Steady-state function of the ubiquitous mammalian Na/H exchanger (NHE1) in relation to dimer coupling models with 2Na/2H stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1(-/-) skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K(1/2)) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K(1/2) for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K(1/2) for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K(1/2) for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in "parallel" at alkaline pH. In the second "serial" model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry.

R2-recanalization of spontaneous carotid artery dissection

BACKGROUND AND PURPOSE: We set out to investigate the predictors and time course for recanalization of spontaneous dissection of the cervical internal carotid artery (SICAD). METHODS: We prospectively included 249 consecutive patients (mean age, 45+/-11 years) with 268 SICAD. Ultrasound examinations were performed at presentation, during the first month, and then at 3, 6, and 12 months, and clinical follow-ups after 3, 6, and 12 months. RESULTS: Of 268 SICADs, 20 (7.5%) presented with first 6 months after the onset of symptoms. Initial occlusion reduces the likelihood of complete recanalization, whereas presentation with local symptoms and signs only increases it.

NIHSS score and arteriographic findings in acute ischemic stroke

BACKGROUND AND PURPOSE: To test the hypothesis that the National Institutes of Health Stroke Scale (NIHSS) score is associated with the findings of arteriography performed within the first hours after ischemic stroke. METHODS: We analyzed NIHSS scores on hospital admission and clinical and arteriographic findings of 226 consecutive patients (94 women, 132 men; mean age 62+/-12 years) who underwent arteriography within 6 hours of symptom onset in carotid stroke and within 12 hours in vertebrobasilar stroke. RESULTS: From stroke onset to hospital admission, 155+/-97 minutes elapsed, and from stroke onset to arteriography 245+/-100 minutes elapsed. Median NIHSS was 14 (range 3 to 38), and scores differed depending on the arteriographic findings (P<0.001). NIHSS scores in basilar, internal carotid, and middle cerebral artery M1 and M2 segment occlusions (central occlusions) were higher than in more peripherally located, nonvisible, or absent occlusions. Patients with NIHSS scores > or =10 had positive predictive values (PPVs) to show arterial occlusions in 97% of carotid and 96% of vertebrobasilar strokes. With an NIHSS score of > or =12, PPV to find a central occlusion was 91%. In a multivariate analysis, NIHSS subitems such as "level of consciousness questions," "gaze," "motor leg," and "neglect" were predictors of central occlusions. CONCLUSIONS: There is a significant association of NIHSS scores and the presence and location of a vessel occlusion. With an NIHSS score > or =10, a vessel occlusion will likely be seen on arteriography, and with a score > or =12, its location will probably be central.

Use of a computerized closed-loop sodium nitroprusside titration system for antihypertensive treatment after open heart surgery

This study evaluates the clinical applicability of administering sodium nitroprusside by a closed-loop titration system compared with a manually adjusted system. The mean arterial pressure (MAP) was registered every 10 and 30 sec during the first 150 min after open heart surgery in 20 patients (group 1: computer regulation) and in ten patients (group 2: manual regulation). The results (16,343 and 2,912 data points in groups 1 and 2, respectively), were then analyzed in four time frames and five pressure ranges to indicate clinical efficacy. Sixty percent of the measured MAP in both groups was within the desired +/- 10% during the first 10 min. Thereafter until the end of observation, the MAP was maintained within +/- 10% of the desired set-point 90% of the time in group 1 vs. 60% of the time in group 2. One percent and 11% of data points were +/- 20% from the set-point in groups 1 and 2, respectively (p less than .05, chi-square test). The computer-assisted therapy provided better control of MAP, was safe to use, and helped to reduce nursing demands.

Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms

BACKGROUND: Marfan syndrome (MFS) is a heritable disorder of connective tissue, affecting principally skeletal, ocular, and cardiovascular systems. The most life-threatening manifestations are aortic aneurysm and dissection. We investigated changes in the proteome of aortic media in patients with and without MFS to gain insight into molecular mechanisms leading to aortic dilatation. METHODS AND RESULTS: Aortic samples were collected from 46 patients. Twenty-two patients suffered from MFS, 9 patients had bicuspid aortic valve, and 15 patients without connective tissue disorder served as controls. Aortic media was isolated and its proteome was analyzed in 12 patients with the use of 2-dimensional difference gel electrophoresis and mass spectrometry. We found higher amounts of filamin A C-terminal fragment, calponin 1, vinculin, microfibril-associated glycoprotein 4, and myosin-10 heavy chain in aortic media of MFS aneurysm samples than in controls. Regulation of filamin A C-terminal fragmentation was validated in all patient samples by immunoblotting. Cleavage of filamin A and the calpain substrate spectrin was increased in the MFS and bicuspid aortic valve groups. Extent of cleavage correlated positively with calpain 2 expression and negatively with the expression of its endogenous inhibitor calpastatin. CONCLUSIONS: Our observation demonstrates for the first time upregulation of the C-terminal fragment of filamin A in dilated aortic media of MFS and bicuspid aortic valve patients. In addition, our results present evidence that the cleavage of filamin A is highly likely the result of the protease calpain. Increased calpain activity might explain, at least in part, histological alterations in dilated aorta.

Could full-body digital X-ray (LODOX-Statscan) screening in trauma challenge conventional radiography?

ATLS Guidelines recommend single plain radiography of the chest and pelvis as part of the primary survey. Such isolated radiographs, usually obtained by bedside machines, can result in limited, low-quality studies that can adversely affect management. A new digital, low-radiation imaging device, the "Lodox Statscan" (LS), provides full-body anterior and lateral views based on enhanced linear slot-scanning technology in just over 5 minutes. We have the first LS in Europe at our facility. The aim of this study was to compare LS with computed tomographic (CT) scanning, as the gold standard, to determine the sensitivity of LS investigation in detecting injuries to the chest, thoracolumbar spine, and pelvis from our own experience, and to compare our findings with those of conventional radiography in the literature.

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery--a randomized controlled trial

OBJECTIVE: Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. DESIGN:: Double-blind, randomized, placebo-controlled trial. SETTING: One Swiss University Hospital. PATIENTS: One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTION: Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. MEASUREMENTS AND MAIN RESULTS: The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. CONCLUSION: This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

Pralines from a smaller gift box taste better

This study shows that taste ratings of repeatedly chosen pralines decrease more when the gift box is large compared to small. Within their first choices consumers select the most preferred praline less often from the large assortment. These results are discussed in the light of variety seeking and dysfunctional choice.

The Madras Presidency’s Prisons and the British Empire, 1820s–1850s

This paper is based on the observation that projects to reform prisons in British India in the first half of the 19th century were remarkably parallel to those in Britain and other colonies of the British Empire. Therefore, it will be asked to what extent local discussions about imprisonment in India were connected to developments in the metropole, in other parts of the empire, and elsewhere in the colony and how such imperial connections influenced local practices. Recent studies on colonial India’s prisons have focused on the British possessions in north India, whereas the Madras Presidency’s penal history is as of yet mostly unstudied. The paper will look on two initiatives of prison reform undertaken by the Madras Government; firstly, an inquiry made in the 1820s to combat the high mortality in the jails, and secondly, attempts throughout the 1840s and 1850s to construct a penitentiary along the lines of penal systems in other parts of India and the British Empire. The two case studies promise insights into the body of knowledge about punishment that was accumulated in British India, its entanglement with debates in other parts of the empire, and the emergence of ‘imperial standards’ of imprisonment in the course of the 19th century.

What Is a Minor Stroke?

Background and Purpose— The term “minor stroke” is often used; however a consensus definition is lacking. We explored the relationship of 6 “minor stroke” definitions and outcome and tested their validity in subgroups of patients. Methods— A total of 760 consecutive patients with acute ischemic strokes were classified according to the following definitions: A, score ≤1 on every National Institutes of Health Stroke Scale (NIHSS) item and normal consciousness; B, lacunar-like syndrome; C, motor deficits with or without sensory deficits; D, NIHSS ≤9 excluding those with aphasia, neglect, or decreased consciousness; E, NIHSS ≤9; and F, NIHSS ≤3. Short-term outcome was considered favorable when patients were discharged home, and favorable medium-term outcome was defined as a modified Rankin Scale score of ≤2 at 3 months. The following subgroup analyses were performed by definition: sex, age, anterior versus posterior and right versus left hemispheric stroke, and early (0 to 6 hours) versus late admission (6 to 24 hours) to the hospital. Results— Short-term and medium-term outcomes were most favorable in patients with definition A (74% and 90%, respectively) and F (71% and 90%, respectively). Patients with definition C and anterior circulation strokes were more likely to be discharged home than patients with posterior circulation strokes (P=0.021). The medium-term outcome of older patients with definition E was less favorable compared with the outcome of younger ones (P=0.001), whereas patients with definition A, D, and F did not show different outcomes in any subgroup. Conclusions— Patients fulfilling definition A and F had best short-term and medium-term outcomes. They would be best suited to the definition of “minor stroke.”

Differences in Demographic Characteristics and Risk Factors in Patients With Spontaneous Vertebral Artery Dissections With and Without Ischemic Events

Spontaneous vertebral artery dissection (sVADs) mainly cause cerebral ischemia, with or without associated local symptoms and signs (headache, neck pain, or cervical radiculopathy), or with local symptoms and signs only.

The Benefits of Intravenous Thrombolysis Relate to the Site of Baseline Arterial Occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)

In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET).

Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion

Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease.

The lectin-like domain of tumor necrosis factor improves lung function after rat lung transplantation--potential role for a reduction in reactive oxygen species generation

To test the hypothesis that the lectin-like domain of tumor necrosis factor, mimicked by the TIP peptide, can improve lung function after unilateral orthotopic lung isotransplantation. Because of a lack of a specific treatment for ischemia reperfusion-mediated lung injury, accompanied by a disrupted barrier integrity and a dysfunctional alveolar liquid clearance, alternative therapies restoring these parameters after lung transplantation are required.

Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers

To study the changes in blood volume and hormones controlling sodium and water homeostasis after infusions of 0.9% saline, Gelofusine (4% succinylated gelatin in 0.7% saline, weight-average molecular weight 30 kD), and Voluven (6% hydroxyethyl starch in 0.9% saline, weight-average molecular weight 130 kD) in healthy volunteers.