Protocol for a double-blind randomised placebo-controlled trial of lithium carbonate in patients with amyotrophic lateral sclerosis (LiCALS) [Eudract number: 2008-006891-31].

BACKGROUND: Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder characterised by loss of motor neurons leading to severe weakness and death from respiratory failure within 3-5 years. Riluzole prolongs survival in ALS. A published report has suggested a dramatic effect of lithium carbonate on survival. 44 patients were studied, with 16 randomly selected to take LiCO3 and riluzole and 28 allocated to take riluzole alone. In the group treated with lithium, no patients had died (i.e., 100% survival) at the end of the study (15 months from entry), compared to 71% surviving in the riluzole-only group. Although the trial can be criticised on several grounds, there is a substantial rationale from other laboratory studies that lithium is worth investigating therapeutically in amyotrophic lateral sclerosis. METHODS/DESIGN: LiCALS is a multi-centre double-blind randomised parallel group controlled trial of the efficacy, safety, and tolerability of lithium carbonate (LiCO3) at doses to achieve stable 'therapeutic' plasma levels (0.4-0.8 mmol/L), plus standard treatment, versus matched placebo plus standard treatment, in patients with amyotrophic lateral sclerosis. The study will be based in the UK, in partnership with the MND Association and DeNDRoN (the Dementias and Neurodegnerative Diseases Clinical Research Network). 220 patients will be recruited. All patients will be on the standard treatment for ALS of riluzole 100 mg daily. The primary outcome measure will be death from any cause at 18 months defined from the date of randomisation. Secondary outcome measures will be changes in three functional rating scales, the ALS Functional Rating Scale-Revised, The EuroQOL (EQ-5D), and the Hospital Anxiety and Depression Scale.Eligible patients will have El Escorial Possible, Laboratory-supported Probable, Probable or Definite amyotrophic lateral sclerosis with disease duration between 6 months and 36 months (inclusive), vital capacity ≥ 60% of predicted within 1 month prior to randomisation and age at least18 years. DISCUSSION: Patient recruitment began in June 2009 and the last patient is expected to complete the trial protocol in November 2011. TRIAL REGISTRATION: Current controlled trials ISRCTN83178718

Respiratory muscle strength as a predictive biomarker for survival in amyotrophic lateral sclerosis

Rationale: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking. Objectives: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator-free survival, up to 3 years. Methods: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter. Measurements and Main Results: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilation-free survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation. Conclusions: The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value

On RR couplings on D-branes at order O(α′2)O(\alpha'^2)

Recently, it has been found that there are couplings of the RR field strength $F^{(p)}$ and the B-field strength $H$ on the world volume of D$_p$-branes at order ${\cal O}(\alpha'^2)$. These couplings which have both world-volume and transverse indices, are invariant under the linear T-duality transformations. Consistency with the nonlinear T-duality indicates that the RR field strength $F^{(p)}$ in these couplings should be replaced by ${\cal F}^{(p)}=d{\cal C}^{(p-1)}$ where ${\cal C}=e^{B}C$. This replacement, however, reproduces some non-gauge invariant terms. On the other hand, the nonlinear terms are invariant under the linear T-duality transformations at the level of two B-fields. This allows one to remove some of the nonlinear terms in ${\cal F}^{(p)}$. We fix this by comparing the nonlinear couplings with the S-matrix element of one RR and two NSNS vertex operators. Our results indicate that in the expansion of ${\cal F}^{(p)}$ one should keep only the B-field gauge invariant terms, e.g. $B\wedge dC^{(p-3)}$ where both indices of B-field lie along the brane. Moreover, in this case one should replace $B$ with $B+2\pi\alpha'f$ to have the $B$-field gauge invariance.Comment: 23 pages, Latex file, 1 figure; v2:typos corrected, to appear in JHE

Intercomparison of nitrous acid (HONO) measurement techniques in a megacity (Beijing)

Nitrous acid (HONO) is a key determinant of the daytime radical budget in the daytime boundary layer, with quantitative measurement required to understand OH radical abundance. Accurate and precise measurements of HONO are therefore needed; however HONO is a challenging compound to measure in the field, in particular in a chemically complex and highly polluted environment. Here we report an intercomparison exercise between HONO measurements performed by two wet chemical techniques (the commercially available a long-path absorption photometer (LOPAP) and a custom-built instrument) and two broadband cavity-enhanced absorption spectrophotometer (BBCEAS) instruments at an urban location in Beijing. In addition, we report a comparison of HONO measurements performed by a time-of-flight chemical ionization mass spectrometer (ToF-CIMS) and a selected ion flow tube mass spectrometer (SIFT-MS) to the more established techniques (wet chemical and BBCEAS). The key finding from the current work was that all instruments agree on the temporal trends and variability in HONO (r2 > 0.97), yet they displayed some divergence in absolute concentrations, with the wet chemical methods consistently higher overall than the BBCEAS systems by between 12 % and 39 %. We found no evidence for any systematic bias in any of the instruments, with the exception of measurements near instrument detection limits. The causes of the divergence in absolute HONO concentrations were unclear, and may in part have been due to spatial variability, i.e. differences in instrument location and/or inlet position, but this observation may have been more associative than casual

Physician career satisfaction within specialties

<p>Abstract</p> <p>Background</p> <p>Specialty-specific data on career satisfaction may be useful for understanding physician workforce trends and for counseling medical students about career options.</p> <p>Methods</p> <p>We analyzed cross-sectional data from 6,590 physicians (response rate, 53%) in Round 4 (2004-2005) of the Community Tracking Study Physician Survey. The dependent variable ranged from +1 to -1 and measured satisfaction and dissatisfaction with career. Forty-two specialties were analyzed with survey-adjusted linear regressions</p> <p>Results</p> <p>After adjusting for physician, practice, and community characteristics, the following specialties had significantly higher satisfaction levels than family medicine: pediatric emergency medicine (regression coefficient = 0.349); geriatric medicine (0.323); other pediatric subspecialties (0.270); neonatal/prenatal medicine (0.266); internal medicine and pediatrics (combined practice) (0.250); pediatrics (0.250); dermatology (0.249);and child and adolescent psychiatry (0.203). The following specialties had significantly lower satisfaction levels than family medicine: neurological surgery (-0.707); pulmonary critical care medicine (-0.273); nephrology (-0.206); and obstetrics and gynecology (-0.188). We also found satisfaction was significantly and positively related to income and employment in a medical school but negatively associated with more than 50 work-hours per-week, being a full-owner of the practice, greater reliance on managed care revenue, and uncontrollable lifestyle. We observed no statistically significant gender differences and no differences between African-Americans and whites.</p> <p>Conclusion</p> <p>Career satisfaction varied across specialties. A number of stakeholders will likely be interested in these findings including physicians in specialties that rank high and low and students contemplating specialty. Our findings regarding "less satisfied" specialties should elicit concern from residency directors and policy makers since they appear to be in critical areas of medicine.</p

Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum

Two-stage directed self-assembly of a cyclic [3]catenane.

Interlocked molecules possess properties and functions that depend upon their intricate connectivity. In addition to the topologically trivial rotaxanes, whose structures may be captured by a planar graph, the topologically non-trivial knots and catenanes represent some of chemistry's most challenging synthetic targets because of the three-dimensional assembly necessary for their construction. Here we report the synthesis of a cyclic [3]catenane, which consists of three mutually interpenetrating rings, via an unusual synthetic route. Five distinct building blocks self-assemble into a heteroleptic triangular framework composed of two joined Fe(II)3L3 circular helicates. Subcomponent exchange then enables specific points in the framework to be linked together to generate the cyclic [3]catenane product. Our method represents an advance both in the intricacy of the metal-templated self-assembly procedure and in the use of selective imine exchange to generate a topologically complex product.This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC) and a Marie Curie fellowship for J.J.H. (ITN-2010–264645). The authors thank the Diamond Light Source (UK) for synchrotron beamtime on I19 (MT7984 and MT8464).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.220

Sperm Swimming Velocity Predicts Competitive Fertilization Success in the Green Swordtail Xiphophorus helleri

Sperm competition is expected to favour the evolution of traits that influence the performance of sperm when they compete to fertilize a female's eggs. While there is considerable evidence that selection favours increases in sperm numbers, much less is known about how sperm quality contributes towards competitive fertilization success. Here, we determine whether variation in sperm quality influences competitive fertilization success in the green swordtail Xiphophorus helleri, a highly promiscuous livebearing fish. We use artificial insemination as a method of controlled sperm delivery and show that sperm swimming velocity is the primary determinant of fertilization success when ejaculates from two males compete to fertilize a female's eggs. By contrast, we found no evidence that sperm length had any effect on siring success. We also found no evidence that pre- and postcopulatory sexual traits were phenotypically integrated in this species, suggesting that the previous observation that reproductive skew favours males with high mating rates is unlikely to be due to any direct association between sperm quality and male sexual ornamentation