Demonstration of a 120° hybrid based simplified coherent receiver on SOI for high speed PON applications.

We demonstrate the first simplified coherent receiver using a 120° hybrid on silicon-on-insulator (SOI) for high speed PON applications. This coherent receiver integrates an inverse taper edge coupler for the received signal, a vertical grating coupler for the local oscillator input, a polarization splitter and rotator (PSR), a 120° hybrid based on a 3×3 multimode interference (MMI) coupler, and three germanium photodetectors. We achieved 25 Gbit/s two-level pulse amplitude modulation (PAM-2) transmission over 30 km standard single mode fiber (SMF) in the C-band without any digital signal processing (DSP) (e.g., pre-emphasis, pulse shaping, equalization, nonlinearity compensation) and dispersion compensation (e.g., optical or digital) either at the transmitter or at the receiver. The requirements for frequency and phase locking of the local oscillator (LO) were avoided due to the use of intensity modulated signals. Receiver sensitivities of -23.70 dBm, -20.30 dBm, and -15.10 dBm are achieved at a bit error rate (BER) below the hard-decision forward error correction (HD-FEC) threshold (i.e., 3.8 × 10-3) in back-to-back (B2B), after 21 km and 30 km, respectively. We also demonstrate 25 Gbit/s PAM-4 transmission achieving receiver sensitivities of -15.30 dBm, -13.90 dBm, and -9.50 dBm below the HD-FEC threshold in B2B, after 10.5 km and 21 km, respectively.

Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease.

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7G213R) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7F318L). Compared to Clcn7+/+ mice, 12-week-old Clcn7F318L/+ mice have significantly increased trabecular bone volume, consistent with Clcn7F318L acting as a dominant negative mutation. Clcn7F318L/F318L and Clcn7F318L/G213R mice die by 1month of age and resemble Clcn7 knockout mice, which indicate that p.F318L mutant protein is non-functional and p.F318L and p.G213R mutant proteins do not complement one another. Since it has been reported that treatment with interferon gamma (IFN-G) improves bone properties in Clcn7G213R/+ mice, we treated Clcn7F318L/+ mice with IFN-G and observed a decrease in osteoclast number and mineral apposition rate, but no overall improvement in bone properties. Our results suggest that the benefits of IFN-G therapy in patients with Albers-Schönberg disease may be mutation-specific.

The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia.

OBJECTIVE: To evaluate the long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release (XR) from an oral antipsychotic in patients with schizophrenia. Reasons for switching included insufficient efficacy, tolerability, and/or non-acceptability. The primary endpoint was the percentage of patients achieving an improvement in Clinical Global Impression - Clinical Benefit (CGI-CB) scale scores. RESEARCH DESIGN AND METHODS: A 24-week, international, multicentre, open-label, prospective study ( www.clinicaltrials.gov : NCT00640601). After a 7-14 day enrolment period (depending whether prior antipsychotic mono- or combination therapy), all patients received quetiapine XR 300 mg once daily (day 1), 600 mg/day (day 2), 600-800 mg/day (day 3) and 400-800 mg/day thereafter, with down-titration and discontinuation of prior antipsychotic by day 4. RESULTS: A total of 62% of patients completed the study and 56.9% (LOCF, ITT) achieved a significant improvement in CGI-CB (95% CI [0.51, 0.63]; p = 0.02). Switches due to insufficient efficacy showed a significant improvement (60%, 95% CI [0.51, 0.68]; p = 0.02), compared to 54.4% ([0.44, 0.64]; p = 0.38) and 52.4% ([0.36, 0.68]; p = 0.76) of switches due to insufficient tolerability and non-acceptability respectively (both p = ns). Patients previously on olanzapine and quetiapine IR showed a significant improvement in CGI-CB (62.6% [p = 0.02] and 61.2% [p = 0.04], respectively). Somnolence (18.0%) and dizziness (14.6%) were the main adverse events. Anticholinergic use decreased from 7.1 to 2.7%. Overall mean weight gain was 0.4 kg; 12.9% of patients experienced a weight gain of ≥7% and 15% experienced a clinically relevant shift in triglycerides from baseline. CONCLUSIONS: A majority of patients switched from other antipsychotics to quetiapine XR experienced clinical benefit. This was supported by all other efficacy outcomes regardless of the reason for switching. Safety data confirmed quetiapine XR was safe and well tolerated. The open-label design and lack of a placebo group represent limitations.

Activation of atypical protein kinase Czeta toward TC10 is regulated by high-fat diet and aerobic exercise in skeletal muscle.

We determined whether sustained aerobic exercise reverses high-fat diet-induced impairments in the c-Cbl associated protein (CAP)/Casitas b-lineage lymphoma (c-Cbl) signaling cascade in rodent skeletal muscle. Sprague-Dawley rats were placed into either control (n = 16) or high-fat-fed (n = 32) diet groups for 4 weeks. During a subsequent 4-week experimental period, 16 high-fat-fed rats remained sedentary, 16 high-fat-fed rats completed 4 weeks of exercise training, and control animals were sedentary and remained on the control diet. After the intervention period, animals were subjected to hind limb perfusions in the presence (n = 8 per group) or absence (n = 8 per group) of insulin. In the plasma membrane fractions, neither high-fat feeding nor exercise training altered adaptor protein with PH and SH2 domains, (APS), c-Cbl, or TC10 protein concentrations. In contrast, CAP protein concentration and insulin-stimulated plasma membrane c-Cbl tyrosine phosphorylation were reduced by high-fat feeding; but exercise training reversed these impairments. Of note was that insulin-stimulated atypical protein kinase Czeta kinase activity toward TC10 was reduced by high-fat feeding but normalized by exercise training. We conclude that sustained (4 weeks) exercise training can reverse high-fat diet-induced impairments on the CAP/c-Cbl pathway in high-fat-fed rodent skeletal muscle. We also provide the first evidence that the CAP/c-Cbl insulin signaling cascade in skeletal muscle may directly interact with components of the classic (phosphoinositide 3-kinase dependent) insulin signaling cascade.

Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial.

BACKGROUND: Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects. METHODS: This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of < or =10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ). RESULTS: Adjunctive quetiapine (mean dose 386mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8+/-9.0) to week 12 (9.0+/-10.2) (-20.6; p<0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5kg at week 12) or laboratory assessments. CONCLUSION: The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.

Exercise training-induced improvements in insulin action.

Individuals with insulin resistance are characterized by impaired insulin action on whole-body glucose uptake, in part due to impaired insulin-stimulated glucose uptake into skeletal muscle. A single bout of exercise increases skeletal muscle glucose uptake via an insulin-independent mechanism that bypasses the typical insulin signalling defects associated with these conditions. However, this 'insulin sensitizing' effect is short-lived and disappears after approximately 48 h. In contrast, repeated physical activity (i.e. exercise training) results in a persistent increase in insulin action in skeletal muscle from obese and insulin-resistant individuals. The molecular mechanism(s) for the enhanced glucose uptake with exercise training have been attributed to the increased expression and/or activity of key signalling proteins involved in the regulation of glucose uptake and metabolism in skeletal muscle. Evidence now suggests that the improvements in insulin sensitivity associated with exercise training are also related to changes in the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle such as the AMP-activated protein kinase (AMPK) and the protein kinase B (Akt) substrate AS160. In addition, increased lipid oxidation and/or turnover is likely to be another mechanism by which exercise improves insulin sensitivity: exercise training results in an increase in the oxidative capacity of skeletal muscle by up-regulating lipid oxidation and the expression of proteins involved in mitochondrial biogenesis. Determination of the underlying biological mechanisms that result from exercise training is essential in order to define the precise variations in physical activity that result in the most desired effects on targeted risk factors, and to aid in the development of such interventions.

Equilibrium structure and stability in a frequency-dependent, two-population diploid model.

We investigate the equilibrium structure for an evolutionary genetic model in discrete time involving two monoecious populations subject to intraspecific and interspecific random pairwise interactions. A characterization for local stability of an equilibrium is found, related to the proximity of this equilibrium with evolutionarily stable strategies (ESS). This extends to a multi-population framework a principle initially proposed for single populations, which states that the mean population strategy at a locally stable equilibrium is as close as possible to an ESS.

Ouabain stimulates unidirectional and net potassium efflux in resting mammalian skeletal muscle.

The present study compared ouabain-sensitive unidirectional K+ flux into (JinK) and out of (JoutK) perfused rat hindlimb skeletal muscle in situ and mouse flexor digitorum brevis (FDB) in vitro. In situ, 5 mM ouabain inhibited 54 +/- 4% of the total JinK in 28 +/- 1 min, and increased the net and unidirectional efflux of K+ within 4 min. In contrast, 1.8 mM ouabain inhibited 40 +/- 8% of the total JinK in 38 +/- 2 min, but did not significantly affect JoutK. In vitro, 1.8 and 0.2 mM ouabain decreased JinK to a greater extent (83 +/- 5%) than in situ, but did not significantly affect 42K loss rate compared with controls. The increase in unidirectional K+ efflux (JoutK) with 5 mM ouabain in situ was attributed to increased K+ efflux through cation channels, since addition of barium (1 mM) to ouabain-perfused muscles returned JoutK to baseline values within 12 min. Perfusion with 5 mM ouabain plus 2 mM tetracaine for 30 min decreased JinK 46 +/- 9% (0.30 +/- 0.03 to 0.16 +/- 0.02 micromol x min(-1) x g(-1)), however tetracaine was unable to abolish the ouabain-induced increase in unidirectional K+ efflux. In both rat hindlimb and mouse FDB, tetracaine had no effect on JoutK. Perfusion of hindlimb muscle with 0.1 mM tetrodotoxin (TTX, a Na+ channel blocker) decreased JinK by 15 +/- 1%, but had no effect on JoutK; subsequent addition of ouabain (5 mM) decreased JinK a further 32 +/- 2%. The ouabain-induced increase in unidirectional K+ efflux did not occur when TTX was perfused prior to and during perfusion with 5 mM ouabain. We conclude that 5 mM ouabain increases the unidirectional efflux of K+ from skeletal muscle through a barium and TTX-sensitive pathway, suggestive of voltage sensitive Na+ channels, in addition to inhibiting Na+/K+-ATPase activity.

Variability in centred house-of-cards mutation models.

Convergence of variability in phenotypic models with balance between selection and mutation is analysed. The mutation assumed occurs with weak probability and brings down the evolutionary process built up by selection around the mean in the population. Gaussian approximations are used.

Optimal sex ratios in structured populations.

In this paper, we develop a general method to determine evolutionary equilibrium sex ratios and to check evolutionary stability, continuous stability and invadability in exact genetic models with or without dominance. This method is then applied to three kinds of models for structured populations: the first one concerns Hamilton's LMC model, except that only a fraction beta of female offspring mate with male offspring born in the same colonies, while a fraction 1-beta mate with male offspring chosen at random within the whole population; in the second model, it is assumed that partial dispersal of inseminated females occurs after mating; in the third model, partial dispersal of male and female offspring occurs before mating. In the first model, the effect of population regulation is studied while, in the other models, two kinds of dispersal are considered: proportional and uniform.

Fundamental theorem of natural selection and frequency-dependent selection: analysis of the matrix game diploid model.

Following Ewens' interpretation about Fisher's fundamental theorem of natural selection, the matrix game model for diploid populations undergoing non-overlapping, discrete generations is investigated. The total genetic variance is decomposed and it is shown that the partial change in the mean fitness, which is equal to the additive genetic variance over the mean fitness, can be thought of as a change due only to the partial changes in the phenotypic frequencies.

Stability analysis of the partial selfing selection model.

We undertake a detailed study of the one-locus two-allele partial selfing selection model. We show that a polymorphic equilibrium can exist only in the cases of overdominance and underdominance and only for a certain range of selfing rates. Furthermore, when it exists, we show that the polymorphic equilibrium is unique. The local stability of the polymorphic equilibrium is investigated and exact analytical conditions are presented. We also carry out an analysis of local stability of the fixation states and then conclude that only overdominance can maintain polymorphism in the population. When the linear local analysis is inconclusive, a quadratic analysis is performed. For some sets of selective values, we demonstrate global convergence. Finally, we compare and discuss results under the partial selfing model and the random mating model.

Evolutionarily stable strategy in a sex- and frequency-dependent selection model.

In this paper, a sex-dependent matrix game haploid model is investigated. For this model, since the phenotypes of female and male individuals are determined by alleles located at a single locus and are sex dependent, any given genotype corresponds to a strategy pair. Thus, a strategy pair is an ESS if and only if the allele corresponding to this strategy pair cannot be invaded by any mutant allele. We show that an ESS equilibrium must be locally asymptotically stable if it exists.

Stochastic effects in LMC models.

LMC (local mate competition) was first introduced by W. D. Hamilton to explain extraordinary female-biased sex ratios observed in a variety of insects and mites. In the original model, the population is subdivided into an infinite number of colonies founded by a fixed number of inseminated females producing the same very large number of offspring. The male offspring compete within the colonies to inseminate the female offspring and then these disperse at random to found new colonies. An unbeatable sex ratio strategy is found to be female-biased. In this paper, the effects of having colonies of random size and foundresses producing a random finite number of offspring are considered. The exact evolutionarily stable strategy (ESS) sex ratio is deduced and comparisons with previous approximate or numerical results are made. As the mean or the variance of brood size increases, the ESS sex ratio becomes more female-biased. An increase in the variance of colony size increases the ESS proportion of males when the mean brood size and colony size are both small, but decreases this proportion when the mean brood size or the mean colony size is large.

Fisher's fundamental theorem of natural selection revisited.

W. J. Ewens, following G. R. Price, has stressed that Fisher's fundamental theorem of natural selection about the increase in mean fitness is of general validity without any restrictive assumptions on the mating system, the fitness parameters, or the numbers of loci and alleles involved, but that it concerns only a partial change in mean fitness. This partial change is obtained by replacing the actual genotypic fitnesses by the corresponding additive genetic values and by keeping these values fixed in the change of the mean with respect to changes in genotype frequencies. We propose an alternate interpretation for this partial change which uses partial changes in genotype frequencies directly consequent on changes in gene frequencies, the fitness parameters being kept constant. We argue that this interpretation agrees more closely with Fisher's own explanations. Moreover, this approach leads to a decomposition for the total change in mean fitness which explains, unifies, and extends previous decompositions. We consider a wide range of models, from discrete-time selection models with nonoverlapping generations to continuous-time models with overlapping generations and age effects on viability and fecundity, which is the original framework for Fisher's fundamental theorem.

On the non-existence of an optimal migration rate.

We show that an optimal migration rate may not exist in a population distributed over an infinite number of individual living sites if empty sites occur. This is the case when the mean number of offspring per individual mu is finite. We make the assumption of uniform migration to other sites whose rate is determined by the parent's genotype or the offspring's genotype at a single locus in a diploid hermaphrodite population undergoing random mating. In both cases, for mu small enough, any population at fixation would go to extinction. Moreover, in the latter case, for intermediate values of mu, the only fixation state that could resist the invasion of any mutant would lead the population to extinction. These are the two conditions for the non-existence of an optimal migration rate. They become less stringent as the cost for migration expressed by a coefficient of selection 1-beta becomes larger, that is closer to 1. The results are obtained assuming that the allele at fixation is either nondominant or dominant. Although the optimal migration rate is the same in both cases when it exists, the optimality properties may differ.

Person-based information from Canadian hospital discharge data.

Statistics summarizing Canadians' use of hospital services are usually based on simple discharge totals, without any attempt to distinguish which discharges may have belonged to the same person. This leads to a distorted view of the prevalence of illness and the resources required to serve each patient. Statistics based on the number of people going to hospital shed new light on the demand for resources by various groups, now and in the future.

The fundamental theorem of natural selection in Ewens' sense (case of many loci).

We correct an equation characterizing the additive allelic effects on fitness determined at many loci without the assumption of random mating given in Ewens (1989, 1992) and we show that the additive genetic variance in fitness divided by the mean fitness is equal to a partial change in the mean fitness from one generation to the next as stated in Ewens (1989).