying degrees. The R. henselae to R. quintana antibody titers were greater than or equal to 1:256 in each case. Marked improvement in vision occurred after treatment with either oral ciprofloxacin hydrochloride and prednisone or doxycycline hyclate. Rochalimaea species should be considered in the differential diagnosis of intraocular inflammation and inflammatory optic neuropathy. Appropriate treatment may result in marked improvement in visual acuity.

[Complications of the intravascular treatment of intracranial aneurysms using metal microcoils. Embolization using coils in intracranial aneurysms]. / Complications du traitement endovasculaire des anévrysmes intracrâniens par micro-spires métalliques. Embolisation par coils des anévrysmes intracrâniens.

Embolization of intracranial aneurysms with coils. The authors present the results and complications of microcoils embolization of intracranial aneurysms in 28 patients. Fibers platinum microcoils were used (Target Therapeutic) 28 patients (males: 6, females: 22; mean age: 51 years) were treated, 27 suffered from sub-arachnoid hemorrhage (SAH) and one presented with a pseudotumoral syndrome (giant aneurysm). All patients were evaluated on the day of treatment, according to the World Federation of Neuro-Surgeon classification (W.F.N.S.) of SAH and after 4 months of follow-up. At a mean follow-up period of 4 months, according to Glasgow Outcome Scale (G.O.S.) there were 13 cases of good results, 5 cases of "moderate disability", 2 cases of "severe disability", 2 cases of "vegetative state" and 6 deaths. Complications were observed in 11/28 cases. Coils migration and malposition in the parent artery were linked to the procedure (mechanical detachable coil) and resulted in severe deficit (one case), transient disability (one case) or went unnoticed (4 cases). Primary or secondary complete occlusion was achieved in 8/28 patients (32%). A majority of cases (11 cases) ended with stable residual aneurysmal sac lumen while rebleeding occurred in 3 patients and was responsible for 2 deaths. In the third case a favourable outcome was obtained after balloon occlusion of the parent artery.

Cognitive predictors of vigilance.

Three studies are reported of individual differences in performance of high event rate vigilance tasks. In each study, measures of attentional resource availability and elementary cognitive components of sustained attention were correlated with vigilance performance. It was predicted that correlates of vigilance should vary with two parameters of the task: the type of target discrimination required (simultaneous or successive) and the type of stimuli used (sensory or symbolic). Speed and accuracy of controlled, resource-demanding visual search predicted overall perceptual sensitivity on three out of four successive tasks used, but only one out of four simultaneous tasks, partially confirming the hypothesis that successive tasks are more strongly resource-limited than simultaneous tasks. Other correlates of overall level vigilance did not appear to vary systematically with task parameters. Few correlates of temporal decrement in perceptual sensitivity were found, possibly for statistical reasons. The data suggest that measures of controlled search may be useful in predicting vigilance on certain real-world tasks, although a substantial part of the variance of vigilance tasks may not be predictable from short cognitive tasks.

The retrieval of controlled and automatic aspects of meaning on direct and indirect tests.

The literature concerning implicit memory presents conflicting evidence on the importance of meaning in recovering recently studied words. When the same cues are used during testing, indirect instructions reduce levels of processing effects relative to those obtained with direct instructions, suggesting that meaning is not as likely to be retrieved on indirect tests. However, with certain cues, meaning set size of the studied words affects performance even under indirect instructions, suggesting that meaning is retrieved on such tests. The purpose of the present experiments was to resolve this apparent inconsistency. In Experiment 1, the effects of levels of processing and meaning set size were evaluated under direct and indirect test instructions, with the use of stem and word-fragment cues. In other experiments, beginning and ending stem cues were compared, and levels, set size, and instructional effects were evaluated using meaning cues. The findings indicated that levels effects were determined more by test instructions than by test cues, and that set size effects were determined more by test cues than by test instructions. Implications are discussed for transfer-appropriate processing viewpoints and for a model in which it is assumed that performance is determined by searching either explicit or implicit memories.

Implicit processing in the cued recall of young and old adults.

Two cued recall experiments were reported in which younger and older subjects studied target words varying in number of preexperimental associates. In Experiment 1, targets were studied in either the absence or presence of meaning-related context cues, with recall always prompted by the cues. In the absence of context, words with smaller sets of associates were easier to recall than those with larger sets, but this effect was reduced for older subjects. The presence of a study context cue facilitated recall and eliminated the effect of associative set size for both ages. In Experiment 2, targets were studied and tested in the presence of unrelated words. In this situation, words with smaller sets of associates were less likely to be recalled than words with larger sets; again the effect was reduced for older subjects. The results are interpreted as an age decrement in processing implicitly activated information.

Aging and the stability of activation and sampling in cued recall.

Age effects in cued recall were investigated as a function of activation and sampling of preexisting associates of the test cue. Young adults, community-dwelling elderly, and elderly patients studied lists of unrelated words and were tested with extralist cues. Preexperimental strength between test cues and studied words was manipulated to discern differences in activation, and normative size of the set of associates was manipulated to discern differences in sampling. Test delay and prior testing were also manipulated in Experiment 1. Although large age effects were found with phonemic and taxonomic test cues, young and older subjects showed comparable effects of strength and set size, suggesting that age effects were not due to activation and sampling differences. Test delay and prior testing also had comparable effects. Implications for age effects in episodic cued recall are discussed.

Stabbed in the back.

Yet another kick in the teeth or stab in the back for the nursing profession.

Proteinase-like peptidase activities in malignant and non-malignant gastric tissue.

Activities of several proteinase-like peptidases have been determined in homogenates of malignant tissue, non-malignant tissue adjacent to the tumour (A-NM) and non-malignant tissue distant to the tumour (D-NM) from 17 patients undergoing surgery for histologically confirmed gastric malignancies. In homogenates of malignant tissues the activities of collagenase, cathepsin B, cathepsin (B+L), cathepsin H and cathepsin D were significantly higher than in D-NM tissues. By contrast, the levels of plasminogen activator were significantly lower in malignant tissues than in the D-NM tissues. Furthermore, the activities of collagenase-like and the cysteine-proteinase-like peptidases in the A-NM tissues were lower than in malignant tissues but higher than in the D-NM tissues. Separation of full-thickness non-malignant tissues into mucosal and seromuscular layers revealed significantly higher activities in the former. The elevated levels of these proteinase-like peptidases in homogenates of gastric cancer tissue suggests an important role for these enzymes in tumour invasion.

Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis.

Lewy body-like hyaline inclusions in the soma and swollen, cord-like cell processes are characteristic alterations of the anterior horn cells in familial amyotrophic lateral sclerosis (ALS) with posterior column and spinocerebellar tract involvement. A fine structural analysis of these two structures has been performed in two brothers from a family ("C" family) previously described by Kurland and Mulder in 1955. The perikaryal hyaline inclusions consisted of accumulations of randomly oriented neurofilaments interspersed with thick linear densities associated with granular material. Some of the accumulations showed a central condensation. Cord-like, swollen neuronal processes were composed, for the most part, of numerous neurofilaments arranged parallel to the long axes. Dense structures were sometimes observed within the large bundles of filaments. They were composed of ill-defined dense, granular and fibrillar material associated with scattered vesicles and mitochondria. These dense areas were sometimes surrounded by various amounts of fine filaments, approximately 5 nm in diameter.

Coagulation abnormalities in patients undergoing myocardial revascularization.

One hundred patients were screened for hypercoagulability preoperatively and on the third, seventh, tenth, fourteenth, and twenty-first days postoperatively. Patients found to have hypercoagulability were treated with heparin, aspirin, and Coumadin. When the abnormality was present preoperatively, treatment was continued for the duration of the patient's life. Those patients in whom abnormalities developed postoperatively were given anticoagulants until cardiac catheterization 6 months following their operation. Twenty-four of the 100 patients had no coagulation abnormalities preoperatively or postoperatively. Fifteen patients were found to have abnormality prior to operation. Their predominant abnormality was low antithrombin III activity. Sixty-one patients became hypercoagulable postoperatively. Predominant abnormality in this group of patients was increased thrombin generation and increased platelet adhesiveness. Evaluation of patients in this study group revealed a decrease in the incidence of pulmonary embolism, an increase in the patency of vein grafts, and the elimination of anticoagulant therapy in 24 percent of the patients.

Coagulation factors influencing thrombosis of aorta-coronary bypass grafts.

Thirty patients in whom all aorta-coronary artery vein grafts became occluded within one year of operation, as demonstrated by cardiac catheterization, were evaluated for hypercoagulability. A total of 59 grafts were constructed in these patients. At operation, blood flows of 35 to 90 c.c. per minute were measured through the grafts. In 23 of the 30 patients, the blood was to be hypercoagulable, as evidenced by a low level of antithrombin III activity, high thrombin generation index, high factor VII values, or high platelet adhesivity. Another group of 11 patients (total number of grafts, 23) had all grafts patent at cardiac catheterization. These patients had flows through the grafts ranging from 20 to 125 c.c. per minute. None of the patients with patent grafts had hypercoagulable blood. The status of runoff was comparable between the patients with open grafts and those with occluded grafts.

Fulminant hepatitis and lymphocyte sensitization due to propylthiouracil.

Fulminant hepatic failure developed in a 24-year-old black woman who had been treated with propylthiouracil and propranolol for hyperthyroidism. Clinical and biochemical recovery followed discontinuation of drug therapy. Liver biopsy disclosed submassive hepatic necrosis. During the acute phase of the disease, lymphocyte transformation studies revealed sensitization of the patient's lymphocytes to propylthiouracil but not to propranolol. Sensitization remained demonstrable 2 months after cessation of the former drug. Lymphocytes obtained from a hyperthyroid patient treated with propylthiouracil without complications failed to show evidence of sensitization. These observations indicate that submassive hepatic necrosis may result from treatment with propylthiouracil and are consistent with the notion that sensitization mechanisms may be responsible for the hepatic injury induced by this drug.