Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine

A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 of the Na(v)1.5 sodium channel and leading to a non-expression of the mutant allele, was prescribed the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Floxyfral), 100 mg per day. His normal baseline ECG changed to a characteristic Brugada-Type-1-ECG pattern. To investigate whether fluvoxamine may reduce the cardiac sodium current, the effect of this drug was studied on the wild-type voltage-gated cardiac sodium channel Na(v)1.5 stably expressed in HEK293 cells. Patch-clamp recording showed a 50% inhibition of the current at a concentration of 57.3 microM. In our patient, no arrhythmia occurred but the proarrhythmic potential of SSRI in patients with SCN5A mutations cannot be excluded. Therefore, we advise 12-lead ECG control after administering SSRI in these patients.

Preoperative MRI findings and functional outcome after selective dorsal rhizotomy in children with bilateral spasticity

PURPOSE: To identify MRI characteristics that may predict the functional effect of selective dorsal rhizotomy (SDR) in children with bilateral spastic paresis. METHODS: We performed SDR in a group of 36 patients. The gross motor functioning measure-66 (GMFM-66) was applied before and after SDR. Available cerebral MRIs were retrospectively classified into three diagnostic groups: periventricular leucomalacia (PVL; n = 10), hydrocephalus (n = 2), and normal (n = 6). In patients with PVL, we scored the severity of the MR abnormalities. We compared the changes in the GMFM-66 after SDR in the diagnostic groups. In patients with PVL, we correlated the severity of the MR abnormalities with the changes in the GMFM-66. RESULTS: The mean follow-up period was 5 years and 4 months (range, 1 year and 1 month to 9 years). The best improvement in gross motor function was observed in patients with normal MRI, and the slightest improvement was observed in patients with hydrocephalus. The severity of the PVL did correlate with the GMFM-66 score before SDR but not with the functional effect of SDR. CONCLUSION: We conclude that with respect to gross motor skills, the improvements after SDR are good in patients with no MRI abnormalities. In the patients with hydrocephalus, the improvements after SDR were insignificant. In patients with PVL, the improvements were intermediate and did not correlate with the degree of PVL.

Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration

For geographic atrophy (GA) due to age-related macular degeneration (AMD) there is so far no approved treatment option. Usually, increased autofluorescence (AF) levels of different patterns adjacent to the atrophic area indicate lipofuscin-laden retinal pigment epithelium (RPE) cells at a high risk for apoptosis. Herein, SRT was used to selectively treat these cells to stimulate RPE proliferation, in order to reduce or ideally stop further growth of the atrophic area.

Sonographic visualization and ultrasound-guided blockade of the greater occipital nerve: a comparison of two selective techniques confirmed by anatomical dissection

BACKGROUND: Local anaesthetic blocks of the greater occipital nerve (GON) are frequently performed in different types of headache, but no selective approaches exist. Our cadaver study compares the sonographic visibility of the nerve and the accuracy and specificity of ultrasound-guided injections at two different sites. METHODS: After sonographic measurements in 10 embalmed cadavers, 20 ultrasound-guided injections of the GON were performed with 0.1 ml of dye at the classical site (superior nuchal line) followed by 20 at a newly described site more proximal (C2, superficial to the obliquus capitis inferior muscle). The spread of dye and coloration of nerve were evaluated by dissection. RESULTS: The median sonographic diameter of the GON was 4.2 x 1.4 mm at the classical and 4.0 x 1.8 mm at the new site. The nerves were found at a median depth of 8 and 17.5 mm, respectively. In 16 of 20 in the classical approach and 20 of 20 in the new approach, the nerve was successfully coloured with the dye. This corresponds to a block success rate of 80% (95% confidence interval: 58-93%) vs 100% (95% confidence interval: 86-100%), which is statistically significant (McNemar's test, P=0.002). CONCLUSIONS: Our findings confirm that the GON can be visualized using ultrasound both at the level of the superior nuchal line and C2. This newly described approach superficial to the obliquus capitis inferior muscle has a higher success rate and should allow a more precise blockade of the nerve.

Sensitive and selective detection of free FXIII activation peptide: a potential marker of acute thrombotic events

Coagulation factor XIII (FXIII) stabilizes fibrin fibers and is therefore a major player in the maintenance of hemostasis. FXIII is activated by thrombin resulting in cleavage and release of the FXIII activation peptide (AP-FXIII). The objective of this study was to characterize the released AP-FXIII and determine specific features that may be used for its specific detection. We analyzed the structure of bound AP-FXIII within the FXIII A-subunit and interactions of AP-FXIII by hydrogen bonds with both FXIII A-subunit monomers. We optimized our previously developed AP-FXIII ELISA by using 2 monoclonal antibodies. We determined high binding affinities between the antibodies and free AP-FXIII and demonstrated specific binding by epitope mapping analyses with surface plasmon resonance and enzyme-linked immunosorbent assay. Because the structure of free AP-FXIII had been characterized so far by molecular modeling only, we performed structural analysis by nuclear magnetic resonance. Recombinant AP-FXIII was largely flexible both in plasma and water, differing significantly from the rigid structure in the bound state. We suggest that the recognized epitope is either occluded in the noncleaved form or possesses a structure that does not allow binding to the antibodies. On the basis of our findings, we propose AP-FXIII as a possible new marker for acute thrombotic events.

Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

ABSTRACT : INTRODUCTION : V2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock. METHODS : After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V2R-antagonist (1 g/kg per hour), AVP (0.05 g/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 g/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary. RESULTS : Compared to AVP- and placebo-treated animals, the selective V2R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V2R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V2R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V2R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V2R-antagonist group. In addition, the selective V2R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025). CONCLUSIONS : Selective V2R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

The risk of musculoskeletal disorders for workers due to repetitive movements during tomato harvesting

Tomatoes are the most common crop in Italy. The production cycle requires operations in the field and factory that can cause musculoskeletal disorders due to the repetitive movements of the upper limbs of the workers employed in the sorting phase. This research aims to evaluate these risks using the OCRA (occupational repetitive actions) index method This method is based firstly on the calculation of a maximum number of recommended actions, related to the way the operation is performed, and secondly on a comparison of the number of actions effectively carried out by the upper limb with the recommended calculated value. The results of the risk evaluation for workers who manually sort tomatoes during harvest showed a risk for the workers, with an exposure index greater than 20; the OCRA index defines an index higher than 3.5 as unacceptable. The present trend of replacing manual sorting onboard a vehicle with optical sorters seems to be appropriate to reduce the risk of work-related musculoskeletal disorders (WMSDs) and is supported from both a financial point of view and as a quality control measure.

Selective REM sleep deprivation in narcolepsy

Narcolepsy is characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, including cataplexy. The aim of this study was to assess REM sleep pressure and homeostasis in narcolepsy. Six patients with narcolepsy and six healthy controls underwent a REM sleep deprivation protocol, including one habituation, one baseline, two deprivation nights (D1, D2) and one recovery night. Multiple sleep latency tests (MSLTs) were performed during the day after baseline and after D2. During D1 and D2 REM sleep was prevented by awakening the subjects at the first polysomnographic signs of REM sleep for 2 min. Mean sleep latency and number of sleep-onset REM periods (SOREMs) were determined on all MSLT. More interventions were required to prevent REM sleep in narcoleptics compared with control subjects during D1 (57 ± 16 versus 24 ± 10) and D2 (87 ± 22 versus 35 ± 8, P = 0.004). Interventions increased from D1 to D2 by 46% in controls and by 53% in narcoleptics (P < 0.03). Selective REM sleep deprivation was successful in both controls (mean reduction of REM to 6% of baseline) and narcoleptics (11%). Both groups had a reduction of total sleep time during the deprivation nights (P = 0.03). Neither group had REM sleep rebound in the recovery night. Narcoleptics had, however, an increase in the number of SOREMs on MSLT (P = 0.005). There was no increase in the number of cataplexies after selective REM sleep deprivation. We conclude that: (i) REM sleep pressure is higher in narcoleptics; (ii) REM sleep homeostasis is similar in narcoleptics and controls; (iii) in narcoleptics selective REM sleep deprivation may have an effect on sleep propensity but not on cataplexy.

The selective determination of sulfates, sulfonates and phosphates in urine by CE-MS

Metabolite identification and metabolite profiling are of major importance in the pharmaceutical and clinical context. However, highly polar and ionic substances are rarely included as analytical tools are missing. In this study, we present a new method for the determination of urinary sulfates, sulfonates, phosphates and other anions of strong acids. The method comprises a CE separation using an acidic BGE (pH

Identification of selective norbornane-type aspartate analogue inhibitors of the glutamate transporter 1 (GLT-1) from the chemical universe generated database (GDB)

A variety of conformationally constrained aspartate and glutamate analogues inhibit the glutamate transporter 1 (GLT-1, also known as EAAT2). To expand the search for such analogues, a virtual library of aliphatic aspartate and glutamate analogues was generated starting from the chemical universe database GDB-11, which contains 26.4 million possible molecules up to 11 atoms of C, N, O, F, resulting in 101026 aspartate analogues and 151285 glutamate analogues. Virtual screening was realized by high-throughput docking to the glutamate binding site of the glutamate transporter homologue from Pyrococcus horikoshii (PDB code: 1XFH ) using Autodock. Norbornane-type aspartate analogues were selected from the top-scoring virtual hits and synthesized. Testing and optimization led to the identification of (1R*,2R*,3S*,4R*,6R*)-2-amino-6-phenethyl-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid as a new inhibitor of GLT-1 with IC(50) = 1.4 ?M against GLT-1 and no inhibition of the related transporter EAAC1. The systematic diversification of known ligands by enumeration with help of GDB followed by virtual screening, synthesis, and testing as exemplified here provides a general strategy for drug discovery.

Effect of selective dorsal rhizotomy on gait in children with bilateral spastic paresis: kinematic and EMG-pattern changes

Selective dorsal rhizotomy (SDR) is an effective treatment for reducing spasticity and improving gait in children with spastic cerebral palsy. Data concerning muscle activity changes after SDR treatment are limited.

Selective inferior petrosal sinus sampling without venous outflow diversion in the detection of a pituitary adenoma in Cushing's syndrome

Conventional MRI may still be an inaccurate method for the non-invasive detection of a microadenoma in adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) with ovine corticotropin-releasing hormone (oCRH) stimulation is an invasive, but accurate, intervention in the diagnostic armamentarium surrounding CS. Until now, there is a continuous controversial debate regarding lateralization data in detecting a microadenoma. Using BIPSS, we evaluated whether a highly selective placement of microcatheters without diversion of venous outflow might improve detection of pituitary microadenoma.