Introduction
============

The use of tobacco dates back as early as 5,000--3,000 BC, when tobacco plants were first cultivated in South America (Gately, [@B50]). Initially, tobacco was regarded has a medicinal plant to be used for medical purposes such as, a painkiller for earaches and toothaches (Balls, [@B6]). However, later studies clearly established the deleterious effects of tobacco smoking on health (Peto et al., [@B93]). As a result, the progressive establishment of more restrictive anti-tobacco laws has discouraged tobacco smoking worldwide. These new restrictions and public health campaigns have dramatically decreased tobacco use. However, there is a high rate of tobacco consumption among individuals that suffer from mental disorders such as, major depression disorder (MDD), schizophrenia, and post-traumatic stress disorder (PTSD; Leonard et al., [@B73]; Weaver and Etzel, [@B127]; Thorndike et al., [@B120]; Buggia-Prevot et al., [@B26]; Aubin et al., [@B5]). The idea that tobacco consumption in these populations is a form of self-medication is controversial and some evidence suggests that smoking is associated with poorer mental health outcomes in some mental disorders such as, bipolar and schizoaffective disorder (Dodd et al., [@B39]). The desire to identify the component of tobacco that may explain this correlation has encouraged the study of the mental effect(s) of nicotine \[3-(1-methyl-2-pyrrolidinyl) pyridine\], an alkaloid that is present in tobacco leaves, over the psychiatric symptoms. Nicotine treatment had been shown to improve cognitive function including attention, concentration, executive function, and learning and memory (Elzinga and Bremner, [@B43]; Horner and Hamner, [@B62]; Bowie and Harvey, [@B14]; Gray and Roth, [@B54]; Tapia et al., [@B115]; Burriss et al., [@B28]; Luck and Gold, [@B79]; Terry et al., [@B118]; Hinkelmann et al., [@B60]; Johnsen and Asbjornsen, [@B65]; Veltmeyer et al., [@B124]; Baune et al., [@B7]). However, nicotine's undesirable cardiovascular and addictive side-effects have limited its therapeutic use (Karaconji, [@B66]). Recently, new studies have shown that the main metabolite of nicotine, an alkaloid named cotinine \[(5*S*)-1-methyl-5-(3-pyridyl)-pyrrolidin-2-one\], has beneficial therapeutic properties, while not having nicotine's negative side-effects. In preclinical studies, cotinine has shown to improve reference and working memories, attention, and the extinction of fear memory, as well as to reduce both the startle response and anxiety in animal models of aging, Alzheimer's disease (AD), PTSD, and schizophrenia (Figure [1](#F1){ref-type="fig"}). Here the psychopharmacology and the potential therapeutic use of cotinine are discussed.

![**A schematic comparison of the behavioral effects of nicotine and cotinine**.](fphar-03-00173-g001){#F1}

Discussion
==========

Cotinine pharmacokinetic
------------------------

Cotinine is an alkaloid found in tobacco leaves and the main metabolite of nicotine. The active form of cotinine, the isomer S(-)-cotinine accumulates in the body after tobacco consumption. The pharmacokinetic profiles of cotinine administered orally or intravenously have been investigated in humans. These reports show that cotinine is well-absorbed orally (De Schepper et al., [@B38]), has a long plasma half-life (19--24 h; Benowitz et al., [@B8]; Benowitz and Sharp, [@B9]) and crosses the blood-brain barrier (Riah et al., [@B96]). Approximately 80--85% of nicotine is metabolized in the liver and converted into cotinine by enzymes such as cytochrome P450 2A6 (CYP2A6; Lewis et al., [@B78]) and cytochrome P4502A5 (CYP2A5) in human and mouse, respectively (Donato et al., [@B40]; Visoni et al., [@B125]).

In humans, cotinine is excreted in the urine, mainly as trans-3′-hydroxycotinine (90% of cotinine) and glucuronide (Caldwell et al., [@B29]; Ghosheh and Hawes, [@B52]; Kuehl and Murphy, [@B70]).

The expression of different variants of the CYP2A6 gene, coding for enzymes with different catalytic activities, influences the level of cotinine achieved in the body after nicotine consumption and, seems to influence nicotine addiction (Malaiyandi et al., [@B81]; Strasser et al., [@B110]). For example, individuals that express a catalytically deficient form of CYP2A6 (i.e., CYP2A6\*4) showed a lower rate of cigarette consumption compared with individuals that express the normal allele (Yamanaka et al., [@B130]). The alleles that express the polymorphic forms of the CYP2A6 gene, with low or high enzymatic activity, are distinctly represented in diverse ethnic groups (Bramer and Kallungal, [@B19]; Nakajima et al., [@B88]). The distinct expression of the different forms of CYP2A6 may explain the varying metabolism of cotinine observed in individuals of diverse ethnic backgrounds (Nakajima et al., [@B88]). Therefore cotinine metabolism and, consequently, smoking behavior can be influenced by ethnicity. Furthermore, other factors such as the consumption of a specific food can also affect cotinine metabolism (Nakajima et al., [@B88]). For example, some components of grapefruit juice inhibit the activity of CYP2A6 and, consequently, cotinine synthesis (Tassaneeyakul et al., [@B116]; Hukkanen et al., [@B63]).

Cotinine pharmacodynamic effects
--------------------------------

Early studies of cotinine effects in humans showed that cotinine has a good safety profile (Borzelleca et al., [@B12]; Bowman and Mc, [@B15]). One of these seminal studies demonstrated that daily doses of cotinine of up to 1,800 mg for a period of 4 days did not induce deleterious side-effects in humans (Bowman and Mc, [@B15]). Another clinical study investigating the psychogenic effects of cotinine showed that when administered intravenously to abstinent smokers, this compound reduced the self-reported irritability and tobacco cravings experienced by the participants (Benowitz et al., [@B8]). A follow-up phase II clinical study investigated the effects of cotinine on smoking cessation in an inpatient, 10-day study in abstinent cigarette smokers (Hatsukami et al., [@B58]). This study showed that oral cotinine treatment of up to 160 mg/day had no addictive, cardiovascular (e.g., heart rate and blood pressure), or behavioral effects in individuals between 21 and 42 years of age (Hatsukami et al., [@B58]). A follow-up study from the same research group also found that cotinine at the doses studied did not help with tobacco cessation and antagonized the reduction of the withdrawal symptoms induced by a nicotine patch (Hatsukami et al., [@B57]). These results confirmed that orally administered cotinine exhibits behavioral effects in humans, likely by modulating the nAChR sensitivity to agonists; however, this concept requires further experimental validation.

### Cotinine is a cognitive enhancer in a mouse model of Alzheimer's Disease

Cotinine has been shown to prevent working and reference memory loss in a mouse model of AD (Echeverria et al., [@B42]). In this study, the ability of cotinine to prevent plaque development and memory loss in the Tg6799 mice (Ohno et al., [@B90]) was investigated. Two-month-old Tg and same age non-Tg (NT) mice were orally treated with vehicle (PBS) or 2.5 mg/kg of cotinine for 4.5 months via gavage and tested for working memory using the circular platform, the Radial Arm Water maze (RAWM), and cognitive interference tests. These behavioral study showed that cotinine prevented memory loss in Tg6799 mice and significantly decreased plaques burden in the cortex of the Tg6799 mice. Cotinine treatment also reduced the number and size of the amyloid plaques. The decrease in plaque load also correlated with a decrease in the levels of insoluble Aβ in the cortex of the cotinine-treated Tg mice when compared with the vehicle-treated Tg mice (Echeverria et al., [@B42]). This evidence suggest that cotinine may be a new therapeutic agent against this devastating condition (Echeverria and Zeitlin, [@B41]).

### Cotinine reduced anxiety and fear in a mouse model of PTSD -- like symptoms

Post-traumatic stress disorder is an anxiety disorder that appears after exposure to life-threatening events (Martenyi et al., [@B82]). PTSD is characterized by symptoms such as anxiety, fear, working memory impairment, hyperarousal, emotional numbing, and sleep disorders. These symptoms have been associated with a permanent alteration of the physiological response to stress induced by over-activation of the hypothalamus-pituitary-adrenal axis (Yehuda et al., [@B131]). These changes are generally accompanied by dysregulation of several neurotransmitter systems including the serotoninergic, dopaminergic, noradrenergic, and cholinergic systems. The hyperarousal and aggressive behavior observed in patients with PTSD are caused, at least in part, by a decrease in serotonin neurotransmission (Nutt, [@B89]). Consistent with this idea, serotonin reuptake inhibitors (SSRIs) such as paroxetine and sertraline are currently used in the treatment of PTSD (Brady et al., [@B16]; Davidson et al., [@B37]; Brady and Clary, [@B17]; Corchs et al., [@B33]; Stein et al., [@B109]). Because serotonin promotes acetylcholine release, and acetylcholine signaling positively affects attention and memory, an increase of serotonin levels in the brain, may simultaneously improve mood, reduce aggressiveness (Buhot et al., [@B27]), and positively affect cognitive abilities. Although SSRIs are useful in the treatment of PTSD (Cohen et al., [@B32]), they are effective only in a small percentage of patients (approximately 30%; Veltmeyer et al., [@B124]).

Post-traumatic stress disorder patients are commonly heavy smokers, and an association between tobacco dependence and PTSD has previously been established (Hapke et al., [@B56]). In the search of new drugs that could diminish fear and anxiety and enhance the extinction of fear memories, rodent models of fear conditioning (FC) has been extensively used. These animal models have permitted to characterize the effect of drugs, including cotinine, over anxiety, fear, and contextual memory in anxiety disorders. FC is a broadly used model of associative memory that involves the pairing of neutral conditioning stimuli (CS; sound and context) with an aversive unconditioned stimulus (US; electric shock). After conditioning, the presentation of the CS alone elicits both a conditioned fear response (freezing behavior) and anxiety in the animal. Experimentally, the extinction of contextual fear (FE) after FC is expressed as a progressive decrease in fear responses attained after repetitive exposures to the CS (context) in the absence of the pairing with an aversive US (Steckler and Risbrough, [@B108]).

A devastating symptom in PTSD is the failure to extinguish traumatic memories that force the patient to continue re-experiencing the trauma (Izquierdo et al., [@B64]). Thus, the identification of drugs that would enable the extinction of fear memories would be an essential therapeutic goal.

One recent study investigated the effect of pre- and post-treatment with cotinine over the stability of contextual fear memory after repetitive or single re-exposure to the CS (Zeitlin et al., [@B133]). Male adult mice were pre-treated or post-treated with cotinine before or after FC, respectively, and tested for fear responses and anxiety after being exposed to the CS (context). These studies showed that cotinine accelerated the extinction and reduced the stability of the contextual fear memory. FE is considered a "new learning" process that involves the acquisition of inhibitory memories that compete with the original fear memory consolidation. For this reason, it has been proposed that cognitive enhancers may have a positive effect over the extinction of fear memories. Thus the improvement of cognitive abilities induced by cotinine may be relevant for its effects on FE. Thus, cotinine may promote the extinction of contextual fear memory by stimulating the acquisition of new inhibitory memories.

In addition, because cotinine reduces anxiety and helps to extinguish fear memory, it is feasible that cotinine may also be useful, alone or in a combined treatment, with psychotherapy to reduce both non-cognitive and cognitive symptoms of PTSD. However, these ideas need to be tested in placebo-controlled clinical trials.

### Cell signaling changes associated with fear extinction triggered by cotinine

This enhancement of contextual FE in mice subjected to FC described above, correlated with an increase in the extracellular signal-regulated kinases (ERK)1/2 (ERKs) activity in the hippocampus (Chen et al., [@B30]; Fischer et al., [@B45]). This increase has been regarded as a key molecular event during the fear extinction process because this brain region is involved in contextual FE (Bouton et al., [@B13]; Quirk and Mueller, [@B94]) and also because that ERK1/2 inhibition immediately after memory retrieval prevented the extinction of contextual memory (Chen et al., [@B30]). Consistent with these findings, the enhancement of FE induced by cotinine treatment in the C57BL/6, mice positively correlated with an increase in the levels of the active form of ERK1/2 (phospho-ERKs) in the hippocampus.

In addition this study showed that cotinine also reduced anxiety in the conditioned mice. Since it has been demonstrated that cotinine inhibited serotonin reuptake and increased its spontaneous release in rat brains (Fuxe et al., [@B49]), an increase in serotonin in the brain induced by cotinine may explain the reduction in anxiety after FC in the cotinine-treated mice. A similar effect may also explain the common perception of a "calming effect" experienced by tobacco smokers.

Cotinine, is a memory enhancer in animal models of schizophrenia-like symptoms
------------------------------------------------------------------------------

### Effect of smoking on psychiatric symptoms in schizophrenia

Schizophrenia is a mental disorder characterized by cognitive deficits and both positive and negative symptoms (Van Snellenberg, [@B123]). The positive symptoms include delusions, hallucinations, and difficulty in thought organization and oral expression. The negative symptoms include deficits in attention and motivation, social withdrawal, and emotional numbness (Van Snellenberg, [@B123]). Although the causes of schizophrenia are not well understood, abnormalities in the activity of several neurotransmitters such as, dopamine, acetylcholine, gamma-aminobutyric acid (GABA), and glutamate have been proposed (Lang et al., [@B71]). Since the development of clozapine, current drugs used to treat schizophrenia are mostly antagonists of the serotoninergic/dopaminergic signaling systems. These drugs have been effective in the management of positive psychotic symptoms; however, they do not effectively target the negative symptoms and cognitive deficits observed in schizophrenic patients. Thus, the identification of new drugs are needed to adequately treat these symptoms (Biedermann and Fleischhacker, [@B11]; Karam et al., [@B67]).

Patients with schizophrenia may often die prematurely due to health risk factors commonly associated with this condition including obesity and smoking behavior (Sagud et al., [@B104]; van Os and Kapur, [@B122]; von Hausswolff-Juhlin et al., [@B126]; Kelly et al., [@B68]).

A percentage of patients report, that smoking helps in decreasing psychiatric symptoms (Glynn and Sussman, [@B53]) which, become worse during tobacco withdrawal (Dalack and Meador-Woodruff, [@B35]). There are few and incomplete clinical data supporting the therapeutic effects of cotinine in psychiatric conditions, however, in one clinical study it was found that smoking high-nicotine cigarettes, compared to smoking de-nicotinized cigarettes, reduced negative symptoms without affecting positive symptoms (Smith et al., [@B106]). This effect is considered to be the result of the increase of dopamine levels in the nucleus accumbens and prefrontal cortex induced by nicotine (Corrigall and Coen, [@B34]). This increase in dopamine may stimulate active coping, improve attention, environmental engagement, and emotional responding, that are commonly absent in schizophrenic patients with prominent negative symptoms.

Cognitive impairment is one of the main challenges experienced by these patients. Growing evidence suggests that a deficit in cholinergic neurotransmission plays an important role in mediating cognitive deficits (Araki et al., [@B4]; Levin, [@B76]; Money et al., [@B87]). This evidence suggests that activation of the nicotinic receptors can be useful in treating some symptoms of schizophrenia particularly the cognitive deficits (Taly et al., [@B114]; Toyohara and Hashimoto, [@B121]).

### The nicotinic receptors as targets of cotinine effects in schizophrenia

The nicotinic receptors are involved in mediating attention, sensory gating, and learning and memory (AhnAllen, [@B3]; Yakel, [@B129]). The most broadly expressed nicotinic receptor (90%) is formed by α4 and β2 subunits and binds nicotine with high affinity while, not binding α-bungarotoxin (McGehee and Role, [@B85]); this receptor is highly represented in the striatum and substantia nigra and, poorly expressed in the neocortex and hippocampus (Rubboli et al., [@B103]).

No less relevant, although less expressed, is the α7 nicotinic acetylcholine receptor (α7 nAChR), a low affinity receptor for nicotine that is highly expressed in the midbrain, neocortex, thalamus, and hippocampus, with lower levels in the striatum (Sugaya et al., [@B112]; Freedman et al., [@B48]; Rubboli et al., [@B102],[@B103]). This receptor that has high affinity for α-bungarotoxin (McGehee and Role, [@B85]) and, plays a key role mediating several cognitive functions including attention, memory, executive function, and sensory gating (Woodruff-Pak and Gould, [@B128]; Leiser et al., [@B72]; AhnAllen, [@B3]).

A cholinergic deficit has been proposed as a factor leading to cognitive impairment in schizophrenia. Numerous studies have shown that expression of the α7 nAChR is decreased in the brains of patients with schizophrenia when compared to healthy controls (Breese et al., [@B20]; Leonard et al., [@B74]). This idea is supported by clinical evidence showing that the acetylcholinesterase inhibitor, galantamine, which increases the synaptic levels of acetylcholine, improved the cognitive abilities in patients with schizophrenia (Ago, [@B1]; Ago et al., [@B2]).

The high rate of smoking in individuals with schizophrenia, although not a evidence of causation, has permitted speculation of the beneficial effect of a tobacco-derivative, but not smoking itself (Dalack and Meador-Woodruff, [@B36]) on some schizophrenia symptoms such as working memory impairment (Leonard et al., [@B75], [@B73]). For example, evidence has been reported suggesting that α7 nAChR expression is significantly lower in schizophrenic non-smokers than in control non-smokers (Mexal et al., [@B86]).

In a rat model of Schizophrenia-like symptoms, the administration of nicotine attenuated the working memory deficits induced by the dopamine antagonist dizocilpine (Levin et al., [@B77]; Ciamei et al., [@B31]). In patients with schizophrenia, nicotine administration via a nasal spray has shown to ameliorate deficits in working memory, attention, and anxiety (Smith et al., [@B107]; Buckley et al., [@B25]). In addition, other clinical studies have shown that chronic treatment with nicotine improved the cognitive abilities in schizophrenic patients treated with antipsychotics (McEvoy et al., [@B84]; Freedman et al., [@B47]).

Several modulators of nAChRs have been tested against schizophrenia. For example, a partial agonist of the α7 nAChR, DMXB-A (GTS-21) was investigated in a phase 2 clinical study investigating the therapeutic effects of this drug over the symptoms of schizophrenia. Although GTS-21 improved some negative symptoms, it did not ameliorate the cognitive deficits observed in schizophrenic patients (Olincy and Stevens, [@B92]; Freedman et al., [@B47]).

Despite cotinine acting as a weak agonist (100 times less potent than nicotine) of the nAChRs, in rats it reversed the cognitive deficits induced by antagonism of the glutamate receptor, *N*-methyl-[d]{.smallcaps}-aspartate receptor (NMDAR), with ketamine. In this rodent model cotinine improved sustained attention and attenuated behavioral alterations induced by ketamine (Terry et al., [@B117]).

This pro-cognitive effect is not limited to rodent models of this disorder as cotinine, at similar doses, also improved performance accuracy on the delayed matching to sample (DMTS) task in aged rhesus monkeys. The DMTS task assesses recognition memory for novel non-verbal patterns, and tests short-term visual memory. This test has 19 outcome measures, including latency to response, the number of correct choices selected, and the probability of an error after a correct or incorrect response. In this task, cotinine-treated monkeys performed significantly better than vehicle-treated controls (Terry et al., [@B119]), indicating that cotinine improved visual short-term memory. These results also suggest that cotinine is a general cognitive enhancer that is useful in different species and types of cognitive abilities.

But the positive effects of cotinine are not limited to cognitive abilities. A recent study tested the effect of acute subcutaneous (0.03--10 mg/kg) and chronic oral administration of cotinine on sustained attention and behavioral alterations in rats induced by the glutamate (NMDA) antagonist MK-801 (Terry et al., [@B117]). The effects of cotinine were assessed in a five-choice serial reaction timed task (5CSRTT), a test broadly used to measure visual attention and impulsivity in rats. The 5CSRTT is implemented in a specially designed operant chamber with multiple response locations ("nine-hole box") using food reinforcers to maintain performance on baseline sessions (about 100 trials). The test gives the rat a brief 0.5 s visual stimulus, measuring the time, and accuracy of the animal's reactions, as well as the errors made by the rat. The 5CSRTT is used for measuring various aspects of attentional control over performance with its main measures of accuracy, premature responding, correct response latencies, and latency to collect earned food pellets (Robbins, [@B100]; Robinson et al., [@B101]).

The results showed that acute treatment with cotinine diminished MK-801-induced impairments in accuracy and elevations in timeout responses while increasing the number of completed trials. Furthermore, chronic treatment with cotinine induced similar beneficial effects even when the difficulties of the task were increased. The authors concluded that cotinine was useful in improving sustained attention and, in decreasing the impulsive and compulsive behaviors that were related to the postulated glutamate receptor signaling dysfunction in schizophrenia (Terry et al., [@B117]).

### Effect of cotinine on sensory gating in animal models of schizophrenia

A deficit in sensory gating is also a characteristic of schizophrenic patients as well as patients with other psychiatric conditions such as PTSD, borderline personality disorder, and bipolar disorder (Braff et al., [@B18]; Swerdlow et al., [@B113]). Individuals with this deficit cannot filter out irrelevant stimuli, as their brains are unable to inhibit its responsiveness to similar and repeated stimuli. The activation of cholinergic nicotinic receptors in the hippocampus is one of the main molecular mechanisms that control this inhibitory gating. Because the α7 nAChR is required for supporting sensory gating abilities (Freedman et al., [@B46]), a cognitive ability that is reduced in the patients with schizophrenia, this receptor is considered a potential therapeutic target for diminishing sensory gating deficit in this disorder (Olincy and Stevens, [@B92]).

The NMDAR antagonist, dizocilpine, or the dopamine agonist, apomorphine are used in rodents to induce memory and sensory gating deficits resembling those observed in persons with schizophrenia (Seillier and Giuffrida, [@B105]). For example, apomorphine is used to induce in rodents the deficit in prepulse inhibition (PPI) observed in schizophrenia. PPI is the decrease in the startle response to an auditory stimulus after repetitive exposure to the stimulus and a measure of sensory gating. The sensory gating deficit is expressed as an increase in the startle response (Geyer, [@B51]). To assess the effect of drugs on PPI animals are treated with vehicle, or the study drug, and are exposed to a weak acoustic stimulus (the prepulse); then, changes in the reflexive flinching response (startle) displayed as a result of a second stimulus of higher intensity (the pulse) is measured. Effective antipsychotic agents prevent the inhibition of PPI induced by psychogenic compounds such as apomorphine and dizolcipine. Previous studies have shown that nicotine blocks the apomorphine-induced disruption of the PPI of the acoustic startle in rats (Suemaru et al., [@B111]).

In fact, several studies have reported a positive effect of smoking on sensory gating and cognitive function in schizophrenia. In one study, the relationship between sensory gating and smoking levels was assessed by investigating the correlation between PPI and smoking behavior in schizophrenic and control patients (Rabin et al., [@B95]). The authors found that schizophrenic non-smokers have poorer PPI performances than schizophrenic smokers, whose levels did not differ from non-schizophrenic controls.

In addition to the observed effects of nicotine on sensory gating, other studies have demonstrated that nicotine also improved other schizophrenic symptoms (Lyon, [@B80]). These results support the view that smoking is a form of self-medication to alleviate psychotic symptoms and the unpleasant side-effects of antipsychotics (Matthews et al., [@B83]). Interestingly, cotinine, the long-lived metabolite of nicotine, also ameliorated the apomorphine-induced deficits in PPI of the acoustic startle response in rats (Risner et al., [@B99]; Terry et al., [@B119]). This result suggested that cotinine may have antipsychotic effects and underlie the beneficial effects of nicotine on attention and sensory gating, in addition to its predicted positive effect over working memory. In addition, as mentioned before, cotinine facilitates fear extinction a measure of executive function which has been found also impaired in people suffering from schizophrenia (Holt et al., [@B61]). Unfortunately, no clinical studies have been performed to investigate the effect of cotinine over these symptoms in schizophrenia.

Molecular mechanisms potentially mediating the beneficial effects of cotinine on cognition
------------------------------------------------------------------------------------------

Thus far, the molecular mechanisms of cotinine action have been elusive. A previous report suggested that cotinine binds to an unknown type of receptor (Riah et al., [@B97]). Unfortunately, no follow-up studies pursued the characterization of this "cotinine receptor". Other study based in the fact that cotinine increased serotonin levels in the rat brain, investigated whether granisetron, a 5HT(3) receptor antagonist, could enhance the efficacy of the nicotine patch. The results indicated that 5HT(3) antagonism was an unlikely mechanism of cotinine's actions (Hatsukami et al., [@B59]). On the other hand, pharmacological evidence using ^125^I-labeled α-bungarotoxin and \[^3^H\] nicotine to differentiate subtypes of nAChRs affinities show that cotinine is a weak agonist of the α7 nAChRs and nicotine has more than 100 times higher affinity than cotinine for agonist binding sites of both subtypes of receptors. In addition the toxicological analysis using acute intraperitoneal injections of drugs in saline, showed that cotinine has in comparison to nicotine less than 1.5% toxicity (Table [1](#T1){ref-type="table"}; Riah et al., [@B98]).

######

**Potencies and affinities of cotinine and nicotine to different subtypes of nAChRs in the rat brain and values of acute toxicity in mice**.

             \*I/IC~50~ \[^3^H\] nicotine   I/IC~50~ ^125^I-labeled α-bungarotoxin   Male      Female
  ---------- ------------------------------ ---------------------------------------- --------- --------- --------- ---------
  Nicotine   100/(2 ± 0.1) × 10^−7^         100/(1 ± 0.3) × 10^−5^                   31 ± 4    43 ± 6    37 ± 6    51 ± 9
  Cotinine   100/(2 ± 0.2) × 10^−3^         100/(1 ± 0.2) × 10^−3^                   2 ± 0.1   4 ± 0.1   3 ± 0.1   4 ± 0.1

*\*I/IC50, percentage maximum inhibition/concentration of drug that inhibits 50% radioligand binding (in M). Values of IC50, mean ± SD. LD, lethal dose with nicotine attributed 100% toxicity (Riah et al., [@B98])*.

It has been suggested that α7 nAChRs is not the main target of cotinine (Riah et al., [@B98]) and other type of receptors for cotinine have been suggested (Riah et al., [@B97]). Also, using \[^3^H\]dopamine release assays and ligand-binding autoradiography in monkey striatum, it was concluded that cotinine functionally interacts with both α4β2 and α3α6β2 nAChR subtypes in the caudate with a IC~50~ for the inhibition of specific agonists in the micromolar range (O'Leary et al., [@B91]). In recent years, we and others have proposed that cotinine functions as a positive allosteric modulator of α7 nAChRs (Buccafusco et al., [@B22]; Zeitlin et al., [@B133]). Positive allosteric modulators, are compounds that facilitate endogenous neurotransmission without directly stimulating the target receptors (Bertrand and Gopalakrishnan, [@B10]; Faghih et al., [@B44]). For example the compound PNU-120596, acts as a positive allosteric modulator of nAChRs both *in vitro* and *in vivo* (see Young et al., [@B132]). PNU-120596 inhibited the ability of amphetamine to suppress auditory gating in rats, suggesting its potential for use in schizophrenia, characterized by auditory gating deficits. The effects of PNU-120596 *in vitro* were shown to be mediated by α7 nAChRs. As a positive allosteric modulator, PNU-120596 positively modulates nicotinic cholinergic neurotransmission mostly by preventing receptor desensitization. Because, cotinine has been shown to be a memory enhancer (Echeverria et al., [@B42]), and also inhibit sensory gating disruption it has been speculated that can have similar beneficial effects on memory in AD or schizophrenia (Hajos and Rogers, [@B55]). However this is highly speculative at this point and needs to be demonstrated.

Another hypothesis proposed to explain the beneficial effects of cotinine on cognition is the theory of desensitization of specific population of the α7nAChRs. This hypothesis speculates that cotinine desensitization of the α7 nAChRs expressed on inhibitory GABAergic neurons of the hippocampus, may result in the activation of excitatory glutamate receptors mediating the synaptic plasticity changes required for memory (Buccafusco et al., [@B23], [@B22]). Functional assays of human α7 nAChR expressed in *Xenopus leavis* oocytes showed that cotinine acted as weak agonists at the human α7 nAChR (1% response at 1 mM) and inhibited the response to ACh with IC~50~ value of 175 μM (Briggs and McKenna, [@B21]). Although this hypothesis is intriguing, the doses required for inducing the receptor desensitization are higher than those showing pharmacological effects and direct evidence that cotinine may have this effect in the brain is still missing. The idea of a desensitization of the α7nAChR induced by cotinine is contradictory with the fact that in mice, the chronic treatment with cotinine induced the activation of the Akt/GSK3β signaling pathway, which is activated by the α7 nAChR, in both the hippocampus and cortex (Echeverria et al., [@B42]). In fact, cotinine prevented apomorphine-induced deficits in PPI of acoustic startle in rats (Buccafusco and Terry, [@B24]), a behavioral task that greatly depends on the activity of the α7 nAChR. The effects of cotinine can be better explained by cotinine functioning as a positive allosteric modulator of the human α7 nAChR.

As a positive modulator, cotinine may improve learning and memory performance and reverse the apomorphine-induced deficits of PPI, in addition to stimulating the protein kinase B (Akt)/GSK3β pathway. Furthermore, stimulation of α7 nAChR signaling may explain the neuroprotective effects of cotinine because Akt can promote neuronal survival via several mechanisms including stimulation of the expression of anti-apoptotic factors such as CREB and Bcl-2 while inactivating pro-apoptotic enzyme such as Ask1 (Kim et al., [@B69]). Evidence of an allosteric effect of cotinine on the α7 nAChR or other receptors.

Conclusion
==========

Altogether the evidence suggests that cotinine is less toxic and has different mechanism(s) of action than nicotine. Cotinine's properties and the preclinical evidence of its nootropic effects in animal models of psychiatric conditions, suggests that cotinine as a pure agent, in absence of nicotine, represents a new therapeutic agent to reduce anxiety, facilitate the extinction of fear memories, and improve attention and working memory in individuals with psychiatric conditions such as AD.

Conflict of Interest Statement
==============================

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This material is the result of work supported with resources and the use of facilities at the Bay Pines VA Healthcare System and the James A. Haley Veterans' Hospital. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. This work was also supported by the Bay Pines Foundation, Inc., and a grant obtained from the James and Esther King Biomedical Research Program 1KG03-33968 (to Valentina Echeverria Moran). Also, I am especially grateful to Dr. Hugo Fernandez, who has recently departed, for his friendship, guidance, and generous support to cotinine research. The scientific community will be forever indebted to you.

[^1]: Edited by: Nick Andrews, Harvard Medical School, USA

[^2]: Reviewed by: Li Zhang, National Institutes of Health, USA; Mariela Fernanda Perez, Universidad Nacional de Córdoba, Argentina

[^3]: This article was submitted to Frontiers in Neuropharmacology, a specialty of Frontiers in Pharmacology.


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While the NBA’s brightest stars and pride of the Red, White and Blue took a breather during a timeout at last night’s USA Basketball Showcase in Las Vegas, an Air Force serviceman named Nathanial Mills threw down one of the nastiest dunks that didn’t involve someone throwing a ball from the sunroof of a Kia.


Failure of late intensification therapy to improve a poor result in childhood lymphoblastic leukemia.
This clinical study, begun in 1975, tested the efficacy of early and delayed intensification treatments in children with acute lymphoblastic leukemia. Regardless of presenting features, all patients received 4 weeks of conventional induction therapy with daily prednisone and weekly vincristine and daunorubicin. One-third were randomized to receive, in addition, two doses of asparaginase during induction therapy, while another one-third received four doses of both asparaginase and cytarabine after remission induction. Preventive central nervous system therapy uniformly included 2400 rads cranial irradiation and five doses of intrathecal methotrexate. Remissions were maintained with daily p.o. mercaptopurine and weekly i.v. methotrexate. Of the 277 assessable patients, 254 (92%) entered complete remission, and 102 (37%) remain clinically free of leukemia for 4.6 to 8.0 years (median, 6.3 years). The three treatment groups showed no significant differences in either remission induction rate or outcome, even when the analysis was based on risk assignment. A "late intensification" phase of therapy, added to the maintenance protocol for 65 patients who had been in continuous complete remission for 14 to 30 months, failed to extend remission durations, as judged from statistical comparison with matched controls (p = 0.84). When tested as a time-dependent covariate in the Cox proportional-hazards model, delayed intensification again showed no important effect on duration of complete remission. We conclude that limited early or aggressive late intensification of therapy, as described here, does not improve outcome in childhood acute lymphoblastic leukemia.


Perfect for packaging samples, creating promotional giveaways or for retail sale, this small Silver mesh pouch with zipper closure is just the right size for a few essential makeup or skin care must-haves.


1. Field of the Invention
This invention relates to an interchangeable lens for a camera, and more particularly to an interchangeable lens which can transmitt the lens side information to the camera body side provided with a lens information discriminating device or to various accessory devices of the camera.
2. Description of the Prior Art
As an interchangeable lens of this type, there is known one in which is provided a variable resistor whose resistance value is variable in response to the movement of the diaphragm drive ring or the range ring of the lens. In such a lens, the information can only be taken out as single information and no lens is known to applicants which permits the information to be taken out synthetically as well as singly. Also, it has heretofore been practised to provide the mount of the lens with a terminal portion whereat the resistance value of the variable resistor appears and to provide the body mount of the camera with a terminal receiving portion to be opposed to the terminal portion of the lens, and to connect together the terminal portion and the terminal receiving portion by the coupling operation of the lens and the camera body, thereby accomplishing electrical connection therebetween.
This has resulted in a disadvantage in that where a lens capable of generating information is combined with a camera which does not have the function of receiving such information, no transmission of the information can take place therebetween.


/************************************************************************
* Copyright (c) 2009-2010,  Microchip Technology Inc.
*
* Microchip licenses this software to you solely for use with Microchip
* products.  The software is owned by Microchip and its licensors, and
* is protected under applicable copyright laws.  All rights reserved.
*
* SOFTWARE IS PROVIDED "AS IS."  MICROCHIP EXPRESSLY DISCLAIMS ANY
* WARRANTY OF ANY KIND, WHETHER EXPRESS OR IMPLIED, INCLUDING BUT
* NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS
* FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT.  IN NO EVENT SHALL
* MICROCHIP BE LIABLE FOR ANY INCIDENTAL, SPECIAL, INDIRECT OR
* CONSEQUENTIAL DAMAGES, LOST PROFITS OR LOST DATA, HARM TO YOUR
* EQUIPMENT, COST OF PROCUREMENT OF SUBSTITUTE GOODS, TECHNOLOGY
* OR SERVICES, ANY CLAIMS BY THIRD PARTIES (INCLUDING BUT NOT LIMITED
* TO ANY DEFENSE THEREOF), ANY CLAIMS FOR INDEMNITY OR CONTRIBUTION,
* OR OTHER SIMILAR COSTS.
*
* To the fullest extent allowed by law, Microchip and its licensors
* liability shall not exceed the amount of fees, if any, that you
* have paid directly to Microchip to use this software.
*
* MICROCHIP PROVIDES THIS SOFTWARE CONDITIONALLY UPON YOUR ACCEPTANCE
* OF THESE TERMS.
*/

#ifndef DEVICE_H
#define DEVICE_H

#include <QString>
#include <QVariant>
#include <QLinkedList>
#include <QList>

#define CFG_MAX 8

/*!
 * Provides microcontroller device specific parameters, address calculations, and
 * assembly code tools.
 */
class Device
{
public:
    enum Families
    {
        Unknown = 0, Baseline = 1, PIC16, PIC17, PIC18, PIC24, dsPIC30, dsPIC33, PIC32
    };

    Device();

    void setUnknown(void);

    static int toInt(const QVariant& value);
    static unsigned int toUInt(const QVariant& value);

    int id;
    Families family;
    unsigned int commandMask;
    QString name;

    int bytesPerWordEEPROM;
    int bytesPerWordFLASH;
    int bytesPerAddressFLASH;   // number of bytes per address
    unsigned int eraseBlockSizeFLASH;    // number of bytes erased at a time
    int writeBlockSizeFLASH;    // number of bytes written at a time
    unsigned int flashWordMask;
    unsigned int blankValue;

    unsigned int startFLASH;
    unsigned int endFLASH;

    unsigned int startBootloader;
    unsigned int endBootloader;

    // Interrupt Vector Table variables -- only for PIC24
    unsigned int startIVT;
    unsigned int endIVT;
    unsigned int startAIVT;
    unsigned int endAIVT;
    unsigned int* IVT;
    unsigned int* AIVT;

    bool hasEeprom(void);
    bool hasUserMemory(void);
    bool hasConfigAsFlash(void);
    bool hasConfigAsFuses(void);
    bool hasConfig(void);
    bool hasConfigReadCommand(void);
    bool hasEraseFlashCommand(void);
    bool hasEncryption(void);
    int maxPacketSize(void);

    unsigned int startDeviceId;
    unsigned int endDeviceId;
    unsigned int deviceIdMask;
    unsigned int configWordMask;

    unsigned int startEEPROM;
    unsigned int endEEPROM;

    unsigned int startUser;
    unsigned int endUser;

    unsigned int startConfig;
    unsigned int endConfig;

    unsigned int startGPR;
    unsigned int endGPR;

    struct MemoryRange
    {
        unsigned int start;
        unsigned int end;
    };

    struct ConfigFieldSetting
    {
        QString name;
        QString cname;
        QString description;
        unsigned int bitMask;
        unsigned int bitValue;
    };

    struct ConfigField
    {
        unsigned int rowId;
        QString name;
        QString cname;
        QString description;
        unsigned int mask;
        unsigned int width;
        bool hidden;
        QList<ConfigFieldSetting> settings;
    };

    struct ConfigWord
    {
        unsigned int rowId;
        QString name;
        unsigned int address;
        unsigned int defaultValue;
        unsigned int implementedBits;
        QList<ConfigField> fields;
    };
    QList<ConfigWord> configWords;

    struct SFR
    {
        QString name;
        unsigned int address;
        QString access;
        QString POR;
        QString MCLR;
        QString WDT;
    };
    QList<SFR> SFRs;

    struct Trap
    {
        QString name;
        QString description;
        unsigned int number;
    };
    QList<Trap> Traps;

    struct IRQ
    {
        QString name;
        QString description;
        unsigned int number;
    };
    QList<IRQ> IRQs;

    unsigned int FromHexAddress(unsigned int hexAddress, bool& error);
    unsigned int* eepromPointer(unsigned int address, unsigned int* data) const;
    unsigned int* flashPointer(unsigned int address, unsigned int* data) const;
    void IncrementFlashAddressByInstructionWord(unsigned int& address) const;
    void IncrementFlashAddressByBytes(unsigned int& address, unsigned int bytes) const;
    unsigned int FlashBytes(unsigned int startAddress, unsigned int endAddress) const;
    void RemapResetVector(unsigned int* memory) const;
    bool HasValidResetVector(unsigned int* data) const;
    bool ResetVectorJumpsToBootloader(unsigned int* data) const;
    ConfigWord ConfigWordByAddress(unsigned int address);

protected:
    int findInstruction(unsigned int* data, unsigned int opcode, unsigned int opcodeMask, unsigned int endAddress) const;
};

#endif // DEVICE_H


12 F.3d 205
NOTICE: Fourth Circuit I.O.P. 36.6 states that citation of unpublished dispositions is disfavored except for establishing res judicata, estoppel, or the law of the case and requires service of copies of cited unpublished dispositions of the Fourth Circuit.NEWPORT NEWS SHIPBUILDING AND DRY DOCK COMPANY, Petitioner,v.Woodrow J. KINCAID; Director, Office of Workers'Compensation Programs, United States Department ofLabor, Respondents.
No. 93-1683.
United States Court of Appeals,Fourth Circuit.
Argued:  October 25, 1993.Decided:  December 3, 1993.

On Petition for Review of an Order of the Benefits Review Board.
Lawrence Philip Postol, Seyfarth, Shaw, Fair-Weather & Geraldson, for Petitioner.
Lauri J. Stomski, Office of the Solicitor, United States Department of Labor, for Respondents.
Thomas S. Williamson, Jr., Solicitor of Labor, Carol A. De Deo, Associate Solicitor, Janet R. Dunlop, Counsel for Longshore, Office of the Solicitor, United States Department of Labor, for Respondent.
Ben.Rev.Bd.
VACATED AND REMANDED.
Before LUTTIG and WILLIAMS, Circuit Judges, and SPROUSE, Senior Circuit Judge.
PER CURIAM:

OPINION

1
Newport News Shipbuilding and Dry Dock Company petitions for review of a Benefits Review Board order affirming an administrative law judge's denial of relief under section 8(f) of the Longshore and Harbor Workers' Compensation Act, 33 U.S.C. 908(f).  We vacate the decision and order of the Benefits Review Board and remand to the administrative law judge for reconsideration in light of  Director, Office of Workers' Compensation Programs v. Newport News Shipbuilding and Dry Dock Co., 8 F.3d 175 (4th Cir. 1993).

I.

2
The relevant facts are detailed in the administrative law judge's opinion below, Kincaid et al. v. Newport News Shipbuilding and Dry Dock Co., No. 90-LHC-2193 (Dep't of Labor, July 18, 1991), and we summarize them only to the extent needed for the disposition of this appeal.

3
Respondent-Claimant Woodrow J. Kincaid was exposed to asbestos while working for Newport News Shipbuilding and Dry Dock Company (Newport News) from 1939 to 1941, and from 1946 to 1983, at which point he retired from Newport News' employ.  He subsequently sought benefits under the Longshore and Harbor Workers' Compensation Act, as amended, 33 U.S.C. Sec. 901 et seq.  (the Act), alleging that he had asbestosis resulting from his work-related exposure to asbestos, but was denied benefits by an administrative law judge in a 1984 order.  After Kincaid submitted new evidence indicating respiratory impairment in 1988, Newport News accepted responsibility for a work-related injury and commenced voluntary payments for Kincaid's permanent partial disability under section 908(c)(23) of the Act.  Newport News subsequently filed a claim for relief under section 908(f), which protects employers from paying compensation for disabilities that result in part from health conditions not caused by the claimant's employment.1

4
An administrative law judge (ALJ) denied Newport News' request for relief, finding that, to the extent Kincaid had a pre-existing disability, Newport News failed to prove that Kincaid's disability was "materially and substantially greater" than it would have been without the pre-existing disability.  See 33 U.S.C.Sec. 908(f)(1).  Although Newport News' staff physician, Dr. Harmon, testified that Kincaid's disability was materially and substantially greater due to his pre-existing disability, the ALJ rejected Dr. Harmon's testimony as unsubstantiated by medical evidence, and concluded that, because Newport News failed to submit any medical evidence to support Dr. Harmon's opinion, it failed to satisfy its burden of proof.  The Benefits Review Board affirmed the ALJ's decision and order, and Newport News brought this appeal.

5
In a case decided after briefing and argument in the instant appeal, Director, Office of Workers' Compensation Programs v. Newport News Shipbuilding and Dry Dock Co., --- F.3d ----, No. 92-1864 (4th Cir.  Oct. 29, 1993), this circuit specifically addressed the proof required of employers to establish that an employee's disability is "materially and substantially greater than that which would have resulted" from the work-related injury alone.  33 U.S.C. Sec. 908(f)(1).  In that case we held that satisfying this standard

6
requires quantification of the level of impairment that would ensue from the work-related injury alone.  In other words, an employer must present evidence of the type and extent of disability that the claimant would suffer if not previously disabled when injured by the same work-related injury.

7
Newport News, No. 92-1864, slip op. at 19 (emphasis added).

8
Under this standard, it is clear that Newport News cannot make out a claim for relief without producing evidence quantifying the impairment Kincaid would suffer if he only had asbestosis.2  Although Dr. Harmon did testify that Kincaid's disability would be "far less" if he only had asbestosis, J.A. at 47, he never specified exactly how great a disability would result from Kincaid's asbestosis alone, a showing that is required under the standard we recently adopted.  Newport News, No. 92-1864, slip op. at 19.  Because this circuit's standard for establishing entitlement to section 908(f)(1) relief was only adopted after the parties had briefed and argued this appeal, they should have another opportunity to have their evidence considered and their claims adjudicated under that standard.  Accordingly, we vacate the decision below and remand for reconsideration in light of Newport News.

VACATED AND REMANDED

1
 Under section 908(f)(1), an employer's liability is limited where it is found that the employee has a permanent partial disability, found not to be due solely to that injury, and such disability is materially and substantially greater than that which would have resulted from the subsequent injury alone

2
 The standard articulated in Newport News applies to all permanent partial disabilities "found not to be due solely to that injury," including disabilities, such as Kincaid's, covered by section 908(c)(23).  33 U.S.C. Sec. 908(f)(1);  Newport News, slip op. at 19


"""Formatting of UML elements like attributes, operations, stereotypes, etc."""

import re
from typing import Tuple

from gaphor.core.format import format
from gaphor.UML import uml as UML

# Do not render if the name still contains a visibility element
no_render_pat = re.compile(r"^\s*[+#-]", re.MULTILINE | re.S)
vis_map = {"public": "+", "protected": "#", "package": "~", "private": "-"}

@format.register(UML.Property)
def format_property(
    el,
    visibility=False,
    is_derived=False,
    type=False,
    multiplicity=False,
    default=False,
    tags=False,
):
    """Create a OCL representation of the attribute, Returns the attribute as a
    string. If one or more of the parameters (visibility, is_derived, type,
    multiplicity, default and/or tags) is set, only that field is rendered.
    Note that the name of the attribute is always rendered, so a parseable
    string is returned.

    Note that, when some of those parameters are set, parsing the string
    will not give you the same result.
    """
    name = el.name

    if name and no_render_pat.match(name):
        return name

    # Render all fields if they all are set to False
    if not (visibility or is_derived or type or multiplicity or default):
        visibility = is_derived = type = multiplicity = default = True

    s = []

    if name and visibility:
        s.append(vis_map[el.visibility])
        s.append(" ")

    if name and is_derived and el.isDerived:
        s.append("/")

    if name:
        s.append(name)

    if type and el.typeValue:
        s.append(f": {el.typeValue}")
    elif type and el.type and el.type.name:
        s.append(f": {el.type.name}")

    if multiplicity:
        s.append(format_multiplicity(el))

    if default and el.defaultValue:
        s.append(f" = {el.defaultValue}")

    if tags:
        slots = [format(slot) for slot in el.appliedStereotype[:].slot if slot]
        if slots:
            s.append(" { %s }" % ", ".join(slots))
    return "".join(s)

def format_association_end(el) -> Tuple[str, str]:
    """Format association end."""
    name = ""
    n = []
    if el.name:
        n.append(vis_map[el.visibility])
        n.append(" ")
        if el.isDerived:
            n.append("/")
        n.append(el.name)

        name = "".join(n)

    m = [format_multiplicity(el, bare=True)]
    slots = [format(slot) for slot in el.appliedStereotype[:].slot if slot]
    if slots:
        m.append(" { %s }" % ",\n".join(slots))
    mult = "".join(m)

    return name, mult

@format.register(UML.Operation)
def format_operation(
    el,
    pattern=None,
    visibility=False,
    type=False,
    multiplicity=False,
    default=False,
    tags=False,
    direction=False,
):
    """Create a OCL representation of the operation, Returns the operation as a
    string."""
    name = el.name
    if not name:
        return ""
    if no_render_pat.match(name):
        return name

    # Render all fields if they all are set to False
    if not (visibility or type or multiplicity or default or tags or direction):
        visibility = type = multiplicity = default = tags = direction = True

    s = []
    if visibility:
        s.append(f"{vis_map[el.visibility]} ")

    s.append(name)
    s.append("(")

    for p in el.formalParameter:
        s.append(
            format(
                p,
                direction=direction,
                type=type,
                multiplicity=multiplicity,
                default=default,
            )
        )
        if p is not el.formalParameter[-1]:
            s.append(", ")

    s.append(")")

    rr = el.returnResult and el.returnResult[0]
    if rr:
        s.append(format(rr, type=type, multiplicity=multiplicity, default=default))
    return "".join(s)

@format.register(UML.Parameter)
def format_parameter(
    el, direction=False, type=False, multiplicity=False, default=False
):
    s = []
    if direction:
        s.append(f"{el.direction} ")

    s.append(el.name or "")

    if type and el.typeValue:
        s.append(f": {el.typeValue}")

    if multiplicity:
        s.append(format_multiplicity(el))

    if default and el.defaultValue:
        s.append(f" = {el.defaultValue}")
    # if p.taggedValue:
    #     tvs = ', '.join(filter(None, map(getattr, p.taggedValue,
    #                                      ['value'] * len(p.taggedValue))))
    #     s.append(' { %s }' % tvs)
    return "".join(s)

@format.register(UML.Slot)
def format_slot(el):
    return f'{el.definingFeature.name} = "{el.value}"'

@format.register(UML.NamedElement)
def format_namedelement(el, **kwargs):
    """Format named element."""
    return el.name or ""

@format.register(UML.MultiplicityElement)
def format_multiplicity(el, bare=False):
    m = ""
    if el.upperValue:
        m = f"{el.lowerValue}..{el.upperValue}" if el.lowerValue else f"{el.upperValue}"
    return f"[{m}]" if m and not bare else m

@format.register(UML.Relationship)
def format_relationship(el):
    return el.__class__.__name__

@format.register(UML.Generalization)
def format_generalization(el):
    return f"general: {el.general and el.general.name or ''}"

@format.register(UML.Dependency)
def format_dependency(el):
    return f"supplier: {el.supplier and el.supplier.name or ''}"

@format.register(UML.Extend)
def format_extend(el):
    return f"extend: {el.extendedCase and el.extendedCase.name or ''}"

@format.register(UML.Include)
def format_include(el):
    return f"include: {el.addition and el.addition.name or ''}"


Catastrophizing and health-related quality of life: a 6-year follow-up of patients with chronic low back pain.
A pain rehabilitation model that focused on emotions was implemented to influence catastrophizing by, and health-related quality of life (HRQL) for, persons with chronic low back pain. Twelve individuals, 7 men and 5 women (aged 33 to 57 years), all with long-term pain despite treatment, were included in the study and a single case research experimental design (SCRED) was used to follow the patterns of coping with pain for 6 years. The HRQL was measured before and 6 years after the intervention. Coping strategies and HRQL were evaluated with the Coping Strategy Questionnaire (CSQ) and the SF-36, respectively. The evaluation of pain coping strategies after 3 years found decreased catastrophizing, a decrease that had continued 3 years later. HRQL showed significantly improved mental health and impaired physical capacity at the 6-year follow-up. Changes in catastrophizing or in HRQL did not appear to influence self-scored bodily pain. Altered catastrophizing appeared to be a long-term process. This research indicates the need for rehabilitation programs to assess and evaluate patients' pain and their need for improved quality of life, rather than focusing only on the elimination of pain.


Storm Lake

Storm Lake’s tremendous dredging program would not be as far along as it is were it not for the locally organized work crew and infrastructure. As we have noted before, City Infrastructure Director Pat Kelly volunteered to ramrod the operation and the city council agreed. That pledge led to the creation of the Lake Improvement Commission, an authority formed by Storm Lake, Buena Vista County, Lakeside and the Lake Preservation Association with advisory support from the Iowa Department of Natural Resources.

With the city of Storm Lake located on the shores of our lake, it’s imperative that first responders be prepared in the event of a lake emergency. Buena Vista Regional Medical Center paramedics participated in a training drill facilitated by Storm Lake Public Safety.

The Iowa Department of Natural Resources issues a weekly fishing report on Thursdays in an effort to provide the latest information heading into the weekend. The weekly fishing report is compiled from information gathered from local bait shops, angler creel surveys, and county and state parks staff. For current information, contact the district fisheries office at the phone number listed at the end of each district report.

The Storm Lake trapshooting high school and middle school teams will compete in the Scholastic Clay Target Championships at the Iowa State Trap Shooting Association home grounds north of Cedar Falls June 4-6.

The high school team members will shoot 200 targets at the two-day event and the middle school students will shoot 100 targets.

Storm Lake (including Little Storm Lake): Boaters should use caution around the dredge barge, booster pump barge, and pipeline. Walleye regulations for Storm Lake are three fish per day, all fish between 17 and 22 inches must be released and only one over 22 inches may be kept. Walleye is fair. Anglers are picking up 12 to 13 inch and 17 to 19 inch walleye. Try trolling shad colored crankbaits in 7 to 9 feet of water. Channel catfish is fair. Use traditional catfish baits.

Storm Lake (including Little Storm Lake): The city is in the process of getting the dredge machine out on the lake. Boaters should be aware of the dredge barge, booster pump, and pipeline in the water. Walleye regulations for Storm Lake are three fish per day, all fish between 17 and 22 inches must be released and only one over 22 inches may be kept. Walleye is good. Anglers are catching walleye using plastics, crankbaits, leaches, and minnows fished along the east and south sides of the lake.

Storm Lake: Walleye is good. Anglers are catching walleye using plastics, crank baits, leaches, and minnows fished along the east and south sides of the lake. Anglers are doing well fishing along the dredge cuts between Chautauqua Point and the big island. Fishing the dredge cuts between the big island and Shorty’s Island has also been productive for walleye. Yellow perch is slow. A few perch have been picked up with minnows along the east side of the lake. White bass is good.


at is prob of picking 3 q when three letters picked without replacement from {m: 5, n: 4, u: 3, q: 7}?
35/969
What is prob of picking 1 i, 1 u, and 1 g when three letters picked without replacement from {g: 6, u: 8, i: 2, b: 2}?
2/17
Calculate prob of picking 2 j and 1 r when three letters picked without replacement from {m: 2, a: 1, h: 4, j: 3, x: 1, r: 1}.
3/220
Four letters picked without replacement from qhqljhtqjhhhqhqh. Give prob of picking 1 h, 1 q, 1 l, and 1 t.
1/52
Calculate prob of picking 1 x, 1 u, and 1 s when three letters picked without replacement from {x: 4, s: 1, r: 2, a: 4, j: 1, u: 2}.
2/91
What is prob of picking 1 h, 1 x, and 2 u when four letters picked without replacement from {y: 3, u: 3, w: 6, x: 1, h: 2, k: 5}?
2/1615
Three letters picked without replacement from wwzwccdzdddcddzwdtdw. What is prob of picking 1 z, 1 d, and 1 t?
2/95
Three letters picked without replacement from {g: 11, f: 5}. Give prob of picking 1 g and 2 f.
11/56
Two letters picked without replacement from {a: 5, h: 10, d: 4}. What is prob of picking 2 d?
2/57
Calculate prob of picking 3 d when three letters picked without replacement from pddddpdddppddppdddd.
286/969
Three letters picked without replacement from ooohtototogo. Give prob of picking 1 g and 2 t.
3/220
Two letters picked without replacement from {z: 1, d: 1, u: 2, q: 1}. Give prob of picking 1 z and 1 d.
1/10
Calculate prob of picking 1 x and 1 c when two letters picked without replacement from jpjcxdjpxp.
2/45
Two letters picked without replacement from xxcmnmxxzxnn. What is prob of picking 1 c and 1 x?
5/66
Two letters picked without replacement from {l: 4, w: 2, s: 1, a: 2, i: 1}. Give prob of picking 1 i and 1 a.
2/45
Calculate prob of picking 1 k and 2 s when three letters picked without replacement from {s: 11, k: 5}.
55/112
What is prob of picking 1 b, 1 w, and 1 l when three letters picked without replacement from {l: 5, b: 7, w: 1}?
35/286
What is prob of picking 2 f and 2 d when four letters picked without replacement from iidiiifii?
0
Three letters picked without replacement from {d: 1, o: 10, q: 3, g: 1, c: 2, s: 1}. Give prob of picking 1 s, 1 g, and 1 q.
1/272
Calculate prob of picking 1 l and 1 x when two letters picked without replacement from kwxqwqllqlkkklllk.
3/68
Calculate prob of picking 1 u, 1 d, and 2 k when four letters picked without replacement from {u: 4, k: 2, h: 2, d: 3}.
2/55
What is prob of picking 1 i and 1 a when two letters picked without replacement from {t: 1, x: 1, l: 2, i: 2, s: 1, a: 1}?
1/14
Three letters picked without replacement from {w: 4, q: 7, u: 3, m: 1, i: 1}. Give prob of picking 1 u, 1 q, and 1 i.
3/80
Three letters picked without replacement from beiiqeqeeieeeeb. Give prob of picking 2 b and 1 e.
8/455
What is prob of picking 4 u when four letters picked without replacement from ibquguggukuiig?
1/1001
Three letters picked without replacement from szzsszzsssssz. What is prob of picking 3 z?
5/143
What is prob of picking 1 x and 1 b when two letters picked without replacement from {b: 5, x: 3, y: 3, g: 3, o: 2}?
1/8
Four letters picked without replacement from {n: 3, t: 1, v: 3, j: 4}. Give prob of picking 1 v and 3 j.
2/55
Calculate prob of picking 1 o, 2 c, and 1 n when four letters picked without replacement from {n: 6, c: 3, v: 2, t: 5, o: 1}.
9/1190
Calculate prob of picking 1 g and 3 j when four letters picked without replacement from jjjjjjjcgjj.
14/55
What is prob of picking 2 a when two letters picked without replacement from {y: 1, a: 3, u: 3}?
1/7
Four letters picked without replacement from ssqsssqssqqqqssq. What is prob of picking 4 q?
1/52
Calculate prob of picking 1 t and 1 x when two letters picked without replacement from ssxxgxsxxgxsxgxtxx.
10/153
Three letters picked without replacement from oeeoeeeooeoeooeneeee. Give prob of picking 1 o, 1 n, and 1 e.
7/95
What is prob of picking 1 v and 1 g when two letters picked without replacement from {v: 4, h: 2, g: 2}?
2/7
Two letters picked without replacement from fehh. Give prob of picking 1 h and 1 e.
1/3
Two letters picked without replacement from {r: 8, q: 1, f: 1, y: 1, u: 4}. Give prob of picking 1 f and 1 r.
8/105
Two letters picked without replacement from {w: 1, v: 1, l: 1, t: 1, p: 3, o: 5}. What is prob of picking 1 v and 1 t?
1/66
Three letters picked without replacement from {n: 17, t: 3}. What is prob of picking 3 n?
34/57
Calculate prob of picking 4 r when four letters picked without replacement from yprpprypxxuzxxzrpypr.
1/4845
What is prob of picking 1 t and 2 h when three letters picked without replacement from ihhiiitciiitiihi?
3/280
Calculate prob of picking 1 q and 1 e when two letters picked without replacement from {e: 5, d: 2, o: 2, g: 4, q: 7}.
7/38
Two letters picked without replacement from {e: 3, p: 1, u: 1, c: 2, g: 3, b: 8}. What is prob of picking 1 e and 1 u?
1/51
Four letters picked without replacement from {g: 2, d: 2, r: 1, x: 2, l: 1}. What is prob of picking 2 d, 1 g, and 1 l?
1/35
Calculate prob of picking 1 e and 1 j when two letters picked without replacement from ejhvgheghh.
2/45
Two letters picked without replacement from gcpxxiixncgncc. Give prob of picking 1 i and 1 n.
4/91
What is prob of picking 1 j and 1 p when two letters picked without replacement from pppj?
1/2
What is prob of picking 1 w and 1 e when two letters picked without replacement from {z: 2, b: 1, w: 2, e: 1, t: 1}?
2/21
What is prob of picking 1 e and 1 p when two letters picked without replacement from {e: 4, j: 1, p: 9}?
36/91
Two letters picked without replacement from {j: 1, o: 1, c: 2, k: 1}. What is prob of picking 2 c?
1/10
What is prob of picking 2 u and 2 k when four letters picked without replacement from {s: 4, k: 2, c: 9, u: 3}?
1/1020
Three letters picked without replacement from ttvtvsvvvvvlttsttt. Give prob of picking 1 t, 1 s, and 1 l.
1/51
Three letters picked without replacement from nnnnnnn. What is prob of picking 3 n?
1
What is prob of picking 1 f and 2 p when three letters picked without replacement from {p: 7, s: 1, f: 6}?
9/26
Three letters picked without replacement from ooooaoooaoooooooooo. Give prob of picking 1 o and 2 a.
1/57
What is prob of picking 1 p, 1 q, and 2 i when four letters picked without replacement from poooqipqoooiqipoqoio?
24/1615
Four letters picked without replacement from zszeizeszsczsise. What is prob of picking 2 z and 2 s?
5/91
What is prob of picking 2 r when two letters picked without replacement from {r: 11, t: 5}?
11/24
Three letters picked without replacement from xxxxvvxvxvxxxxxvxx. Give prob of picking 1 x and 2 v.
65/408
Two letters picked without replacement from {h: 5, w: 3}. What is prob of picking 2 h?
5/14
Four letters picked without replacement from kkkzkykykuzkkuyzzkk. What is prob of picking 2 u, 1 z, and 1 y?
1/323
Two letters picked without replacement from {b: 6}. What is prob of picking 2 b?
1
Two letters picked without replacement from {c: 1, g: 2, l: 1, f: 1}. Give prob of picking 1 c and 1 g.
1/5
Four letters picked without replacement from tedtyetete. What is prob of picking 1 t and 3 e?
8/105
Calculate prob of picking 1 q and 1 f when two letters picked without replacement from {q: 3, t: 6, v: 1, f: 2, p: 2}.
6/91
Three letters picked without replacement from {y: 4, m: 1, n: 1, r: 2}. Give prob of picking 1 r, 1 y, and 1 m.
1/7
What is prob of picking 3 c when three letters picked without replacement from {h: 6, c: 7}?
35/286
What is prob of picking 2 c and 1 n when three letters picked without replacement from {n: 5, c: 2}?
1/7
Two letters picked without replacement from qqzqz. Give prob of picking 1 q and 1 z.
3/5
What is prob of picking 3 c when three letters picked without replacement from fcfffccfcf?
1/30
Three letters picked without replacement from waaiawswswggwaww. Give prob of picking 1 i and 2 w.
3/80
Three letters picked without replacement from hxjqxxxqijhdqih. Give prob of picking 1 q, 1 x, and 1 h.
36/455
Four letters picked without replacement from iiycccz. What is prob of picking 2 z, 1 i, and 1 y?
0
Calculate prob of picking 1 o and 1 z when two letters picked without replacement from {o: 1, v: 2, z: 1}.
1/6
Four letters picked without replacement from {m: 3, r: 2, t: 4,


Q:

PostgreSQL: Restoring 1 file from a directory format dump

I've got a large'ish (> 700GB) PostgreSQL database.  I'm working on importing it into AWS RDS.  I realize there are modules that will cause problems, we're dealing with that separately, so for right now, I am just working on migrating the data to RDS.
I'm migrating to and from PostgreSQL 9.4.5 using pg_dump and pg_restore 9.4.5.
Several hours into the transfer (pg_dump to pg_restore with a directory format), I checked the log and realized there is one thing (possibly a table?) owned by the Postgres user I was unaware of.
I found the line in the toc.dat file that made the call and unpacked the .dat.gz file to find it only contains "\." (sans the quotes) in it.
So, my question is, short of stopping the transfer and starting over, is there a way to simply transfer that specific command and file once the import is completed?
Here are the relevant details.
The pg_dump command:
pg_dump -h localhost -p 5432 -d DBNAME -U USERNAME -F d -f /mnt/backup -j 7

The pg_restore command:
pg_restore --dbname=DBNAME --no-tablespaces --host=HOSTNAME --port=5432 --username=USERNAME --verbose -F d -j 6 /mnt/backup

The section from the toc.dat file.  I realize the directory format outputs in binary format, but I am hoping that the fact that this is identifiable means there is a way to go back and fix that one error.
^@^F^@^@^@public^A^A^@^@^@^@^H^@^@^@postgres^@^E^@^@^@false^@^C^@^@^@173^A^A^@^@^@^@    ^@^@^@10393.dat^@W<^@^@^@^A^@^@^@^@^A^@^@^@0^@^E^@^@^@26106^@^N^@^@^@search_name_66^@
^@^@^@TABLE DATA^@^C^@^@^@^@^@^@^@^@^@^@^@^@^@^@]^@^@^@COPY search_name_66 (place_id, search_rank, address_rank, name_vector, centroid) FROM stdin;

The actual error reported by pg_restore:
pg_restore: [archiver (db)] Error from TOC entry 10393; 0 16787 TABLE DATA spatial_ref_sys postgres

A:

I found the line in the toc.dat file that made the call and unpacked
  the .dat.gz file to find it only contains "\." (sans the quotes) in
  it.

\. is not a command, it marks the end of data in a COPY stream.
If the corresponding data file inside the dump contains only that, then the source table was empty.
Also note that you can pg_restore --list to list the contents of a dump in directory or compressed format.
You may also restore the contents of an individual table into an SQL file rather than in the target database, then modify that file as convenient, and play it into the target. See the pg_restore manpage for more.


Q:

Invariant Violation: requireNativeComponent: "FastImageView" was not found in the UIManager in react native

When I'm writting this code error is showing please let me know, Where i'm worng?
import React, { Component } from 'react';
    import {
      StyleSheet,
      Text,
      View,
      TouchableOpacity,
      FlatList,
      Modal,
    } from 'react-native';
import FastImage from 'react-native-fast-image'

const Imagegallery = () => (
    <FastImage
        style={{ width: 200, height: 200 }}
        source={{
            uri: 'https://unsplash.it/400/400?image=1',
            priority: FastImage.priority.normal,
        }}
        resizeMode={FastImage.resizeMode.contain}
    />
)

export default Imagegallery

A:

After installing react-native-fast-image you have to run pod command in you ios directory.
So run this command :

cd ios
  pod install

Then run your project.


Cherry Christmas!

Yesterday was the first day of my planned twoish weeks off from work! I hope many of you also have the chance to take time off from work and breath a little.

The manicure I'm showing today is both part of Nail Art Sunday where the theme is wishlist and is my third dotticure for the Nail Challenge Collaborative.

As for my wishlist, I usually wish for a few things that I for one or another reason have not bought for myself. Lately I would rarely wish for polish, I feel like it makes more sense for me to buy it for myself rather than explicitly asking my family to visit some bigcartel or etsy shop for me. Nothing too exciting is on my list this year and I primarily want to have a good time enjoying the holidays. I hope my manicure in some way can convey that ^-^. I wanted to do cherries and found a lovely manicure by Top Coat It which I used as my inspiration.

My base polish is Pahlish An Caisteal Ruadh, I'm wearing three coats of it for maximum depth and colour. Pahlish has really grown to be one of my favourite brands (if not the favourite brand) this year. I love almost everything Shannon releases, the combination of shimmer and almost-glitter in a jelly base is really a recipe for success. The only thing I don't like is the speed at which her shop updates! Why is the summer and fall collections are already retired? For an international buyer who pay more for shipping than for the polish itself, being able to order my favourites of the last couple of collections would be preferable.

Polishes used: Pahlish An Caisteal Ruadh, China Glaze Cranberry Splash, Handy stamping polish in Tangerine, Handy stamping polish in Intensity and white acrylic paint. (I did not stamp with the stamping polishes, just used them for their great opacity!)


using Microsoft.Extensions.ObjectPool;
using Microsoft.Extensions.Options;
using RabbitMQ.Client;

namespace Ray.EventBus.RabbitMQ
{
    public class RabbitMQClient : IRabbitMQClient
    {
        private readonly ConnectionFactory connectionFactory;
        private readonly RabbitOptions options;
        private readonly DefaultObjectPool<ModelWrapper> pool;

        public RabbitMQClient(IOptions<RabbitOptions> config)
        {
            this.options = config.Value;
            this.connectionFactory = new ConnectionFactory
            {
                UserName = this.options.UserName,
                Password = this.options.Password,
                VirtualHost = this.options.VirtualHost,
                AutomaticRecoveryEnabled = false
            };
            this.pool = new DefaultObjectPool<ModelWrapper>(new ModelPooledObjectPolicy(this.connectionFactory, this.options));
        }

        public ModelWrapper PullModel()
        {
            var result = this.pool.Get();
            if (result.Pool is null)
            {
                result.Pool = this.pool;
            }

            return result;
        }
    }
}


1. Field of the Invention
This invention generally relates to brassieres and, more particularly, to sports brassieres intended to stabilize a wearer's breasts during athletic activities.
2. Description of the Related Art
Sports brassieres intended to restrain a wearer's breasts during vigorous bodily movements are typically so-called "pullovers" made of a stretchable, elastic fabric. In order to stabilize the breasts against excessive bounce and sway during athletic activities, such brassieres tend to be tight-fitting and, hence, such brassieres tend to tightly bind and flatten the breasts in a band-like manner. Due to the tight fight, such brassieres are somewhat awkward to pull over one's head.
In any event, many wearers find such tight-fitting pullovers or sports tops uncomfortable, because they tend to interfere with certain body movements and to restrict easy breathing. Also, since such pullovers are not adjustable, except for the stretchability of the fabric itself, they are not satisfactory for those users whose breasts are normally not of the same size, or whose breasts tend to grow in size due to physiological reasons.
In addition, many wearers, after performing an athletic activity, would like to relax and breathe more easily, but are prevented from doing so by the tight-fitting pullover. Unless the athletic woman is prepared to go about with unbound breasts, she must change brassieres which, in some cases, may not be feasible.


Evaluating BLS' Pharmaceutical Price Indexes and Impact on CMS' Rx Cost Forecasts The U.S. Bureau of Labor Statistics publishes a monthly Consumer Price Index for Prescription Drugs (CPI-Rx) designed to cover the sum of out-of-pocket costs to consumers plus third party payments to a pharmacy for a representative prescription, and a Producer Price Index for Pharmaceuticals for Human Use - Prescription (PPI-Rx) that measures changes over time in the average selling prices received by domestic manufacturers of prescription pharmaceuticals, excluding imports from other countries and Puerto Rico. The proposed research examines CPI-Rx and PPI-Rx sampling procedures, and the ability of these indexes to track average price changes as brands face generic entry, and an ever smaller share of prescriptions is paid for by cash (uninsured) transactions. Measuring pharmaceutical prices is challenging, in part because when the brand's patents expire, generic manufacturers enter, and as price competition intensifies, prices tend to drop dramatically. Almost 80% of prescriptions are currently dispensed as generics. Legal and regulatory developments in the last decade have complicated price index measurement as generic entry is often constrained in the six months immediately following patent expiration, but is followed by massive generic entry and heightened price competition. We examine whether these price measures are biased upwards. Implementation of Medicare Part D in 2006 increased access and utilization of medicines by seniors and made the federal government a more central payer for prescription drugs. Given the large government role as purchaser, any price mismeasurement has potentially significant consequences for public sector budgeting. An upwards biased CPI-Rx may have contributed to CMS' original and recent overprojections of Medicare Part D spending, since the CPI-Rx serves as an input into CMS's budget projections. In collaboration with economists at the U.S. Bureau of Labor Statistics, we propose to compare BLS' CPI-Rx and PPI-Rx sample composition with data from a much larger set of pharmaceutical transactions tracked by IMS Health's National Prescription Audit (data from about 38,000 pharmacies and 120 mail order firms) and National Sales Perspective (1.5 billion annual transactions involving a large number of manufacturers and wholesalers). Initial research suggests the BLS is relying ever more heavily on price quotes from diminishing cash (uninsured) transactions, whose rates of price growth may differ from insured transactions prices. Price growth of domestically available prescription drugs likely differs from that of drugs manufactured domestically, due to increased importation of low cost generics. We will examine BLS' procedures, compute average price changes under various simulated procedures, compare price index growth using alternative data sources, consider implications for CMS' spending projections, and work with the BLS in examining how these procedures could be revised, augmented or improved.


FROM ubuntu

# Update the apt repository
RUN apt update

# Install dependencies
RUN apt-get update
RUN apt-get install -y build-essential file zsh git sudo ruby curl vim language-pack-en

# take an SSH key as a build argument
ARG PRIVATE_KEY
ARG PUBLIC_KEY

# Create a test user
RUN useradd -ms /bin/bash user && \
        echo "user ALL=(root) NOPASSWD:ALL" > /etc/sudoers.d/user && \
        chmod 0440 /etc/sudoers.d/user

USER user:user

WORKDIR /home/user
RUN touch .bash_profile
RUN mkdir -p .ssh
RUN echo "$PRIVATE_KEY" > .ssh/id_rsa
RUN echo "$PUBLIC_KEY" > .ssh/id_rsa.pub
RUN chmod 600 .ssh/id_rsa
RUN chmod 600 .ssh/id_rsa.pub
RUN ssh-keyscan github.com >> .ssh/known_hosts

RUN mkdir -p code

CMD ["/bin/bash"]


Arterial baroreflex dynamics in normotensive and spontaneously hypertensive rats.
To investigate dynamic or frequency-dependent characteristics of arterial baroreflex control of efferent sympathetic nerve activity in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), we assessed the transfer function from aortic pressure (AP) to renal sympathetic nerve activity (RSNA) using a "white-noise technique." In pentobarbital sodium-anesthetized rats, we recorded RSNA as the output, while AP was randomly perturbed to impose input pressure changes with broad frequencies. We calculated the transfer function from AP to RSNA over the frequency range of 0.01-5 Hz through the spectral analysis of the input and output. The results indicated that the gain, phase shift, and coherence of the transfer function for SHR and for WKY were similar and statistically indistinguishable. The gain was relatively constant below 0.05 Hz but increased steadily by fivefold as frequency increased in the frequency range of 0.05-0.8 Hz. The phase was out of phase where coherence was high. The coherence was high (greater than 0.5) in the frequency range of 0.04-0.8 and 1.00-1.03 Hz but was low in other frequencies. These results suggest that dynamic or frequency-dependent characteristics of arterial baroreflex control of RSNA were not altered in SHR as compared with WKY.


With FY08 complete, I want to discuss my priorities for the year ahead and share my thoughts about the key strategic topics that are on everybody's mind, including Windows, competition with Apple and Google, our software plus services strategy, and Yahoo.

I also have news about an organizational change and a transition in our Senior Leadership Team.

First, I want to thank you for your hard work and the dedication you showed during the past 12 months. FY08 was a milestone year. Our revenue jumped $9.3 billion to more than $60 billion. Operating profit grew 21 percent to $22.5 billion.

These outstanding numbers are the direct result of your commitment to the priorities I outlined last July. A lot has happened since then, but our fundamental strengths, challenges, and strategic goals remain largely the same. Therefore, my priorities are consistent with last year. In FY09 we must continue to:

By focusing on these five areas, we can continue to grow revenue, increase profit, and expand our market share. These priorities are also critical as we work to address key issues surrounding our business in the coming year:

 Windows: The success of Windows is our number one job. With SP1 and the work we've done with PC manufacturers and our software ecosystem, we've addressed device and application compatibility issues in Windows Vista. Now it's time to tell our story. In the weeks ahead, we'll launch a campaign to address any lingering doubts our customers may have about Windows Vista. And later this year, you'll see a more comprehensive effort to redefine the meaning and value of Windows for our customers.

We also have to drive developers to create rich applications for Windows. With Internet Explorer and Silverlight, we have great tools for creating applications that run everywhere. But we also need to make sure developers have the .NET skills to write unique Windows applications using Windows Presentation Foundation. To keep today's Windows applications alive, vibrant, and exciting, we need both--applications that run everywhere and rich client applications.

 Apple: In the competition between PCs and Macs, we outsell Apple 30-to-1. But there is no doubt that Apple is thriving. Why? Because they are good at providing an experience that is narrow but complete, while our commitment to choice often comes with some compromises to the end-to-end experience. Today, we're changing the way we work with hardware vendors to ensure that we can provide complete experiences with absolutely no compromises. We'll do the same with phones--providing choice as we work to create great end-to-end experiences.

 Business and enterprise: Our enterprise and server business has never been stronger--today we are on the verge of becoming the number one enterprise software company. We need to continue to push on all fronts--mail with Exchange, business intelligence with PerformancePoint, virtualization with Hyper-V, and databases with SQL Server. We have to drive our enterprise search capabilities, our unified communications solutions, and our collaboration technologies. And we must continue to compete against Linux in key workloads such as Web servers and high performance computing.

 Software plus services: Some people think software plus services is all about search. But it's really about changing the way software is written and deployed. The future is about having a platform in the cloud and delivering applications across PCs, phones, TVs, and other devices, at work and in the home. It's also about driving change in business models through advertising, subscriptions, and online transactions. Software plus services is a huge opportunity for us to deliver new value on the desktop and the server to all of our customers. This year at PDC, you'll hear more about our cloud platform initiatives and the next versions of our Live and Online technologies.

 Google: We continue to compete with Google on two fronts--in the enterprise, where we lead; and in search, where we trail. In search, our technology has come a long way in a very short time and it's an area where we'll continue to invest to be a market leader. Why? Because search is the key to unlocking the enormous market opportunities in advertising, and it is an area that is ripe for innovation. In the coming years, we'll make progress against Google in search first by upping the ante in R&D through organic innovation and strategic acquisitions. Second, we will out-innovate Google in key areas--we're already seeing this in our maps and news search. Third, we are going to reinvent the search category through user experience and business model innovation. We'll introduce new approaches that move beyond a white page with 10 blue links to provide customers with a customized view of their world. This is a long-term battle for our company--and it's one we'll continue to fight with persistence and tenacity.

 Yahoo: Related to Google and our search strategy are the discussions we had with Yahoo. I want to emphasize the point I've been making all along--Yahoo was a tactic, not a strategy. We want to accelerate our share of search queries and create a bigger pool of advertisers, and Yahoo would have helped us get there faster. But we will get there with or without Yahoo. We have the right people, we've made incredible progress in our technology, and we'll continue to make smart investments that will enable us to build an industry-leading business.

As I mentioned earlier, I have important organizational news. Today we are announcing that the Platforms and Services Division will be split into two businesses: Windows/Windows Live and Online Services. We are also announcing that Kevin Johnson will leave the company. He will work to ensure a smooth transition.

Since 1992, Kevin has been a key contributor to many of this company's most important achievements. As president of the Platforms and Services Division, Kevin has built an incredibly talented organization and laid the foundation for the future success of Windows and our Online Services Business. Over the last 16 years, through everything from his work as head of the company's worldwide sales, marketing, and services efforts, to his leadership in transforming our field operations and repositioning the company to focus on opportunities in emerging markets, Kevin has played a vital role in this company's success. There is no doubt that his passion and dedication will be missed.

Effective immediately, Steven Sinofsky, Jon DeVaan, and Bill Veghte will report directly to me to lead Windows/Windows Live. In the Online Services Business, we will create a new senior leadership position and conduct a search that will span internal and external candidates. In the meantime, Satya Nadella will continue to lead Microsoft's search, ad platform, and MSN engineering efforts, and Brian McAndrews will continue to lead the Advertiser and Publisher Solutions Group. Both Windows/Windows Live and the Online Services Business are led by a strong group of executives on the technical and business side who have the talent and experience to address the challenges we face and drive the next generation of growth and success.

Looking ahead, I see an incredibly bright future for our company. As I said at the June 27th Town Hall for Bill, we are the best in the world at doing software and nobody should be confused about this. It doesn't mean that we can't improve, but nobody is better than we are. Nobody works harder than we do. Nobody is more tenacious than we are. We're investing more broadly and more seriously than anybody else. Our opportunities to change the world have never been greater.

I look forward to working with all of you as we focus on our five priorities in FY09.


Get Connected!

MASNsports.com is your online home for the latest Orioles and Nationals
news, features, and commentary. And now, you can connect with MASN on
every digital level. From web and social media to our new mobile alert service,
MASN has got all the bases covered.

Stephen Strasburg's Historic Debut Added to Nationals Classics

MASN, the television home of the Washington Nationals, will add Stephen Strasburg's historic debut as a Nationals Classic starting this week. The network will re-air the game on Wednesday, July 14th and Sunday, July 18th, both at 7:00 p.m. on MASN and MASN HD.

This special production includes a new introduction from Johnny Holliday and Ray Knight.

In front of a national audience and a sold-out crowd at Nationals Park, Strasburg dominated the Pittsburgh Pirates on June 8th and set a new Nationals record for most strikeouts (14) in one game. To date, Stephen Strasburg is 3-2 with a 2.32 ERA and 61 strikeouts.

With every available Nationals game live and in high definition, an All Star talent team and Nats Xtra before and after every game, MASN provides maximum access to the Washington Nationals. MASN is currently carried on 23 cable and satellite providers throughout a seven-state region.


Q:

How can I remove a stuck liquor decanter stopper?

I had a decanter half full of vodka that has sat in my basement for about a year unused. Now the stopper is stuck on the decanter. How can I get the stopper off to get the sweet sweet vodka out for consumption?

A:

I would recommend not immersing the decanter entirely, but placing it up to the neck in hot water.  This will expand the glass of the decanter slightly, but not the stopper.  That might be enough to let you coax it out.
The shape of your stopper is also convenient for making a little noose for it out of cord/thin rope, to allow you to get some extra purchase on it, to help you prise it out.  So you could hang the decanter and stopper from a beam or similar, and use your weight to pull down on it.  On reflection, and in light of Doug's comment, I'm not convinced this is great advice and should be followed only with serious consideration of the effect on you and the decanter, should the stopper rapidly become unstuck!
As Wayfaring Stranger said, a gentle tap around the sides should help, but be VERY careful not to break the glass, or scratch it. Something not too heavy would be best, and plastic or wooden would avoid scratching - or cover a small hammer with a cloth.


São Julião Lighthouse

The São Julião Lighthouse is located in the fort of the same name, which is the largest sea defence structure in Portugal and is situated on a headland on the north bank of the River Tagus estuary in Oeiras, Lisbon District. It is a square masonry tower and the lantern is painted white, with a red dome.

History
The fort of São Julião da Barra was constructed primarily for defence and follows an irregular pentagonal design. Today it is the national headquarters of the Ministry of National Defence and official residence of the Minister. In 1758 orders were given to build a lighthouse in the fort. However, it is possible that an earlier lighthouse had existed from 1553 but that it was destroyed by the 1755 Lisbon earthquake.
The work initially involved building a stone lantern in 1761 but in 1775 an Argand lamp with a parabolic reflector was installed. Between 1848 and 1865 modernization work was carried out and a 4th Order Fresnel lens was installed, producing a fixed white light, fuelled with gas distilled from wood. From 1880 the lighting was obtained from petroleum gas. The lighthouse underwent further repairs in 1893 and 1913. A foghorn was installed in 1916 but almost immediately thereafter operations ceased until 1918 because of the First World War.

In 1933 a red lamp was installed and, at the same time, the lighthouse was connected to the electricity grid. Integrated in the telecontrol network of the approaches of the port of Lisbon, it was automated in 1980, and became remotely controlled. Together with the Bugio lighthouse it marks the entrance or exit of the Lisbon Bar, the Bugio light being green. The São Julião lighthouse is 24 metres tall, with an altitude of 39 metres.

See also

 List of lighthouses in Portugal

References

External links

Category:Lighthouses in Portugal
Category:Buildings and structures in Oeiras


Rate & Review Product

Separate objects and textures for clouds, land, ocean, city lights and atmosphere to allow for compositing and/or fine tuning. Atmosphere and ocean are procedural textures, so maya is recommended but obj's with textures are also included for the other objects. All textures are 4k.

Thumbnails are straight mental ray renders with no compositing and no adjustment of lights or textures between render shots.


A study of X chromosome linkage with field dependence and spatial visualization.
The purposes of this report are to describe a design for the study of X linkage, to illustrate its application using cognitive test scores, and to offer a linkage hypothesis suggested by these data. Sixty-seven three-son families were examined for two X chromosome marker variables--red-green color vision and Xg(a) blood groups--and given a battery of cognitive tests of field dependence and spatial visualization abilities. Evidence was found to suggest that brothers who are identical in Xg(a) phenotype are more similar to each other in extent of field dependence than brothers who are different in Xg(a) phenotype. This result is tentative because of the small number of informative cases and the many linkage associations examined. If cross-validated, such a finding would be consistent with the proposition that an X chromosome gene contributes to the field dependence cognitive style.