Modafinil in the treatment of idiopathic hypersomnia without long sleep time—a randomized,double‐blind,placebo‐controlled study

In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift work sleep disorder and for idiopathic hypersomnia (IH). In uncontrolled studies, modafinil has been reported to be efficacious in the treatment of sleep disorders. We therefore performed a randomized, placebo‐controlled study with the aim of proving the efficacy of modafinil treatment in these patients. Drug‐free IH patients without long sleep according to ICSD2 criteria, age >18 years and disease duration >2 years were included. After a washout phase, patients at baseline received placebo or 100 mg modafinil in the morning and at noon over 3 weeks, followed by 1 week without medication. At each visit the Epworth Sleepiness Scale (ESS) and Clinical Global Impression (CGI) rating scale were performed. At baseline and on days 8 and 21 four Maintenance of Wakefulness Tests (MWTs)/day or per day were performed. Patients kept a sleep–wake diary throughout the study. Between 2009 and 2011 three sleep centres recruited 33 participants. Compared to placebo, modafinil decreased sleepiness significantly and improved mean sleep latency in the MWT non‐significantly. The CGI improved significantly from baseline to the last visit on treatment. The most frequent adverse events were headaches and gastrointestinal disorders; skin and psychiatric reactions were not reported. The number of reported naps and duration of daytime sleepiness decreased significantly. Total sleep time of nocturnal sleep was slightly reduced. The sleep diaries showed increases in feeling refreshed in the morning; the diurnal diaries showed significant improvement of performance and of exhaustion. Modafinil is an effective and safe medication in the treatment of IH. Adverse events are mild to moderate.     

Nile Red fluorescence spectroscopy reports early physicochemical changes in myelin with high sensitivity

The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human. The method uses a simple staining procedure involving the lipophilic dye Nile Red, whose fluorescence spectrum varies according to the chemical polarity of the microenvironment into which the dye embeds. Nile Red spectroscopy identified histologically intact yet biochemically altered myelin in prelesioned tissues, including mouse white matter following subdemyelinating cuprizone intoxication, as well as normal-appearing white matter in multiple sclerosis brain. Nile Red spectroscopy offers a relatively simple yet highly sensitive technique for detecting subtle myelin changes.

Myelin is a highly ordered, lipid-rich extension of glial cell membrane that facilitates rapid and efficient saltatory conduction of action potentials along axons in the central and peripheral nervous systems. The stability of myelin membranes critically depends on its molecular composition (1–3). Although myelin is maintained roughly at a ratio of 70:30% lipid to protein (4), lipid membranes are highly fluid; changes in lipid composition are defining characteristics of myelin development (5), homeostasis in the adult, and aging in rodents (6, 7), as well as primates (8). Shifts in lipid composition also occur in inflammatory demyelinating disorders like multiple sclerosis (MS) (9, 10). Lipids are even theorized to be targets of immune attacks in autoimmune disorders, a role previously ascribed to proteins (11). Key roles for lipids notwithstanding, tools to interrogate biochemical changes to myelin lipids have largely been restricted to in vitro systems.Once thought to be inert, myelin is now known to be a chemically and structurally dynamic element (12). Specific combinations of proteins and lipids induce formation and compaction of multilamellar vesicles that resemble myelin (13), underscoring the importance of correct chemical composition for assembly. Conversely, alterations in these molecular proportions promote decompaction and myelin vesiculation (3, 14). The polarity of lipid species in cell membranes influences their packing properties and therefore stability (15). Governed by competing thermodynamic forces of lipid curling and hydrocarbon packing (16), myelin sheaths lie at the critical edge of bilayer stability and thus are susceptible to factors in the environment. Indeed, the myelin integrity theory of MS rests on the outsized influence of environmental forces on myelin stability and function (17). Therefore, methods for detecting physicochemical changes in myelin lipid composition in situ would greatly enhance our understanding of early events in myelin development, as well as myelin damage in disease states, with important implications for therapies designed to prevent myelin loss in MS and other demyelinating disorders.The study of myelin lipid biochemistry poses unique challenges (18). Traditional analytical methods, such as thin-layer chromatography and high-performance liquid chromatography (19), depend on tissue homogenization that eliminates informative spatial relationships. Imaging lipid mass spectrometry (20) preserves spatial relationships, but submicron resolution has yet to be realized, and reproducibility at the level of sample preparation remains problematic (21). Coherent anti–Stokes Raman scattering microscopy provides high-resolution, label-free imaging of lipids in histological samples (22), but this method lacks sensitivity and requires expertise in nonlinear optics as well as highly specialized hardware. Finally, fluorescent lipophilic dyes, though widely available and easy to use, have traditionally been employed to detect lipid-rich structures in only a qualitative manner. Conventional fluorescence microscopy is therefore unable to detect subtle shifts in lipid biochemistry. By contrast, Nile Red (NR) is a fluorescent dye that is well situated to report changes in the chemical polarity of cell membranes and myelin, being both lipophilic (23, 24) and differentially fluorescent depending on solvent environment (i.e., exhibits solvatochromism) (25). The current study uses NR fluorescence spectroscopy to identify polarity shifts as an early manifestation of myelin disease prior to overt demyelination. We show that this technique reports subtle biochemical changes in myelin, resulting in a method that is a very sensitive marker of incipient myelin injury.     

Rapid bedside measurement of brain natriuretic peptide in patients with chronic heart failure

BACKGROUND: Brain natriuretic peptide (BNP) levels have been used to assess clinical status and predict prognosis of patients with chronic heart failure (CHF). However, BNP levels can only be measured in specialized laboratories which has hampered its use in daily clinical practice. We compared a new, rapid, BNP assay with a conventional BNP measurement and evaluated the applicability to current practice by comparing it with standard clinical parameters. METHODS: BNP levels were determined in 78 stable CHF patients and 20 controls. The severity of CHF was assessed by determination of New York Heart Association functional class (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption (peak VO(2)), and these parameters were compared to BNP levels. RESULTS: Overall, rapid BNP assessment was highly correlated with the conventional BNP assay (r=0.95, P<0.0001). In the higher ranges (>200 pmol/l), however, correlation was less accurate, and tended to overestimate. BNP levels also strongly correlated with both NYHA class, LVEF and peak VO(2) (all P<0.001). A cut-off value for BNP of 20 pmol/l yielded a sensitivity of 91% and a specificity of 92% to detect the presence of left ventricular systolic dysfunction. CONCLUSIONS: Rapid measurement of BNP levels is comparable to conventional BNP measurement and strongly correlated to clinical tests that are currently used to stratify CHF patients. Wider use of this method may yield a reduction of costly and time-consuming clinical tests and may reduce the medical burden of CHF.     

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis

Purpose

The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).

Susceptibility of Carrion Crows to Experimental Infection with Lineage 1 and 2 West Nile Viruses

West Nile virus (WNV) outbreaks in North America have been characterized by substantial die-offs of American crows (Corvus brachyrhynchos). In contrast, a low incidence of bird deaths has been observed during WNV epidemic activity in Europe. To examine the susceptibility of the western European counterpart of American crows, we inoculated carrion crows (Corvus corone) with WNV strains isolated in Greece (Gr-10), Italy (FIN and Ita09), and Hungary (578/10) and with the highly virulent North American genotype strain (NY99). We also inoculated American crows with a selection of these strains to examine the strains’ virulence in a highly susceptible bird species. Infection with all strains, except WNV FIN, resulted in high rates of death and high-level viremia in both bird species and virus dissemination to several organs. These results suggest that carrion crows are highly susceptible to WNV and may potentially be useful as part of dead bird surveillance for early warning of WNV activity in Europe.     

Use of the fluid column in a cardiac catheter for emergency pacing

Given the not infrequent need for intracardiac pacemaking during intensive cardiac care, a new type of cardiac pacemaker has been designed and tested [1]. With this pacemaker the heart can be stimulated through the fluid column of any conventional catheter, provided it is filled with a 0.9% NaCl solution. This fluid column pacemaker (FCP) is of the “constant current” type. The FCP was tested in 37 animals, in 30 patients in sinus rhythm, and also in two critical patients. In addition to the pacemaker circuit, a special connector was designed, enabling a fast, effective, and safe contact between patient and pacemaker. The FCP is considered to be ideally suited for use in emergency cardiac pacing in intensive care units and other areas where sudden bradycardias may occur and where intrathoracic catheters are inserted for a variety of reasons.     

Antibiotic susceptibility of Atopobium vaginae

Background  

Previous studies have indicated that a recently described anaerobic bacterium, Atopobium vaginae is associated with bacterial vaginosis (BV). Thus far the four isolates of this fastidious micro-organism were found to be highly resistant to metronidazole and susceptible for clindamycin, two antibiotics preferred for the treatment of BV.     

Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease

RATIONALE: Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD. OBJECTIVES: To compare circulating levels of hormones of the pituitary-gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients. METHODS AND MEASUREMENTS: Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex hormone-binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 +/- 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined. MAIN RESULTS: Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p < or = 0.05). The latter finding was also present in 48 non-steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = -0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor alpha. CONCLUSIONS: In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.