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.

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.

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.

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.

Distinct reactions catalyzed by bacterial and yeast trans-aconitate methyltransferases.

The trans-aconitate methyltransferase from the bacterium Escherichia coli catalyzes the monomethyl esterification of trans-aconitate and related compounds. Using two-dimensional (1)H/(13)C nuclear magnetic resonance spectroscopy, we show that the methylation is specific to one of the three carboxyl groups and further demonstrate that the product is the 6-methyl ester of trans-aconitate (E-3-carboxy-2-pentenedioate 6-methyl ester). A similar enzymatic activity is present in the yeast Saccharomyces cerevisiae. Although we find that yeast trans-aconitate methyltransferase also catalyzes the monomethyl esterification of trans-aconitate, we identify that the methylation product of yeast is the 5-methyl ester (E-3-carboxyl-2-pentenedioate 5-methyl ester). The difference in the reaction catalyzed by the two enzymes may explain why a close homologue of the E. coli methyltransferase gene is not found in the yeast genome and furthermore suggests that these two enzymes may play distinct roles. However, we demonstrate here that the conversion of trans-aconitate to each of these products can mitigate its inhibitory effect on aconitase, a key enzyme of the citric acid cycle, suggesting that these methyltransferases may achieve the same physiological function with distinct chemistries.

Preparation of 4'-substituted thymidines by substitution of the thymidine 5'-esters.

tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. When the lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping occurs stereoselectively from either the alpha- or beta-face depending on the electrophile (Scheme 1). Deuterioacetic acid in deuteriomethanol affords mainly the alpha-deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenyl chloride, allyl bromide, and N-fluorobenzenesulfonimide (NFSI), give predominately (or completely) the products of attack from the beta-face (5bcd/4bcd = 3.7:1 to 100:0). The structures of the products were determined by coupling constant analysis of both the initial compounds and the diols 6bcd prepared by ester reduction and by formation of the acetonides 7bc. The methyl ester of the 3'-epimer of thymidylic acid 9 was also prepared from thymidine 1 in nine steps and 74% overall yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attack on either the alpha- or beta-face depending on the electrophile (Scheme 2). Again, deuterioacetic acid in deuteriomethanol affords mainly the beta-deuterated product (11a/10a = 1.6:1) while all other electrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gave predominately (or completely) the product of attack from the alpha-face (8.7:1 to 100: 0). Again, the structures of the products were determined by coupling constant analysis of both the initial compounds, and the diols 12b-e were prepared by reduction of the ester and by formation of the acetonides 13bcd. A rationale has been developed using molecular mechanics calculations to explain the diastereoselectivity that involves staggered axial attack on the sp(2) carbon opposite to the pseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown in Schemes 3-5.

Origins of stereoselectivity in intramolecular Diels-Alder cycloadditions of dienes and dienophiles linked by ester and amide tethers.

B3LYP/6-31+G(d) calculations of structures and relative energies for competing transition states for intramolecular Diels-Alder reactions of substituted 3,5-hexadienyl acrylates and acrylamides show that boatlike conformations are sometimes favored in the forming ring that includes the tether.

Use of negatively reinforcing electrical brain stimulation to detect conventional and nonconventional anxiolytics as well as an anxiogenic drug.

The present study determined whether anxiolytics such as diazepam (DZP), the benzodiazepine (BZD) receptor-selective agonist abecarnil (ABC), or the 5-HT1(A) agent buspirone (BUS) would increase the response latency of rats to switch-off electrical brain stimulation (EBS) of the periaqueductal gray (PAG). We also investigated the effects of pentylenetetrazole (PTZ), a purported anxiogenic. Given acutely, DZP (2.5 and 5 mg/kg, ip) and ABC (0.5 and 1 mg/kg, ip) increased response latency. The BZD receptor antagonist flumazenil (10.0 mg/kg, ip) blocked these effects. Increasing the frequency of EBS reversed the effects of DZP and ABC, suggesting that motor disruption did not account for the increase in latency seen with these drugs. Given acutely, BUS (10.0 mg/kg, ip) also increased response latency, which was likely due to motor disruption because it was not reversed by increasing the frequency of EBS. When BUS (2.5 mg/kg, ip) was given every 8 h for 3 days, an increase in latency was also obtained, which was reversible by increasing the frequency of EBS. Finally, PTZ (10 and 20 mg/kg, ip) shortened the latency to respond. These results (1) suggest that DZP, ABC, and chronic BUS attenuate, whereas PTZ potentiates, the negative reinforcing stimulus (NRS) induced by PAG stimulation, and (2) support the hypothesis that the switch-off procedure accurately detects anxiolytic and anxiogenic drugs.

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.

Preparation of various C-2 branched carbohydrates using intramolecular radical reactions.

A new and efficient method for the facile synthesis of C-2 branched carbohydrates has been developed using an intramolecular radical cyclization fragmentation reaction. The desired C-2 branched glucopyranosides were isolated in 40-84% yield. Additionally, an unexpected furanoside was obtained from a tributyltin iodide-promoted rearrangement of the radical intermediate. The C-2 formyl glycal was also isolated in good yield using tris(trimethylsilyl)silane (TTMSS) as the reducing agent. This method was extended to synthesize a beta C-2 branched glucopyranoside, a C-2 branched galactoside and a C-2 cyano glucopyranoside.

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.

Abecarnil and alprazolam reverse anxiety-like behaviors induced by ethanol withdrawal.

This study investigated the effects of a benzodiazepine partial agonist, abecarnil, and a full agonist, alprazolam, on ethanol withdrawal-induced anxiety-like behaviors in rats. Anxiety was assessed in two models: elevated plus maze and pentylenetetrazol (GABA(A) antagonist) discrimination assay. Male rats received an ethanol-containing (4.5%) liquid diet for 7 to 10 days and were tested for withdrawal symptoms 12 h after termination of the diet. In the elevated plus maze, ethanol-withdrawn rats displayed less open arm activity and total arm entries than pair-fed rats. Abecarnil (0.08-0.32 mg/kg, IP) and alprazolam (0.08-1.25 mg/kg, IP) each produced a dose-dependent, full reversal of ethanol withdrawal-induced reduction of open arm activity, but only alprazolam increased the total arm entries. In the pentylenetetrazol assay, ethanol-withdrawn rats selected the pentylenetetrazol lever (100%) over the salin-lever. Abecarnil (0.04-0.32 mg/kg, IP) and alprazolam (0.08-0.32 mg/kg, IP) dose dependently reduced pentylenetetrazol-lever responding to control levels (10-20%). Alprazolam was more potent than abecarnil in reversing ethanol withdrawal-induced decrease in open arm activities, but showed comparable potency and efficacy to abecarnil in blocking the pentylenetetrazol-like ethanol withdrawal stimulus. These results suggest that abecarnil and alprazolam may have therapeutic potential for treatment of ethanol withdrawal-induced anxiety-like symptoms.

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.

Efficient synthesis of carbocyclic nucleoside, (+/-)-homocarbovir via pi-allylpalladium complex formation from the allyl-N,N-ditosylimide substrate.

The synthesis of a carbovir analogue, (+/-)-homocarbovir (3) was achieved from norbornadiene (4) in seven steps and 27% overall yield. This route involves a Meinwald-type rearrangement, an acid-hydrolysis of N-tosyl bicyclic enamine 5, and a Pd(0)-catalyzed coupling reaction.

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.