Cardiorespiratory fitness and accelerometer-determined physical activity following one year of free-living high-intensity interval training and moderate-intensity continuous training: a randomized trial.

BACKGROUND: Free-living adherence to high-intensity interval training (HIIT) has not been adequately tested. This randomized trial examined changes in cardiorespiratory fitness (CRF) and accelerometer-measured purposeful physical activity over 12 months of free-living HIIT versus moderate-intensity continuous training (MICT). METHODS: Ninety-nine previously low-active participants with overweight/obesity were randomly assigned to HIIT (n = 47) or MICT (n = 52). Both interventions were combined with evidence-based behaviour change counselling consisting of 7 sessions over 2 weeks. Individuals in HIIT were prescribed 10 X 1-min interval-based exercise 3 times per week (totalling 75 min) whereas individuals in MICT were prescribed 150 min of steady-state exercise per week (50 mins 3 times per week). Using a maximal cycling test to exhaustion with expired gas analyses, CRF was assessed at baseline and after 6 and 12 months of free-living exercise. Moderate-to-vigorous physical activity of 10+ minutes (MVPA10+) was assessed by 7-day accelerometry at baseline, 3, 6, 9, and 12 months. Intention to treat analyses were conducted using linear mixed models. RESULTS: CRF was improved over the 12 months relative to baseline in both HIIT (+ 0.15 l/min, 95% CI 0.08 to 0.23) and MICT (+ 0.11 l/min, 95% CI 0.05 to 0.18). Both groups improved 12-month MVPA10+ above baseline (HIIT: + 36 min/week, 95% CI 17 to 54; MICT: + 69 min/week, 95% CI 49 to 89) with the increase being greater (by 33 min, 95% CI 6 to 60) in MICT (between group difference, P = 0.018). CONCLUSION: Despite being prescribed twice as many minutes of exercise and accumulating significantly more purposeful exercise, CRF improvements were similar across 12 months of free-living HIIT and MICT in previously low-active individuals with overweight/obesity.

Prediction of adherence to a gluten-free diet using protection motivation theory among adults with coeliac disease.

BACKGROUND: Coeliac disease is a chronic autoimmune disease that requires strict adherence to a gluten-free diet. However, strict adherence to a gluten-free diet is difficult, with findings from a recent review suggesting that up to 42% of individuals with coeliac disease do not eat a strict gluten-free diet. METHODS: The present study aimed to examine psychosocial predictors of adherence (purposeful and accidental) to a gluten-free diet among adults with coeliac disease over a 1-month period. In this longitudinal study, 212 North American adults with coeliac disease completed online questionnaires at two time points, baseline and 1 month later. RESULTS: The results revealed that intentions partially mediated the effects of symptom severity, self-regulatory efficacy, planning and knowledge on purposeful gluten consumption. Intentions did not mediate the effects of severity, response cost, self-regulatory efficacy, planning and knowledge for accidental gluten consumption but, interestingly, self-regulatory efficacy directly predicted fewer accidental incidents of gluten-consumption. CONCLUSIONS: These findings delineate the differential psychological processes in understanding accidental and purposeful gluten consumption among adults with coeliac disease and emphasise the importance of bolstering self-regulatory efficacy beliefs to prevent accidental and purposeful consumption of gluten.

Motives for adherence to a gluten-free diet: a qualitative investigation involving adults with coeliac disease.

BACKGROUND: Currently , the only treatment for coeliac disease is life long adherence to a strict gluten-free diet. Strict adherence to a gluten-free diet is challenging, with recent reports suggesting that adherence rates range from 42% to 91%. The present study aimed to: (i) identify motives for adhering to a gluten-free diet and (ii) explore factors implicated in adherence and non-adherence behaviour in terms of accidental and purposeful gluten consumption among adults with coeliac disease. METHODS: Two hundred and three adults with coeliac disease completed an online questionnaire. Using a qualitative design, relationships were examined between reported adherence and motivation to follow a gluten-free diet, as well as the onset, duration and severity of symptoms. RESULTS: Feelings of desperation ('hitting rock bottom') and needing to gain or lose weight were associated with the strictest adherence to a gluten-free diet. Participants who accidentally consumed gluten over the past week developed symptoms the most quickly and reported the most pain over the past 6 months. Participants who consumed gluten on purpose over the past week reported a shorter duration of symptoms and less pain over the past 6 months. CONCLUSIONS: Hitting rock bottom and needing to gain or lose weight were factors associated with the strictest adherence, when considered in the context of both accidental and purposeful gluten consumption. Future research is warranted to develop resources to help people with coeliac disease follow a strict gluten-free diet.

Recent advances towards new anti-infective agents that inhibit cell surface protein anchoring in Staphylococcus aureus and other gram-positive pathogens.

Sortase enzymes are attractive targets for the development of new anti-infective agents against Gram-positive pathogens because they covalently anchor virulence factors to the cell wall. Here we review what is known about the mechanism of sortase mediated protein anchoring and discuss recently identified inhibitors of this new important enzyme family.

Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms.

Ethanol withdrawal (EW) produces substantial neurotoxic effects, whereas estrogen is neuroprotective. Given observations that both human and nonhuman female subjects often show less impairment following EW, it is reasonable to hypothesize that estrogens may protect females from the neurotoxic effects of ethanol. This article is based on the assumption that the behavioral deficits seen following EW are produced in part by neuronal death triggered by oxidative insults produced by EW. The EW leads to activation of protein kinase C, especially PKCepsilon, which subsequently triggers apoptotic downstream events such as phosphorylation of nuclear factor-kappaB (NFkappaB) complex. On phosphorylation, active NFkappaB translocates to the nucleus, binds to DNA, and activates caspases, which trigger DNA fragmentation and apoptosis. In contrast, estrogens are antioxidant, inhibit overexpression of PKCepsilon, and suppress expression of NFkappaB and caspases. Estrogen treatment reduces the behavioral deficits seen during EW and attenuates molecular signals of apoptosis. The effects of ethanol and estrogen on each step in the signaling cascade from ethanol exposure to apoptosis are reviewed, and potential mechanisms by which estrogen could produce neuronal protection against the neurotoxicity produced by EW are identified. These studies serve as a guide for continuing research into the mechanisms of the neuroprotective effects of estrogen during EW and for the development of potential estrogen-based treatments for male and female alcoholics.

Glycosylation of fluoroquinolones through direct and oxygenated polymethylene linkages as a sugar-mediated active transport system for antimicrobials.

We report herein the synthesis and biological testing of several glycosylated derivatives of some fluoroquinolone antibiotics. In particular, we have prepared several glycosylated derivatives of ciprofloxacin (2) in which the carbohydrate units are linked to the free secondary amine of the piperazine unit by: (a) no linker (e.g., a glycosylamine), (b) a beta-oxyethyl linker, and (c) a gamma-oxypropyl linker. Both glucose and galactose were used as carbohydrates so that six compounds of this type were prepared, e.g., no linker 4a,b, oxyethyl linker 5a,b, and oxypropyl linker 6a,b. In addition the aryl glycosides of glucose and galactose (7a,b) were prepared from the active 1-(4-hydroxyphenyl)fluoroquinolone (3.) The syntheses of the glycosylamines 4a,b involved the direct condensation of glucose and galactose with the hydrochloride salt of ciprofloxacin (2). For the oxyalkyl-linked compounds, we first prepared the peracetylated omega-bromoalkyl glycopyranosides 14a,b and 15a,b and then coupled them to the allyl ester of ciprofloxacin (11) to give, after saponification to remove all of the esters, the desired fluoroquinolone carbohydrates 5a,b and 6a,b. The final series was prepared from 2,4,5-trifluorobenzoyl chloride (22) which gave 3 in four precedented steps. Coupling of 3 with the peracetylated glucosyl and galactosyl halides 12a,b and 26 afforded, after saponification, the desired aryl glycosides 7a,b. Six of these derivatives of ciprofloxacin-4a,b, 5a,b, and 6a,b-were subjected to microbiological screening. Of the six, compound 6a showed the highest activity. Since 6a would give the hydroxypropyl-substituted ciprofloxacin on hydrolysis and its activity is approximately 4-8 times less than that of ciprofloxacin (2), this implies that compound 6a is probably being actively transported. Thus preliminary results suggest that some of the compounds are stable in culture conditions and may be differentially transported by multiple resistant organisms. In some cases, the addition of a linker and a carbohydrate to ciprofloxacin lessens, but does not eliminate, antimicrobial activity.

Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal.

RATIONALE: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. OBJECTIVES: This study examined sex differences in the anxiogenic stimuli induced by a serotonin (5-HT)(1b,2) agonist, meta-chlorophenylpiperazine (mCPP), prior to ethanol and during EW. METHODS: Gonadectomized or sham-operated adult male and female rats and 17beta-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0-1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. RESULTS: Fewer sham female and beta-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and beta-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. CONCLUSIONS: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and beta-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.

Sex differences in nicotine substitution to a pentylenetetrazol discriminative stimulus during ethanol withdrawal in rats.

RATIONALE: Nicotine and ethanol are frequently co-abused in men and women, but few studies compare common stimulus effects produced by these substances between males and females. OBJECTIVES: This study compared the anxiety-like behavior induced by nicotine prior to and during ethanol withdrawal in intact male, sham-operated female, and ovariectomized (OVX) rats. METHODS: Using an animal model of anxiety, the pentylenetetrazol (PTZ) drug-discrimination assay, rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline and were subjected to the following tests: (1) PTZ-lever selection at 12 h after termination of ethanol diet (4.5% for 10 days); (2) dose-response tests for nicotine (0.08-1.3 mg/kg) prior to ethanol and 1.5, 6, and 7 days after ethanol withdrawal. RESULTS: (1) During acute ethanol withdrawal (12 h), more male rats (43.4%) responded on the PTZ lever than OVX (29%) or sham female (15.3%) rats. (2) For nicotine dose-response tests, more male rats (70%) selected the PTZ lever than OVX (37.5%) or sham female (50%) rats prior to ethanol. At 1.5 days, nicotine fully generalized to the PTZ stimulus in male (100%) and OVX (90%), but only partially in sham female (50%) rats. At 6 days and 7 days after ethanol withdrawal, the PTZ-lever selection decreased, but more male rats (78%) tended to respond on a PTZ lever than OVX (63.6%) or sham female rats (62.5%). CONCLUSIONS: Acute nicotine produces anxiety-like behavior similar to that of PTZ in male and female rats, and this effect of nicotine is intensified during ethanol withdrawal in male and OVX rats, but not in sham female rats.

Conclusive evidence of the trapping of primary ozonides.

[reaction: see text] Anomalous ozonolysis of strained bicyclic allylic alcohols yields alpha-hydroxymethyl ketones. The proposed mechanism involves an unusual trapping of the primary ozonide that undergoes a Grob-like fragmentation instead of dissociating into the Criegee intermediates.

The first reported anionic oxy retro-ene reaction.

Treatment of the diol 6 with KH and 18-C-6 at room temperature gives the cyclopentenone 7 in good yields. Mechanistic analysis reveals that this is the first case of an anionic oxy retro-ene reaction followed by a tandem intramolecular aldol condensation. Reaction: see text.

Enantioselective formal total synthesis of (-)-dysidiolide.

[reaction: see text] An enantioselective formal total synthesis of the sesterterpene (-)-dysidiolide 1 beginning with an intermolecular Diels-Alder reaction of the allene ester 3 and the silyloxydiene 10 is reported.

Synthesis of a fully functionalized protected C1-C11 fragment for the synthesis of the tedanolides.

[figure: see text] The use of several non-aldol aldol processes allows one to prepare a fully functionalized and completely protected C1-C11 fragment that should be useful for the total synthesis of the tedanolides.

Efficient synthesis of the C(1)-C(11) fragment of the tedanolides. The nonaldol aldol process in synthesis.

[reaction: see text] The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C(1)-C(11) fragment 22 of the novel macrocyclic cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into compound 22 using two nonaldol aldol reactions.

Use of optically active cyclic N,N-dialkyl aminals in asymmetric induction.

[reaction: see text]Cyclization of the optically active ketone N,N-dialkyl aminals A affords the diastereomer B as the major product with diastereoselectivities ranging from nearly 1:1 to essentially 100:0 depending on the cyclization studied.

Efficient synthesis of 2-deoxy L-ribose from L-arabinose: mechanistic information on the 1,2-acyloxy shift in alkyl radicals.

[formula: see text] Conversion of the inexpensive L-arabinose 1 into the ethylthio ortho ester 7 followed by generation of the dialkoxyalkyl radical III produces the desired 2-deoxy-L-ribose triester 4 in excellent overall yield. It has been shown that the similar dialkoxyalkyl radical IV is not an intermediate in the 1,2-acyloxy shift of anomeric radical I.

First total synthesis of xestobergsterol A and active structural analogues of the xestobergsterols.

[formula: see text] A novel pentacyclic polyhydroxylated sterol, xestobergsterol A (1a), has been synthesized in 24 steps and in good overall yield from stigmasterol 17. The key steps of the synthesis are the Breslow remote functionalization of the polyoxygenated steroid derived from 25 and the base-catalyzed epimerization-aldol condensation of the dione derived from 27.

Facile preparation of allenic hydroxyketones via rearrangement of propargylic alcohols.

[formula: see text] Treatment of tertiary propargylic alcohols 13 with 3-diazo-2-butanone 6 and catalytic dirhodium tetraacetate in benzene gave good yields of the diastereomeric allenic hydroxyketones 14, with, in some cases, good diastereocontrol. These products are presumably formed via the [2,3]-sigmatropic rearrangement of an alpha-propargyloxy enol derivative. This reaction has been extended to the preparation of homoallylic hydroxyketones from allylic alcohols by reaction with 6 and the rhodium catalyst.

Synthesis of four diastereomeric 3,5-dialkoxy-2,4-dimethylalkanals by a simple extension of the non-aldol aldol process to bis(propionates).

[formula: see text] The synthesis of all four diastereomers of bis(propionates), 3,5-dialkoxy-2,4-dimethylalkanals, by non-aldol aldol chemistry is described. The epoxy alcohols (3, 4) were converted into the mesylates (9, 11) which were cleanly rearranged to the desired 3,5-bis(oxygenated)-2,4-dimethylalkanals (10, 12) in high yield. The epoxy mesylates (13, 16) gave the desired products (14, 17) in good yield on treatment with TMSOTf and a hindered base.

Dopamine release during cocaine self-administration in rats: effect of SCH23390.

This experiment tested the hypotheses that: (1) self-administration of cocaine would produce an increase in dopamine (DA) oxidation current in the nucleus accumbens (n. acc.); and (2) a faster rate of cocaine intake in the presence of a D1 receptor antagonist would produce a greater increase in DA levels. Rats trained to self-administer cocaine under a fixed-ratio 2 schedule were implanted with stearate-modified graphite paste electrodes bilaterally in the n. acc. The effect of pretreatment with the D1 receptor antagonist, SCH23390, on the DA oxidation current associated with self-administration of cocaine (1 mg/inj.) or saline was investigated using chronoamperometry. Pretreatment with SCH23390 produced a 2-fold increase in the amount of cocaine intake. This in turn resulted in a 2-fold increase in the DA oxidation current recorded in the n. acc. Pretreatment with SCH23390 did not, however, produce any significant change in either the number of saline injections received or the DA oxidation current recorded during saline self-administration. These findings show that cocaine increases DA oxidation currents in the n. acc., and that both the rate of cocaine self-administration and the magnitude of these currents increase even further following SCH23390. The results also imply that the baseline rate of cocaine self-administration does not result in the occupation of all possible DA transporter sites.