Unconscious Confusion

Abstract Background Imprecise definitions of syncope and related conditions appear common in the medical literature. To investigate the scope of the problem we systematically searched for definitions in high-ranking medical journals. Methods Literature review of articles on syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension with these keywords in the title, mainly published in the ten journals with the highest impact in the fields of cardiology, internal medicine, and neurology. Results Syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension were defined in only 41%, 34%, 26%, 38%, and 48% of papers respectively. Definitions, when given, differed considerably among papers. Orthostatic hypotension was most frequently defined, with an increase in number and consistency of definitions after publication of a consensus in 1996. Conclusions Syncope and related conditions proved to be infrequently and inconsistently defined in current medical literature. The lack of consistent terminology is likely to harm medical education, research, and patient care. There is a strong need for a systematic terminology for syncope and related conditions.     

Expression of adhesion molecules on peripheral lymphocytes predicts future lesion development in MS

The expression of adhesion molecules (alpha4beta1-integrin, LFA-1, ICAM-1) on T cells, measured by flow cytometry, was compared in different subtypes of multiple sclerosis (MS) and related to future lesion development as seen as delta T1 and T2 lesion load per year on magnetic resonance imaging (MRI). LFA-1 and alpha4beta1-integrin showed higher expression on CD4 and CD8 T lymphocytes in the secondary progressive compared to the relapsing-remitting (CD4: p<0.01, p=ns, p<0.05; CD8: p<0.001, p<0.001, p<0.001, respectively) and primary progressive MS phase (CD4: p<0.001, p<0.01, p<0.05; CD8: p<0.01, p<0.01, p<0.001, respectively). The adhesion molecule expression of alpha4- (r=0.31; p<0.05) and beta1-integrin (r=0.38; p<0.01) on CD4+ cells and of LFA-1beta on both CD4+ and CD8+ (r=0.28, p<0.05) and r=0.29; p<0.05, respectively) cells was significantly related to increase in T2 lesion load. Our study provides further evidence for the involvement of integrins in lesion development, shown as T2 lesions on MRI in MS.     

Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets

SARS coronavirus continues to cause sporadic cases of severe acute respiratory syndrome (SARS) in China. No active or passive immunoprophylaxis for disease induced by SARS coronavirus is available. We investigated prophylaxis of SARS coronavirus infection with a neutralising human monoclonal antibody in ferrets, which can be readily infected with the virus. Prophylactic administration of the monoclonal antibody at 10 mg/kg reduced replication of SARS coronavirus in the lungs of infected ferrets by 3.3 logs (95% CI 2.6-4.0 logs; p<0.001), completely prevented the development of SARS coronavirus-induced macroscopic lung pathology (p=0.013), and abolished shedding of virus in pharyngeal secretions. The data generated in this animal model show that administration of a human monoclonal antibody might offer a feasible and effective prophylaxis for the control of human SARS coronavirus infection.     

The immunoneuroendocrine axis in critical illness: beneficial adaptation or neuroendocrine exhaustion?

PURPOSE OF REVIEW: Over the last years, endocrinology has been incorporated in critical care medicine, and acknowledgment of the complex neuro-endocrine adaption of critical illness has led to new insights and major breakthroughs in clarifying pathophysiological mechanisms and the targeting of therapeutic strategies. This review focuses on the important role of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness and the occurrence of neuroendocrine failure. RECENT FINDINGS: The distinction between acute (activated anterior pituitary function and inactivated peripheral anabolic pathways) and prolonged (reduced neuroendocrine stimulation) critical illness as different neuroendocrine paradigms has brought a new approach to the critically ill patient. The HPA adaptation in the prolonged phase is characterized by hypercortisolism induced by non-ACTH driven pathways as ACTH levels are low. In spite of the high-normal (total) cortisol levels, HPA insufficiency appears to be quite common. On the other hand, there is a marked depletion of corticosteroid-binding globulin (CBG) in the acute phase of critical illness, resulting in increased free and biologically active cortisol. There is a persistent marked depletion of dehydroeplandrosterone sulfate, possibly indicating adrenal exhaustion, while macrophage inhibitory factor is upregulated in sepsis, affecting and contraregulating the biological effects of glucocorticoids. SUMMARY: The endocrine system is highly interrelated with the immune and neural systems, the neuroimmunoendocrine axis is subject to clear biphasic changes in the acute and chronic phases of critical illness, most likely reflecting a beneficial adaptation. These neuroendocrine dynamics should be considered when assessing the neuroendocrine system, in particular the HPA axis.     

Association of early CT abnormalities, infarct size, and apparent diffusion coefficient reduction in acute ischemic stroke

BACKGROUND AND PURPOSE: Diffusion-weighted (DW) imaging is more sensitive for early ischemia than CT, and apparent diffusion coefficient (ADC) mapping permits quantification of the severity of cytotoxic edema. We examined the relationship between early CT findings, ischemic lesion volume on DW images, and edema subtype. METHODS: Patients in whom early signs of ischemia were detected on baseline CT scans were scored CT positive. Baseline DW lesion volumes were compared between the CT-positive and CT-negative patients. In CT-positive patients, we outlined the CT-positive part of the DW lesion and transferred these regions of interest to the corresponding DW sections. The ADC values of the outlined CT-positive areas were then compared with the ADC values of the CT-negative areas within patients. Lesions with significantly increased T2 hyperintensity were excluded to correct for the effect of early vasogenic edema on ADC measurements. RESULTS: Twenty-four patients with cerebral ischemia in whom both CT and DW imaging were performed within 8 hours of symptom onset were entered into the study. Patients with early CT signs of infarction (n = 12) had significantly larger DW lesion volumes than did patients without early CT abnormalities (mean volume, 62.8 versus 14.6 mL; P =. 002). In patients displaying early CT abnormalities, CT-positive regions of the DW lesion had lower relative ADC (rADC) values than did the CT-negative regions, when lesions with significant T2 hyperintensity were excluded (mean rADC, 0.65 versus 0.75; P =.037). CONCLUSION: These findings support the hypothesis that early CT signs of infarction indicate more extensive and severe cerebral ischemia, as reflected by lower ADC.     

Treatment of the triphalangeal thumb

Triphalangeal thumb is a thumb with 3 phalanges and has an estimated incidence of 1 in 25,000 live births. Clinical presentation of triphalangeal thumb can vary considerably. Most strikingly is the long finger-like thumb with clinodactyly, in the same plane as the fingers and may or may not present with an extra thumb. Anatomically, the extra phalanx can have different shapes, from wedge to rectangular. Furthermore, the involved joints, ligaments, muscles, and tendons of the first ray, from distal interphalangeal joint to radiocarpal joint, can be hypoplastic, malformed, or absent with varying degrees of stiffness or instability. Also, the first web can be insufficient, and radial polydactyly as well as other hand deformities can be present. The aim of surgical treatment is to try to reconstruct or correct the anatomic difference and at the same time provide a more acceptable appearance. In our series, depending on the malformation, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing as well as pollicization. Complications are mostly related to structures that have not been reconstructed or corrected during operation. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences.     

Objectivating nasality in healthy and velopharyngeal insufficient children with the Nasalance Acquisition System (NasalView). Defining minimal required speech tasks assessing normative values for Dutch language

OBJECTIVES: (1) To define normative nasalance data for Dutch language with "the NasalView System", and obtain a reference for normality when nasality is evaluated in children. (2) To investigate the minimal number of required speech tasks for a reliable nasalance measurement. METHODS: 55 children (30 normal and 25 velopharyngeal insufficient), aged between 4 and 11 were included. All children had to read or repeat two Dutch passages ((one with a normal amount of nasal consonants (normal passage) and one with none (nonnasal passage)). Further, one normal and one velopharyngeal insufficient subject read a passage in repetition to test the NasalViews reproducibility: (1) For both passages, group means (GM) and standard deviations (S.D.) were used to compute "pathological nasalance boundaries" [GM +/- (2 x S.D.)], in combination with the coefficient of variation (CV), sensitivity, specificity and positive predictive values. (2) With ANOVA all sentences within each passage were tested for significant differences in nasalance. RESULTS: (1) The pathological boundaries were 28.6-41.4% (GM: 35.0) and 21.4-34.7% (GM: 28.1), for the normal and nonnasal passage, respectively. For the normal passage a sensitivity of 96%, a specificity of 93% and a positive predictive value of 92% was computed. For the nonnasal passage these parameters were 96, 95 and 96%, respectively. Intra subject CVs of 3.6% (normal subject) and 1.5% (VI subject) showed good reproducibility of measurements. (2) Within the normal passage only the third sentence was significantly different in nasalance, compared to the entire passage (31.2% versus 35.0%). Within the nonnasal passage the second and fifth sentences were significantly different (23.8 and 24.8% versus 28.1%). However, the individual nonsignificantly different sentences showed a higher variation in nasalance compared to the entire passages. CONCLUSIONS: The NasalView System seems to be reliable and quantifies valid nasalance values when nasality is evaluated. Within both passages high levels of sensitivity, specificity and positive predictive values were obtained. The nonnasal passage discriminates slightly better for hypernasal speech. For the most reliable nasalance measurements, the entire passage should be used.     

8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist

The human histamine H1 receptor (H1R) is an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are known to potently antagonize the H1R, thereby producing some of their side effects. In contrast, the tolerability and potential therapeutic utility of H1R agonism is currently unclear. We have used a cell-based functional assay to evaluate known therapeutics and reference drugs for H1R agonist activity. Our initial functional screen identified three ergot-based compounds possessing heretofore-unknown H1R agonist activity. 8R-lisuride demonstrated potent agonist activity in various assays including receptor selection and amplification technology, inositol phosphate accumulation, and activation of nuclear factor-kappaB with pEC50 values of 8.1, 7.9, and 7.9, respectively, and with varying degrees of efficacy. Based on these assays, 8R-lisuride is the most potent stereospecific partial agonist for the human H1R yet reported. Investigation of the residues involved in histamine and lisuride binding, using H1R mutants and molecular modeling, have revealed that although these ligands are structurally different, the lisuride-binding pocket in the H1R closely corresponds to the histamine-binding pocket. The discovery of a potent stereospecific partial H1R agonist provides a valuable tool to further characterize this important therapeutic target in vitro.     

Diagnostic and therapeutic impact of ambulatory electrocardiography in acute stroke

Detection of paroxysmal atrial fibrillation (PAF) in patients with recent ischemic stroke or TIA suggests a cardioembolic etiology and leads to initiation of oral anticoagulation in suitable candidates. We assessed the diagnostic and therapeutic impact of adding ambulatory electrocardiography (24 hr ECG) to a standardised ischemic stroke workup. METHODS: We measured the frequency of detection of PAF in consecutive stroke patients who underwent 24 hr ECG that was not diagnosed clinically or on a standard 12-lead ECG. RESULTS: One hundred forty five ischemic stroke patients were included. 24 hr ECG was obtained in 136 patients (93.8%). Clinically unsuspected PAF was detected on 24 hr ECG in 7 patients (5.1%). The secondary prevention measure changed from antiplatelet agents to oral anticoagulation in 6 of 7 patients. CONCLUSION: Our findings suggest that ambulatory electrocardiography is a valuable diagnostic tool in the workup of stroke patients. Further prospective studies are needed to identify, subtypes of patients in whom the yield of ambulatory electrocardiography is higher.     

Tumor necrosis factor-alpha and interleukin-1beta mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood

OBJECTIVE: To investigate the role of endotoxin-induced inflammatory mediators in blood on the permeability of endothelial monolayers. DESIGN: Whole blood of healthy volunteers was treated with bacterial lipopolysaccharide (Escherichia coli, B55:05), and the resultant plasma was added to human umbilical venular endothelial cells (HUVEC) cultured on semipermeable membrane inserts (Transwells). SETTING: University hospital laboratory. SUBJECTS: Whole blood of healthy volunteers. INTERVENTIONS: Donor plasma was treated with excess antibodies against either tumor necrosis factor-alpha, interleukin-1beta, or both, before the incubation on HUVEC. MEASUREMENTS AND MAIN RESULTS: The permeability of HUVEC monolayers to fluorescent-labeled albumin and dextran was measured over a 6-hr period, after removal of the stimulus. The production of tumor necrosis factor-alpha and interleukin-1beta in lipopolysaccharide-treated whole blood was determined by radioimmunoassay. Individually, lipopolysaccharide (10 microg/mL), tumor necrosis factor-alpha (10 ng/mL), and interleukin-1beta (50 ng/mL) all increased endothelial permeability by about 2.5-fold. A much larger increase could be achieved by preincubation of lipopolysaccharide (10 microg/mL) in whole blood: the resultant plasma induced a ten-fold increase of the permeability. The permeability response after preincubation of lipopolysaccharide in whole blood was time- and dose-dependent. Moreover, this treatment increased the sensitivity of endothelial monolayers to lipopolysaccharide by a factor of several thousand-fold: Whereas high doses of lipopolysaccharide were required for direct stimulation of the permeability, picomolar amounts of lipopolysaccharide in whole blood induced a similar increase. Significant amounts of tumor necrosis factor-alpha and interleukin-1beta were produced in blood at similar doses of lipopolysaccharide. The addition of antibodies against tumor necrosis factor-alpha or interleukin-1beta to plasma partially but significantly abrogated the permeability increase. However, a complete inhibition could be achieved by the simultaneous addition of anti-tumor necrosis factor-alpha and anti-interleukin-1beta to plasma. CONCLUSIONS: Although lipopolysaccharide is capable of directly inducing endothelial permeability, blood-borne tumor necrosis factor-alpha and interleukin-1beta mediate lipopolysaccharide-induced endothelial permeability at low endotoxin concentrations. These findings support the idea that multifactorial inhibition of inflammatory mediators may improve survival in septic patients.