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Resumen Antecedentes y objetivo El vertigo posicional paroxistico benigno (VPPB) es la causa mas frecuente de vertigo de origen laberintico; su impacto social y en terminos de cuidados de salud es notable. Recientemente se ha demostrado que es clinicamente posible realizar el tratamiento y su comprobacion en la misma sesion, lo cual podria tener repercusion en los costes asistenciales directos e indirectos relacionados con la enfermedad. El objetivo de este trabajo es determinar si el protocolo de tratamiento unisesion del VPPB CP unilateral tipo conductolitiasis es mas eficiente que el protocolo de tratamiento convencional. Materiales y metodos Estudio prospectivo controlado y aleatorizado en 53 pacientes consecutivos diagnosticados de un VPPB CP unilateral tipo conductolitiasis no tratados previamente; 26 pacientes fueron asignados al grupo unisesion y 27 al semanal clasico. Se compararon los costes medio y total de la asistencia, el tiempo de consulta y el impacto en terminos de incapacidad temporal y perdida de productividad para la empresa asociada a la visita medica del paciente. Resultados Los costes medio y total de la asistencia asi como la perdida de productividad para una empresa asociada a la visita medica de los pacientes laboralmente activos fueron significativamente menores en el protocolo unisesion. Tambien el tiempo de consulta cuando se considero el tiempo de desplazamiento al centro. Conclusiones El protocolo de tratamiento unisesion es rapido, efectivo y reduce los costes asistenciales directos e indirectos relacionados con la enfermedad justificando consultas de alta resolucion.

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays revealed a ∼5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. When challenged with KAE609, high-level resistance was obtained more rapidly and at lower inoculum than wild-type parasites. Selections were also successful with an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. Mutations in a previously uncharacterized gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), were validated as causal for resistance to MMV665794 and an analog, MMV007224. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery.

Objectives: To address the prevalence of audiovestibular disorders in patients with primary Raynaud’s Phenomenon (RP). A series of patients with primary RP and secondary RP in the context of systemic sclerosis (SSc) were compared with healthy controls. Methods: A prospective multicenter observational cross-sectional study was conducted in several Otolaryngology and Rheumatology Divisions of tertiary referral hospitals, recruiting 57 patients with RP and 57 age- and gender-matched controls. Twenty patients were classified as primary RP when unrelated to any other conditions and 37 patients who met the 2013 ACR/EULAR classification criteria for SSc were classified as having secondary RP associated with SSc. Audiometric and vestibular testing (vHIT), clinical sensory integration and balance testing (CTSIB), and Computerized Dynamic Posturography (CDP) were performed. Results: As significant differences were found in the age of the two study groups, primary and secondary RP, no comparisons were made between both groups of RP but only with their control groups. No sensorineural hearing loss (SNHL) was recorded in any of our patients with primary RP and no differences were found in the voice audiometry tests with respect to controls. Four of 37 (10.8%) secondary RP patients presented SNHL. Those with SNHL were 7.03 times more likely to have a secondary RP than controls (p < 0.001). The audiometric curve revealed high-frequency hearing loss in 4 patients with RP secondary to SSc, and statistically significant differences were achieved when RP secondary was compared to controls in vHIT gain, caloric test, CTSIB, and CDP. Conclusions: Unlike patients with RP secondary to SSc, patients with primary RP do not show audiovestibular abnormalities. Regarding audiovestibular manifestations, primary RP can be considered a different condition than secondary RP.

Essential tremor (ET) is a neurological disorder characterized primarily by action tremor. Balance impairments in ET patients were formerly considered to be uncommon and simply age-related. However quantitative assessment with posturography has revealed impairments in control of both static and dynamic balance.The aim of the present study is to assess postural stability with different posturographic techniques in ET patients.A prospective cross-sectional study conducted in two University Hospitals. Eleven patients diagnosed with essential tremor and twelve healthy controls were included. Balance assessment were performed with: sensory organization test (SOT) and limits of stability (LOS) of the computer dynamic posturography (CDP), results of free-field body sway analysis with mobile posturography (Vertiguard®), modified timed up and go test (TUG), Dizziness handicap inventory (DHI) and activities-specific balance confidence scale (ABC).Patients with ET showed poorer scores in the SOT than controls for composite balance and somatosensory input. They also performed worse in LOS tests and Vertiguard® device indicated a higher risk of falling. There were no differences in the modified TUG. The mean score of DHI was 15.64 and 85.16 for ABC.Posturography assessment (CDP and Vertiguard®) is more accurate in showing balance impairment in ET patients than clinical evaluation (modified TUG). Balance impairment involves deteriorated processing of somatosensory input which could be explained by cerebellar dysfunction. Balance deficits could be included into future diagnostic criteria.

Objective To determine the reliability and safety of posterior canal BPPV (pc-BPPV) treatment with subsequent assessment of the effectiveness of the maneuver in a single session, compared to the classic weekly procedure. Method A prospective study of two randomized groups of unilateral pc-BPPV was performed: a weekly management group (27 patients) and single-session treatment group (26 patients). The number of maneuvers required to clear pc-BPPV, incidence of side effects (re-entries and canal conversions), and recurrence rates were compared. Results There were no statistically significant differences in the number of maneuvers needed to resolve pc-BPPV, the incidence of side effects, or the recurrence rate between the two groups. Two re-entries were diagnosed in the single-session group, and both were easily and successfully treated. Three early recurrences were found in the single-session group and one spontaneous recovery was encountered in the weekly group. Time required to discharge patients to follow-up was significantly reduced in the single-session group. Conclusion Managing pc-BPPV in one session is safe and reliable, resulting in fewer visits to outpatient clinics and optimization of treatment strategies.

Introduction and objective: Dizziness and imbalance are common symptoms in the elderly and have a great impact on their quality of life. Method: Narrative review. Results: Main factors that condition instability in the elderly and the impact of falls are reviewed, as well as the most profitable tests in diagnosis. Finally, the need to perform a multidisciplinary approach was discussed, highlighting the importance of vestibular rehabilitation in the treatment of these disorders. Conclusions: Instability in the elderly is multifactorial and not only due to physiological reasons. Hence the need to identify precipitating factors, treat them if possible and carry out a multidisciplinary approach that minimizes the morbidity and mortality associated with this process and improve their quality of life. Vestibular rehabilitation can significantly ameliorate balance in the elderly with instability which would lead to a significant reduction in falls.

The head impulse test (HIT) is triggered by the vestibulo-ocular reflex (VOR), complemented by the optokinetic and pursuit systems. This study aimed to evaluate the possibility of individualizing the VOR contribution to the HIT.Thirty-six healthy individuals (19 males, 17 females; age 21-64 years, mean 39 years) underwent horizontal video HIT (vHIT). This was first conducted in darkness, without visual fixation, and then visually tracked.Seventy percent of the impulses delivered ocular responses opposite to the direction of the head, matching its velocity to a point where quick anticompensatory eye movements (SQEM) stopped the response (SQEM mean latency 58.21 ms, interquartile range 50-67 ms). Of these, 75% recaptured the head velocity after culmination. Thirty percent of the responses completed a bell-shaped curve. The completed bell-shaped curve gains and instantaneous gains (at 40, 60, and 80 ms) before SQEM were equivalent for both paradigms. Females completed more bell-shaped traces (42%) than males (15%); p = 0.01. The SQEM latency was longer (62.81 versus 55.71 ms, p0.01), and the time to recapture the bell-shaped curve was shorter (77.51 versus 92.52 ms, p0.01) in females than in males. The gains were comparable between sexes in both paradigms.The VOR effect can be localized in the first 70 ms of the vHIT response. In addition, other influences may take place in estimating the vHIT responses. The study of these influences might provide useful information that can be applied to patient management.

The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite's death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite's calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.

Benign Paroxysmal Positional Vertigo is the most frequent episodic vestibular disorder. The purpose of this guide, requested by the committee on otoneurology of the Spanish Society of Otolaryngology and Head and Neck Surgery, is to supply a consensus document providing practical guidance for the management of BPPV. It is based on the Barany Society criteria for the diagnosis of BPPV. This guideline provides recommendations on each variant of BPPV, with a description of the different diagnostic tests and the therapeutic manoeuvres. For this purpose, we have selected the tests and manoeuvres supported by evidence-based studies or extensive series. Finally, we have also included a chapter on differential diagnosis and a section relating to general aspects in the management of BPPV.

Benign paroxysmal positional vertigo (BPPV) is the most common vertigo of labyrinthine origin, its social and healthcare impact is remarkable. It has recently been shown that single session treatment is as safe and effective as weekly treatment, which could have impact on direct and indirect costs related to the disease. The objective of this study is to determine whether single session treatment of unilateral posterior canal BPPV canalolithiasis is more efficient than conventional treatment.A prospective randomized controlled trial was performed in 53 consecutive patients diagnosed with unilateral posterior canal BPPV canalolithiasis previously untreated: 26 patients were assigned to single session treatment and 27 patients to weekly treatment. Average and total cost of care, consultation time and the impact in terms of temporary disability and loss of productivity for the company due to patients' medical visits were compared.Average and total cost of care and loss of productivity for the company due to patients' medical visits were significantly lower in the single session group. Consultation time was also better in this group when travelling time was considered.The single session protocol is fast, effective and reduces direct and indirect cost of care related to disease justifying high resolution consultations.

Introduction and objective: To maintain balance central nervous system coordinates and integrates information provided by vestibular, visual and proprioceptive systems. Method: Narrative revision. Results: The oculomotor system is composed of the efferent limb of the visual system and the vestibular system as well as interconnected regions throughout the central nervous system that interact to control various eye movements. Its main function is maintaining visual stability and controlling eye movements, but its correct functioning also translates the integrity of the elements involved in the balance and hence its clinical relevance. Its exam is important because its dysfunction could be due to disease of the central nervous system. Besides, it provides a reference to continue testing vestibular function. Conclusions: Therefore, oculomotor exploration is by itself a very extensive and comprehensive evaluation that provides in short time transcendental information for the diagnosis of the patient, so it is necessary to know how to perform it and understand the findings evidenced in it.

Introduction and objective: Caloric test has been the most important test of vestibular function for the last century. A practical approach, including special recommendations for a more accurate completion and interpretation of this test are proposed. Method: Narrative statement. Results and discussion: The caloric test is limited to horizontal canal function and there are not absolute normative values. Thus, the procedures for administering the caloric test and for analysing the responses should be settled with caution. For accurate interpretation of the caloric test, the validity of the results must be stablished first, ruling out artefacts and technical errors. Conclusions: Caloric test is still a sensitive test for detecting common vestibular abnormalities, mainly due to its ability to point to the pathologic labyrinth. But the information from the caloric test must be used along with history, physical examination and other test to make a diagnosis and devise management plans.

Objective To assess the effect of intratympanic methylprednisolone (ITMP) in posterior canal benign paroxysmal positional vertigo (BPPV) that fails treatment involving repositioning maneuver in a case series. Materials and methods Nine patients with persistent posterior canal BPPV after 6 or more repositioning maneuvers were treated by ITMP (two weekly doses of 0.3-0.4 mL at 40 mg/mL) before repeating the repositioning procedures. Results Following ITMP treatment, 7 out of 9 patients were relieved of their symptoms and did not exhibit positional nystagmus after 1 or 2 repositioning maneuvers. The number of positional maneuvers performed before and after ITMP treatment in these 7 patients showed a statistically significant (p=0.016) reduction in the amount of repositioning treatments required. None of the 7 respondent patients showed any relapses during the follow-up period (follow-up range: 11-95 months). Conclusion Administering ITMP before resuming repositioning procedures can be a useful treatment for persistent BPPV of the posterior canal.

Carotid disease, measured as carotid intima-media thickness (CIMT) and carotid plaque (CP), is associated with major adverse cardiac and cerebrovascular events (MACCE) in people without the previous atherosclerotic disease; however, there are few published data in patients undergoing coronary angiography. The aim of the study is to determinate if the carotid disease is associated with MACCE after coronary angiography.A total of 390 consecutive patients underwent coronary angiography after exercise echocardiography and carotid ultrasonography between 2002 and 2013. MACCE was defined as stroke, myocardial infarction due to atherosclerosis progression or death due to a stroke or cardiac event.Two patients were lost (0.5%). During a mean follow-up of 6.0 years (standard deviation of 2.9), 52 patients (13.4%) suffered MACCE. 1, 5, and 10 years, event-free survival was 96.4% (1.0), 88.7% (1.7), and 81.4% (2.8), respectively. Event rates at 10 years were higher in the CP group (23.2% vs. 10.2%, p = 0.013) and in the CIMT0.9 mm group (25.9% vs. 13.3%, p = 0.023). Multivariate analysis showed smoking habit (hazard ratio [HR] 2.51, 95% confidence interval [CI] 1.36-4.62, p = 0.003), glomerular filtration rate (HR 0.98, 95% CI 0.98-0.99), aortic stenosis (HR 2.99, 95% CI 1.24-7.21, p = 0.014), incomplete/no coronary revascularization (HR 1.97, 95% CI 1.06-3.67, p = 0.033), insulin treatment (HR 2.63, 95% CI 1.30-5.31, p = 0.006), and CP (HR 2.36, 95% CI 1.02-5.44, p = 0.044) as predictors of MACCE.CP is an independent predictor of MACCE in patients undergoing coronary angiography.La enfermedad carotídea, definida como grosor de íntima media (GIMC) y placa (PC), se asocia con eventos adversos cardiacos y cerebrovasculares (EACC) en sujetos sin aterosclerosis previa; sin embargo hay pocos datos en pacientes sometidos a coronariografía. El objetivo del estudio es determinar si la enfermedad carotídea se asocia a EACC en pacientes remitidos a coronariografía.Entre 2002 y 2013 390 pacientes fueron sometidos a coronariografía tras ecocardiograma de esfuerzo y ecografía carotídea. Se definió EACC como accidente cerebrovascular, infarto de miocardio por progresión aterosclerótica o muerte por accidente cerebrovascular o causa cardiaca.Durante un seguimiento medio de 6 años (desviación estándar 2, 9) se registraron 2 pérdidas y 52 eventos (13,4%). La supervivencia media libre de eventos a uno, cinco y diez años fue 96.4% (1.0), 88.7% (1.7) y 81.4% (2.8). Hubo mayor número de eventos a 10 años en el grupo de PC (23.2% frente 10.2%, p = 0.013) y GIMC0.9 mm (25,9% frente 13.3%, p = 0.023). En el análisis multivariado los predictores de EACC fueron tabaquismo (hazard ratio [HR] 2.51, intervalo de confianza [IC] al 95% 1.36-4.62, p = 0.003), filtrado glomerular renal (HR 0.98 IC95% 0.98-0.99), estenosis aórtica (HR 2.99, IC 95% 1.24-7.21, p = 0.014), revascularización incompleta/no revascularización (HR 1.97, IC 95% 1.06-3.67, p = 0.033), tratamiento con insulina (HR 2.63, IC 95% 1.30-5.31, p = 0.006) y PC (HR 2.36, 95%CI 1.02-5.44, p = 0.044).La PC es un predictor independiente de EACC en pacientes sometidos a coronariografía.

BACKGROUND: Obesity is a major health problem due to its high prevalence. The relationship between obesity and cardiovascular disease is unclear. Some studies agree that certain conditions associated with obesity, such as physical inactivity or cardiovascular risk factors, are responsible for cardiovascular risk excess among obese people. Carotid intima-media thickness and carotid plaques (CP) have been associated with cardiovascular adverse events in healthy populations, and recent data suggest a higher prevalence of subclinical carotid atherosclerosis in obese and metabolically unhealthy patients. However, there are no studies correlating subclinical atherosclerosis and adverse events (AE) in obese subjects. AIM: To determine the association between carotid disease and AE in obese patients with negative exercise echocardiography (EE). METHODS: From January 1, 2006 to December 31, 2010, 2000 consecutive patients with a suspicion of coronary artery disease were submitted for EE and carotid ultrasonography. Exclusion criteria included previous vascular disease, left ventricular ejection fraction < 50%, positive EE, significant valvular heart disease and inferior to submaximal EE. An AE was defined as all-cause mortality, myocardial infarction and cerebrovascular accident. Subclinical atherosclerosis was defined as CP presence according to Manheim and the American Society of Echocardiography Consensus. RESULTS: Of the 652 patients who fulfilled the inclusion criteria, 226 (34.7%) had body mass indexes ≥ 30 kg/m2, and 76 of them (33.6%) had CP. During a mean follow-up time of 8.2 (2.1) years, 27 AE were found (11.9%). Mean event-free survival at 1, 5 and 10 years was 99.1% (0.6), 95.1% (1.4) and 86.5% (2.7), respectively. In univariate analysis, CP predicted AE [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.17-5.46; P = 0.019]. In multivariable analysis, the presence of CP remained a predictor of AE (HR 2.26, 95%CI 1.04-4.95, P = 0.041). Other predictors identified were glomerular filtration rate (HR 0.98, 95%CI 0.96-0.99; P = 0.023), peak metabolic equivalents (HR 0.83, 95%CI 0.70-0.99, P = 0.034) and moderate mitral regurgitation (HR 5.02, 95%CI 1.42-17.75, P = 0.012). CONCLUSION: Subclinical atherosclerosis defined by CP predicts AE in obese patients with negative EE. These patients could benefit from aggressive prevention measures.

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance., It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al. investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.

[Abstract] Background. Relationship between carotid and coronary artery disease (CAD) in patients undergoing invasive and non-invasive test is unclear. The aim of the study is to evaluate whether carotid disease is associated with CAD in patients submitted to exercise echocardiography (EE) and if it improves the EE ability to predict CAD. Methods. We retrospectively studied 156 subjects without previous vascular disease who underwent EE, carotid ultrasonography and coronary angiography between 2002 and 2013. Positive EE was defined as exercise induced wall motion abnormalities, carotid disease according to Manheim and American Society of Echocardiography Consensus and significant CAD as stenosis ≥50%. Results. Eighty-nine (57.1%) subjects had significant CAD. Factors associated with CAD in multivariate analysis were fasting plasma glucose (odds ratio [OR] 1.02, p = 0.031), pre-test probability of CAD > 65% (OR 3.71, p

Dissecting Plasmodium drug resistance Malaria is a deadly disease with no effective vaccine. Physicians thus depend on antimalarial drugs to save lives, but such compounds are often rendered ineffective when parasites evolve resistance. Cowell et al. systematically studied patterns of Plasmodium falciparum genome evolution by analyzing the sequences of clones that were resistant to diverse antimalarial compounds across the P. falciparum life cycle (see the Perspective by Carlton). The findings identify hitherto unrecognized drug targets and drug-resistance genes, as well as additional alleles in known drug-resistance genes. Science , this issue p. 191 ; see also p. 159

Benign paroxysmal positional vertigo (BPPV) is the most frequent episodic vestibular disorder. It is due to otolith rests that are free into the canals or attached to the cupulas. Well over 90% of patients can be successfully treated with manoeuvres that move the particles back to the utriculus. Among the great variety of procedures that have been described, the manoeuvres that are supported by evidenced-based studies or extensive series are commented in this review. Some topics regarding BPPV treatment, such as controlling the accuracy of the procedures or the utility of post-manoeuvre restrictions are also discussed.

Chemogenetic characterization throughin vitroevolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262Plasmodium falciparumparasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of theP. falciparumresistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence SummaryWhole genome sequencing reveals howPlasmodium falciparumevolves resistance to diverse compounds and identifies new antimalarial drug targets.

Benign Paroxysmal Positional Vertigo is the most frequent episodic vestibular disorder. The purpose of this guide, requested by the committee on otoneurology of the Spanish Society of Otolaryngology and Head and Neck Surgery, is to supply a consensus document providing practical guidance for the management of BPPV. It is based on the Barany Society criteria for the diagnosis of BPPV. This guideline provides recommendations on each variant of BPPV, with a description of the different diagnostic tests and the therapeutic manoeuvres. For this purpose, we have selected the tests and manoeuvres supported by evidence-based studies or extensive series. Finally, we have also included a chapter on differential diagnosis and a section relating to general aspects in the management of BPPV.

The Gram-positive anaerobic human pathogenic bacterium Atopobium vaginae causes most of the cases of bacterial vaginosis and opportunistic infections in immunocompromised patients. In addition to its well-established role in carbohydrate metabolism, D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Streptococcus pyogenes and S. pneumoniae have been reported to act as an extracellular virulence factor during streptococcal infections. Here, we report the crystal structure of GAPDH from A. vaginae (AvGAPDH) at 2.19 Å resolution. The refined model has a crystallographic Rfree of 22.6%. AvGAPDH is a homotetramer wherein each subunit is bound to a nicotinamide adenine dinucleotide (NAD+) molecule. The AvGAPDH enzyme fulfills essential glycolytic as well as moonlight (non-glycolytic) functions, both of which might be targets of chemotherapeutic intervention. We report that AvGAPDH interacts in vitro with the human C5a anaphylatoxin and inhibits C5a-specific neutrophil chemotaxis, thereby suggesting the participation of AvGAPDH in complement-targeted immunoevasion in a context of infection. The availability of high-quality structures of AvGAPDH and other homologous virulence factors from Gram-positive pathogens is critical for drug discovery programs. In this study, sequence and structural differences between AvGAPDH and related bacterial and eukaryotic GAPDH enzymes are reported in an effort to understand how to subvert the immunoevasive properties of GAPDH and evaluate the potential of AvGAPDH as a druggable target., The research leading to these results has received funding from the Spanish Instituto de Salud Carlos III (PI12/01667 to MCV), the Spanish Ministerio de Economía y Competitividad(CTQ2015-66206- C2-2-R and SAF2015-72961-EXP to MCV and SAF2014-54708-R to JRR), CSIC (201620E064), the Regional Government of Madrid (S2010/BD-2316 to JRR, MCV and SRC), and the European Commission (Framework Programme 7 (FP7)) project ComplexINC (Contract No. 279039 to MCV).AVM was supported by the Comunidad de Madrid (S2010/BMD-2316/2326) and the Universidad Complutense de Madrid (CT46/15).

Introduction and objective: Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vertigo, characterized by brief attacks of rotatory vertigo associated with nystagmus, which are elicited by specific changes in head position relative to gravity. The observation of positional nystagmus is essential for the diagnosis of BPPV. The treatment consists in maneuvers of canalith repositioning procedure to move otoconial debris from the affected semicircular canal to the utricle. These guidelines are intended for all who treat the BPPV in their work, with an intention to assist in the diagnosis and application of an appropriate therapeutic method. Method: The experience and analysis of different national and international consensus on BPPV, has allowed to a large group of ENT specialists of the Communities of Castilla y León, Cantabria and La Rioja (Spain), carry out this guide. Results: The different clinical entities are reviewed. BPPV of the posterior semicircular canal, horizontal canal and anterior canal, BPPV affecting several canals, atypical and central BPPV, subjective BPPV and the characteristics of this process in the elderly. Canalith repositioning procedures have been illustrated with explanatory drawings. Discussion and conclusions: Although the pathophysiology of BPPV is canalolithiasis comprising free-floating otoconial debris within the endolymph of a semicircular canal, or cupulolithiasis comprising otoconial debris adherent to the cupula, there are still many issues to be resolved. We think that the best way to find answers is part of using a common methodology in the diagnosis and treatment of these patients., Introducción y Objetivo: El vértigo periférico más frecuente es el Vértigo Posicional Paroxístico Benigno (VPPB), caracterizado por bruscos ataques de sensación rotatoria, que aparecen como consecuencia de determinados cambios en la posición de la cabeza con relación a la gravedad. La observación del nistagmo posicional es fundamental para el diagnóstico de VPPB. El tratamiento consiste en aplicar maniobras de reposición, para intentar trasladar los restos otoconiales libres, desde el conducto semicircular (CS) afectado hasta el utrículo. Esta guía, está orientada para quienes tratan el VPPB, con la intención práctica de ayudarles en el diagnóstico y tratamiento de esta enfermedad. Método: La experiencia y el análisis de diferentes acuerdos nacionales e internacionales sobre el VPPB, han permitido a un amplio grupo de especialistas ORL de las Comunidades de Castilla y León, Cantabria y La Rioja (España), llevar a cabo esta guía. Resultados: Se revisan las diferentes entidades clínicas. VPPB del conducto semicircular posterior (CSP), horizontal (CSA) y anterior (CSA), incluyéndose también el VPPB multicanal, VPPB atípico y central, VPPB subjetivo y las características de este proceso en el anciano. Las maniobras de reposición se han ilustrado con dibujos explicativos. Discusión y conclusiones: Aunque la fisiopatología del VPPB se explica por la presencia de restos otoconiales libres en la endolinfa de uno o varios conductos semicirculares (canalitiasis) y en algunos casos por su adherencia a la cúpula del CS (cupulolitiasis), aún quedan muchas cuestiones por resolver. Pero creemos que la mejor manera de encontrar respuestas parte de utilizar una metodología común en el diagnóstico y tratamiento de estos pacientes.

To determine the recurrence rate of benign positional paroxysmal vertigo (BPPV) and the factors associated to such recurrences.Prospective study.Sixty-nine consecutive patients treated for first episode of BPPV.63 months. Mean follow-up: 47 months.The recurrence rate was 27%. Fifty percent of recurrences occurred in the first 6 months. Nineteen patients had 1 or more recurrence of BPPV; 10 had 1 recurrence, 7 patients had 2, and 2 patients had 3 recurrences. There was no significant difference in the recurrence rate according to sex, age, side, cause of BPPV, or instability after successful treatment. Multi-canal BPPV (log-rank, p = 0.024) and anterior canal BPPV (log-rank, p = 0.029) showed a significantly greater tendency to recur and to do so earlier. There was a significant difference in time to recurrence related to the number of maneuvers used to resolve the initial BPPV episode (log-rank, p = 0.023). Except for cases of BPPV secondary to labyrinthitis or neurolabyrinthitis, at least 70% of the recurrences affected a different side and/or different canal than the primary BPPV.The recurrence rate of BPPV is 27%, and relapse largely occurs in the first 6 months. When BPPV recurrence is suspected, every canal on both sides must be investigated because it is the BPPV syndrome that recurs, rather than BPPV affecting a particular side or canal. Complex cases of BPPV have a greater risk of recurrence.

Background The emergence of Plasmodium falciparum resistance to artemisinins threatens to undermine the effectiveness of artemisinin-based combination anti-malarial therapy. Developing suitable drugs to replace artemisinins requires the identification of new compounds that display rapid parasite killing kinetics. However, no current methods fully meet the requirements to screen large compound libraries for candidates with such properties. This study describes the development and validation of an in vitro parasite viability fast assay for identifying rapidly parasiticidal anti-malarial drugs. Methods Parasite killing kinetics were determined by first culturing unlabelled erythrocytes with P. falciparum in the presence of anti-malarial drugs for 24 or 48 h. After removing the drug, samples were added to erythrocytes pre-labelled with intracellular dye to allow their subsequent identification. The ability of viable parasites to re-establish infection in labelled erythrocytes could then be detected by two-colour flow cytometry after tagging of parasite DNA. Thus, double-stained erythrocytes (with the pre-labelled intracellular dye and the parasite DNA dye) result only after establishment of new infections by surviving parasites. The capacity of the test anti-malarial drugs to eliminate viable parasites within 24 or 48 h could, therefore, be determined. Results The parasite viability fast assay could be completed within 48 h following drug treatment and distinguished between rapidly parasiticidal anti-malarial drugs versus those acting more slowly. The assay was validated against ten standard anti-malarial agents with known properties and results correlated well with established methods. An abbreviated assay, suitable for adaption to medium–high throughput screening, was validated and applied against a set of 20 compounds retrieved from the publically available Medicines for Malaria Venture ‘Malaria Box’. Conclusion The quantification of new infections to determine parasite viability offers important advantages over existing methods, and is amenable to medium–high throughput screening. In particular, the parasite viability fast assay allows discrimination of rapidly parasiticidal anti-malarial candidates.

Aims: To evaluate the outcomes of a modified high uterosacral ligament suspension (HUSLS) performed at vaginal hysterectomy for uterine prolapse. Methods: Prolapse was assessed pre- and postoperatively in 53 consecutive women, using Baden–Walker Halfway and Pelvic Organ Prolapse Quantification systems. Sexually active women completed the Prolapse and Incontinence Sexual Function Questionnaire at follow up. The technique involves placement of one HUSLS suture on each side without a fascial reconstruction. Results: Preoperatively, 37 (66%) women had at least Grade 2 prolapse of the cervix. At mean follow–up of 15 months, 45 (85%) had no vault prolapse and 7 (13%) had Grade 1 prolapse. Nineteen (36%) women were sexually active at follow up and completed the Prolapse and Incontinence Sexual Function Questionnaire. Mean scores for pain, vaginal tightness, partner perception of tightness and vaginal length were 2.8, 3.2, 4.0, and 3.8 respectively, indicating excellent function. Conclusions: We report excellent objective, subjective and sexual function outcomes following this modified HUSLS.

OBJECTIVE To compare the 1-h pad test in women who have urodynamically confirmed stress incontinence (USI) with a patient-based 3-point symptom severity scale and validated quality of life (QoL) questionnaires. PATIENTS AND METHODS In all, 98 women with USI were prospectively recruited; all had a 1-h pad test and completed the validated disease-specific QoL questionnaires, including short forms of the International Consultation on Incontinence Questionnaire (ICIQ-SF), Urogenital Distress Inventory (UDI-6), and Incontinence Impact Questionnaire (IIQ-7). In addition, the severity of incontinence was determined using the Stamey grading scale, a visual analogue scale (VAS) score, and a patient-based 3-point symptom severity scale. RESULTS The VAS, symptom severity scale, Stamey grade, UDI-6, and IIQ-7 failed to correlate significantly with the 1-h pad test. Only the ICIQ-SF correlated significantly with this test. CONCLUSION The ICIQ-SF is easy to administer and, in this study, correlated best with the 1-h pad test in women with pure primary or secondary USI. It incorporates both symptom severity and QoL variables. We recommend its routine use in clinical practice.