Effect of anticholinergics on the overactive bladder and bowel domain of the electronic personal assessment questionnaire (ePAQ).

INTRODUCTION AND HYPOTHESIS: Evidence suggests that OAB (overactive bladder) can occur alongside disorders of the colon, such as irritable bowel syndrome (IBS). Moreover, patients with constipation are more likely to develop OAB symptoms than those without. Anticholinergic medications (AcH) are commonly used for treating OAB, and can result in the unwanted side effects of constipation. We aimed to study the relationship of AcH, and their effects on quality of life using the electronic Personal Assessment Questionnaire (ePAQ) by assessing changes in the bowel and bladder domains, pre- and post-AcH treatment. METHODS: Ninety patients completed the ePAQ pre- and post-AcH treatment from January 2011 to April 2014. Data were collected retrospectively and prospectively, and analysed using a paired t test. Effect size (ES) was calculated for OAB and bowel domains to quantify the effect on QoL. RESULTS: There was a significant improvement in the OAB (p = 0.0005) and bowel domains (p = 0.0005). In the bowel domains, the largest effect size was seen for IBS (0.5) followed by continence (0.4), evacuation (0.375) and a small ES was seen for constipation (0.2). There was a reduction in the "degree of bother" in OAB and bowel domains. CONCLUSIONS: Patients may benefit from the possible effects of AcH on their bowels, and assessment of all aspects of pelvic floor function is important before commencing AcH. This may help to counsel patients, with possibly improved compliance with therapy.

Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes?

AIM: Preoperative radiotherapy has been shown to improve local control in advanced rectal carcinoma compared with surgery alone. Several large randomized trials have confirmed that chemoradiotherapy (CRT) is better than radiotherapy alone. This pilot study was designed to increase the radiation dose using high-dose rate (HDR) brachytherapy boost following preoperative CRT to evaluate whether this strategy improves the outcome of surgery without increase in toxicity. METHOD: Since October 2004, we have used the new rectal HDR applicator for brachytherapy boost in 68 patients following CRT. The patients had CT and MRI Scans as part of staging. All had locally advanced disease either bulky low T2 or T3 with threatened circumferential resection margin and multiple suspicious lymph nodes. They were offered preoperative CRT either by 5-FU infusion 1 g/m(2) day 1-4 (week 1 + 5) or by oral capecitabine 825 mg/m(2) Monday-Friday for 5 weeks together with CT planned external beam RT 45Gy in 25 fractions over 5 weeks (CRT). Those downstage on repeat MRI scan were offered additional HDR Boost 10Gy directly to the tumour followed by surgery 6-8 weeks later [group A]. Four patients proceeded directly to surgery but because of involved resection margin had a HDR brachytherapy boost as postoperative treatment [group B]. Thirty patients were not planned for immediate surgery after CRT and brachytherapy boost, as they were either elderly or considered high risk for anaesthesia [group C]. RESULTS: There were 34 patients (median age 67 (range 39-81) years in group A, including 24 men). The PS was 0-1. The clinical stage at presentation was cT2 in five, cT3 in 23 and T4 in six patients and cN0 in 2, cN1 in 21 and N2 in 11. Thirty-three patients had CRT, and one had radiotherapy alone. All patients completed treatment without interruption. Twenty-nine patients had surgery following CRT and brachytherapy boost including anterior resection in 10 patients, Abdominoperineal excision (APR) in 18 and Hartmann's resection in one. Five patients did not have the intended surgery. Twenty-four (83%) patients had an RO resection compared with 63% having conventional preoperative CRT using bolus 5FU regimes. Pathological complete remission (pCR) was achieved in 9 (31%) compared with 12% patients having conventional CRT. There was no increase in G 3-4 toxicity from RT and no delay in wound healing or increase in anastomotic leakage. One of the four patients in group B developed local recurrence. The thirty patients in group C who had modified radical CRT followed by brachytherapy boost as a definitive treatment will be reported in a further communication. CONCLUSION: Increasing the dose of radiation by HDR brachytherapy boost appears to improve the RO resection and pCR rates compared with conventional CRT. The follow up is too short to judge its effect on disease-free survival. This study will be extended to compare this strategy in a randomized phase III trial with conventional CRT in patients who are not fit for more intensive CRT (HERCULES).

Drag force and surface roughness measurements on freshwater biofouled surfaces.

The detrimental effect of biofilms on skin friction for near wall flows is well known. The diatom genera Gomphonema and Tabellaria dominated the biofilm mat in the freshwater open channels of the Tarraleah Hydropower Scheme in Tasmania, Australia. A multi-faceted approach was adopted to investigate the drag penalty for biofouled 1.0 m x 0.6 m test plates which incorporated species identification, drag measurement in a recirculating water tunnel and surface characterisation using close-range photogrammetry. Increases in total drag coefficient of up to 99% were measured over clean surface values for biofouled test plates incubated under flow conditions in a hydropower canal. The effective roughness of the biofouled surfaces was found to be larger than the physical roughness; the additional energy dissipation was caused in part by the vibration of the biofilms in three-dimensions under flow conditions. The data indicate that there was a roughly linear relationship between the maximum peak-to-valley height of a biofilm and the total drag coefficient.

On the effect of pre-strain and pre-fatigue on the monotonic behaviour of ultra-high strength steels.

The mechanical behaviour of three ultra-high strength steels has been assessed; AerMet100, 300M and the recently developed corrosion resistant high strength steel, MLX-17. Material heat treatment profiles have been utilised to provide performance optimised for the aerospace industry and specimens have been tested to explore tensile and fatigue properties, in particular when combined with pre-strain to simulate the effects of overload. Testing of this kind has not been reported within the literature, particularly amongst ultra-high strength and corrosion-resistant steels. Baseline mechanical performance for all three materials in their heat-treated conditions has been established and properties such as yield strength and ultimate tensile strength have been assessed following a 75% and 95% pre-strain as well as fatigue in combination with a 75% and 95% pre-strain. Under all loading conditions, resultant tensile mechanical properties are not seen to witness a substantial degradation in performance, but an improvement in terms of yield strength and UTS, due to the role of work hardening. An alloy comparison has been carried out and responses are seen to vary slightly as a result of material microstructure. Correlation of pre-strain and pre-fatigue results with respect to baseline properties and microstructure has contributed to advancing the understanding of the mechanical behaviour of the aforementioned ultra-high strength steels.

International Society of Cardiovascular Infectious Diseases Guidelines for the Diagnosis, Treatment and Prevention of Disseminated Mycobacterium chimaera Infection Following Cardiac Surgery with Cardiopulmonary Bypass.

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects.

Fast and singular muscle responses initiate the startle response of Pantodon buchholzi (Osteoglossomorpha).

The startle response of Pantodon buchholzi, the African butterfly fish, is a complete or incomplete ballistic jump resulting from abduction of the pectoral fins. This study analyzed the neuromuscular basis for such a jump by recording in vivo electromyograms (emgs) from the muscles of abduction, the muscularis abductor superficialis (MAS) and the muscularis abductor profundus (MAP). The motor neurons innervating the MAS muscle were localized by retrograde transport of biocytin. The latency between stimulus and the evoked emg in the MAS was less than 5 ms; the latency of the MAP was about 6.5 ms. A single emg was recorded per jump. High speed video demonstrated that onset of a startle movement began within 10 ms of the onset of fin abduction. The emg associated with this movement is short (<2 ms) and followed by a variably-shaped, slower and smaller potential of 10-30 ms duration. The brief period between stimulus and startle response of Pantodon suggests a Mauthner neuron-related response, only with the behavior occurring in the vertical plane. The MAS may act only in a startle response, whereas the MAP might have a role in other behaviors. Elicited jumping habituates after a single trial. Electrophysiological evidence is presented indicating that the innervating motor neurons are suppressed for seconds following a stimulus. The neurons innervating the MAS are located at the medullary-spinal cord junction and possess an average radius of approximately 17.9 mum. These fish have been historically described as 'fresh water' flying fish. As a single emg occurs per startle response, repetitive pectoral activity generating flying cannot be supported. Pantodon 'flight' is ballistic.

High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours: the Clatterbridge experience.

In a systemic review of 8507 patients from 22 randomised trials, radiotherapy has been shown to reduce the risk of local recurrence and death from rectal cancer compared with surgery alone. Recent large randomised trials confirmed that chemoradiotherapy was better than radiotherapy alone. Contact radiotherapy as a boost after external beam radiotherapy (without chemotherapy) has also been shown to improve local control and sphincter preservation in the Lyon 092 trial. Brachytherapy has now been used as preoperative treatment for rectal cancer and showed similar results. The Swedish and Dutch trial results of short-course preoperative radiotherapy have shown improved local control in favour of the radiotherapy group. Similar to the Scandinavian group, investigators from McGill University in Montreal adopted a short course using brachytherapy instead of external beam radiotherapy. However, surgery was delayed for 4-8 weeks to achieve downstaging. The radiation dose was delivered directly on to the tumour and the surrounding normal tissues were spared the effects of radiation. This approach has been shown to reduce the side-effects seen with external beam short-course radiotherapy, but maintains the benefit of improved local control. The Danish group used brachytherapy as a boost after external beam chemoradiotherapy for more advanced rectal tumours and have shown improved pathological complete remission and R0 resection rates. The Mount Vernon group used a similar rectal applicator for inoperable rectal cancer patients and achieved good local and symptom control. The brachytherapy group at Clatterbridge used the same approach as the Danish group, but reduced the external beam radiotherapy dose and increased the brachytherapy dose to lower the side-effects. All 16 patients (100%) had R0 resection compared with 63% with conventional preoperative chemoradiotherapy using a bolus 5-fluorouracil regimen. Pathological complete remission was achieved in seven (44%) patients compared with 2-12% with conventional chemoradiotherapy. There was no increase in grade 3-4 toxicity from radiotherapy and no delay in wound healing or anastamotic leakage. The inclusion of high dose rate brachytherapy seems to increase the pathological complete remission rates and improves the R0 resection rates with no detriment to the side-effects as the increased dose of radiation from the high dose rate boost is confined mainly to the tumour. This treatment may be particularly suitable for elderly patients where intensive chemoradiotherapy regimens are not suitable. Several trials are planned to define the role of preoperative high dose rate brachytherapy in rectal cancer and the results are awaited with interest.

Combined modality treatment of early rectal cancer: the UK experience.

With the introduction of colorectal screening in the UK, more patients will probably be diagnosed with early rectal cancer. The UK has an increasingly elderly population and not all patients diagnosed with early rectal cancer will be suitable for radical surgery. Therefore, a national plan is needed to develop the provision of alternative local treatment with equity of access across the country. Here we review the Clatterbridge Centre for Oncology multimodality treatment policy, which has been in clinical practice since 1993 and we discuss its rationale. Clatterbridge is the only centre in the UK offering Papillon-style contact radiotherapy. In total, 220 patients have been treated over 14 years, most of whom were referred from other centres. One hundred and twenty-four patients received Papillon (contact radiotherapy) as part of their multimodality management. The guidelines of the Association of Coloproctology of Great Britain and Ireland recommend local treatment for T1 tumours<3 cm in diameter, but this refers to treatment by surgery alone. There are no published national guidelines for radiotherapy. We plan each treatment in stages and achieve excellent local control (93% at 3 years) with low morbidity. We conclude that radical local treatment for cure can be offered safely to carefully selected elderly patients. Close follow-up is necessary so that effective salvage treatment can be offered. Because of a lack of randomised trial evidence, at present local radiotherapy is not yet accepted as an alternative option to the gold standard surgical treatment. Even with international collaboration, a randomised trial will be difficult to complete as the number of cases requiring local radiotherapy is small due to the highly selective nature of the treatment involved. However, an observational phase II trial is planned. In addition, the Transanal Endoscopic Microsurgery Users Group is also planning a phase II trial using preoperative radiotherapy. These studies will provide evidence to help establish the true role of radiotherapy in early rectal cancer.

Preliminary test of cigarette nicotine discrimination threshold in non-dependent versus dependent smokers.

BACKGROUND: Despite its potential for understanding tobacco dependence, behavioral discrimination of nicotine via smoking has not been formally examined as a function of nicotine dependence level. METHODS: Spectrum research cigarettes were used to compare non-dependent with dependent smokers on the lowest content of nicotine they could discriminate (i.e., "threshold"). Dependent (n=21; 16M, 5F) or non-dependent (n=7; 4M, 3F) smokers were tested on ability to discriminate between cigarettes with nicotine contents of 17, 11, 5, 2, and 1mg/g, one per session, from an "ultra-low" cigarette with 0.4mg/g (all had 9-10mg "tar"). All abstained from smoking overnight prior to sessions, and number of sessions was determined by the lowest nicotine content they could reliably discriminate from the ultra-low on >80% of trials (i.e., ≥5 of 6). Subjective perceptions and cigarette choice behavior were also assessed and related to discrimination behavior. RESULTS: Discrimination thresholds (and most perceptions) did not differ between dependent and non-dependent smokers, with median thresholds of 11mg/g for both subgroups. Yet, "liking" and puff choice for threshold cigarettes were greater in dependent but not non-dependent smokers, while cigarettes with nicotine contents below threshold did not support "liking" or choice in both groups. CONCLUSIONS: In sum, this preliminary study suggests threshold for discriminating nicotine via smoking may not vary by dependence level, and further study is needed to confirm that cigarettes unable to be discriminated are also not reinforcing.

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine.

RATIONALE: The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement. METHODS: In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence. RESULTS: The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups. CONCLUSIONS: This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.

The role of basal and myogenic factors in the transcriptional activation of utrophin promoter A: implications for therapeutic up-regulation in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by the absence of a muscle cytoskeletal protein, dystrophin. Utrophin is the autosomal homologue of dystrophin. We previously demonstrated that overexpression of utrophin in the muscles of dystrophin-null transgenic mice completely prevented the phenotype arising from dystrophin deficiency. Two independently regulated promoters control utrophin expression and the upstream promoter (promoter A) is synaptically regulated in muscle. In this study, we have investigated basal regulation and myogenic induction of promoter A. Interactions between Ap2 and Sp1 and their cognate DNA motifs are critical for basal transcription from the minimal promoter region. During differentiation of C2C12 myoblasts in vitro, a 2-fold increase in A-utrophin mRNA level was observed. Expression of a reporter gene, whose transcription was driven by a 1.3 kb promoter A fragment, paralleled expression of the endogenous transcript. Myogenic induction mapped to a conserved upstream muscle-specific E-box, which was shown to bind myogenic regulatory factors, transactivating the promoter up to 18-fold in transient assays. This study provides a basis for further understanding the regulatory mechanisms that control utrophin expression in muscle and may facilitate the development of reagents to effect therapeutic up-regulation of utrophin in DMD.

Cytogenetic evidence for premeiotic transformation of human testicular cancers.

To determine the point at which transformation of the germ cell occurs during meiosis in nonseminomatous testicular cancer, the sex chromosome compositions of 15 cell lines derived from primary tumors or metastases of 12 patients with testicular cancer were analyzed by trypsin G-banding analysis and Y-body staining. The simultaneous existence of both X- and Y-chromosomes in a single cell has been confirmed in 14 cell lines. This suggests that transformation of the cell occurs before the first meiotic division because it is known that segregation of X- and Y-chromosomes occurs during the first meiotic division. An incidental finding was the presence of Barr bodies in some cell lines containing more than one X-chromosome, which is consistent with the known primitive nature of testicular cancer and its ability to differentiate independently from the male host.

Prenatal therapy in transient abnormal myelopoiesis: a systematic review.

OBJECTIVE: To systematically review current evidence regarding prenatal diagnosis and management of transient abnormal myelopoiesis (TAM) in fetuses with trisomy 21. A novel case of GATA1-positive TAM, in which following serial in utero blood transfusion clinical improvement and postnatal remission were observed, is included. SEARCH STRATEGY AND DATA COLLECTION: A systematic search of electronic databases (inception to October 2014) and reference lists, hand-searching of journals and expert contact. All confirmed cases of prenatal TAM were included for analysis. Data on study characteristics, design and quality were obtained. RESULTS: Of 73 potentially relevant citations identified, 22 studies were included, describing 39 fetuses. All studies included comprised single case or small cohort studies; overall quality was 'very low'. Fetal/neonatal outcome was poor; 12 stillbirths (30.8%), 4 neonatal deaths (10.2%) and 7 infant deaths (17.9%). In two cases, the pregnancy was terminated (5.1%). TAM was primarily detected in the third trimester (79.4%), and in 14 a retrospective diagnosis was made postpartum. Ultrasound features indicative of TAM included hepatomegaly±splenomegaly (79.5%), hydrops fetalis (30.8%), pericardial effusion (23.1%) and aberrant liquor volume (15.4%). When performed, liver function tests were abnormal in 91.6% of cases. CONCLUSIONS: Prenatal TAM presents a challenging diagnosis, and prognosis is poor, with consistently high mortality. A low threshold to measure haematological and biochemical markers is advised when clinical features typical of TAM are detected in the context of trisomy 21. Larger prospective studies are warranted to accurately ascertain the role of GATA1 analysis and potential value of prenatal therapy.

Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects.

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) results from the deficiency of the enzyme heparan N-sulfatase (NS, EC 3.10.1.1), required for the degradation of heparan sulfate. Molecular defects of 24 Italian MPS IIIA patients were recently reported by our group. We report here two novel mutations: 1040insT and Q365X and the expression studies on 15 of the identified defects. Transient expression of COS cells by cDNA mutagenized to correspond to heparan N-sulfatase mutations Y40N, A44T, 166delG, G122R, P128L, L146P, R150Q, D179N, R182C, R206P, P227R, 1040insT, 1093insG, E369K, R377C did not yield active enzyme, demonstrating the deleterious nature of the mutations. Western blot analysis and metabolic labeling experiments revealed, for cells transfected with wild-type enzyme, a precursor 62-kDa form and a mature 56-kDa form. Western blot resulted, for 11 mutations, in the presence of both forms, indicating a normal maturation of the mutant enzyme. Western blot, metabolic labeling and immunofluorescence experiments suggested, for mutations 166delG, L146P, 1040insT and 1093insG, an increased degradation of the mutant enzymes.

Improving Malawian teachers' mental health knowledge and attitudes: an integrated school mental health literacy approach.

BACKGROUND: Mental health literacy is foundational for mental health promotion, prevention, stigma reduction and care. Integrated school mental health literacy interventions may offer an effective and sustainable approach to enhancing mental health literacy for educators and students globally. METHODS: Through a Grand Challenges Canada funded initiative called 'An Integrated Approach to Addressing the Issue of Youth Depression in Malawi and Tanzania', we culturally adapted a previously demonstrated effective Canadian school mental health curriculum resource (the Guide) for use in Malawi, the African Guide: Malawi version (AGMv), and evaluated its impact on enhancing mental health literacy for educators (teachers and youth club leaders) in 35 schools and 15 out-of-school youth clubs in the central region of Malawi. The pre- and post-test study designs were used to assess mental health literacy - knowledge and attitudes - of 218 educators before and immediately following completion of a 3-day training programme on the use of the AGMv. RESULTS: Results demonstrated a highly significant and substantial improvement in knowledge (p < 0.0001, d = 1.16) and attitudes (p < 0.0001, d = 0.79) pertaining to mental health literacy in study participants. There were no significant differences in outcomes related to sex or location. CONCLUSIONS: These positive results suggest that an approach that integrates mental health literacy into the existing school curriculum may be an effective, significant and sustainable method of enhancing mental health literacy for educators in Malawi. If these results are further found to be sustained over time, and demonstrated to be effective when extended to students, then this model may be a useful and widely applicable method for improving mental health literacy among both educators and students across Africa.

Development of a lateral flow device for in-field detection and evaluation of PCR-based diagnostic methods for Xanthomonas campestris pv. musacearum, the causal agent of banana xanthomonas wilt.

Xanthomonas campestris pv. musacearum (Xcm) is the causal agent of banana xanthomonas wilt, a major threat to banana production in eastern and central Africa. The pathogen is present in very high levels within infected plants and can be transmitted by a broad range of mechanisms; therefore early specific detection is vital for effective disease management. In this study, a polyclonal antibody (pAb) was developed and deployed in a lateral flow device (LFD) format to allow rapid in-field detection of Xcm. Published Xcm PCR assays were also independently assessed: only two assays gave specific amplification of Xcm, whilst others cross-reacted with non-target Xanthomonas species. Pure cultures of Xcm were used to immunize a rabbit, the IgG antibodies purified from the serum and the resulting polyclonal antibodies tested using ELISA and LFD. Testing against a wide range of bacterial species showed the pAb detected all strains of Xcm, representing isolates from seven countries and the known genetic diversity of Xcm. The pAb also detected the closely related Xanthomonas axonopodis pv. vasculorum (Xav), primarily a sugarcane pathogen. Detection was successful in both naturally and experimentally infected banana plants, and the LFD limit of detection was 105 cells mL-1. Whilst the pAb is not fully specific for Xcm, Xav has never been found in banana. Therefore the LFD can be used as a first-line screening tool to detect Xcm in the field. Testing by LFD requires no equipment, can be performed by non-scientists and is cost-effective. Therefore this LFD provides a vital tool to aid in the management and control of Xcm.

Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior.

The effects of short-term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study I, 10 male and 10 female smokers received intermittent doses of 0, 7.5, 15, and 30 micrograms/kg nicotine by way of measured-dose nasal spray, with each dose on a separate day. Self-reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 micrograms/kg nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libitum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 15 micrograms/kg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 micrograms/kg versus placebo, suggesting only partial compensation in smoking behavior with short-term nasal nicotine replacement. These findings support the idea that short-term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partly influenced by factors other than nicotine regulation.

Acute effects of nicotine on resting metabolic rate in cigarette smokers.

The acute effects of nicotine on resting metabolic rate (RMR) were examined to identify a mechanism that may help explain the inverse association between smoking and body weight. Multiple administrations of two nicotine doses (moderate [15 micrograms/kg body wt] and low [7.5 micrograms/kg body wt]) and a placebo (0 micrograms) were presented to 18 male smokers via nasal-spray solution on three separate occasions while RMR was assessed by computerized open-circuit indirect calorimetry. Plasma nicotine levels confirmed the reliability of dosing. RMR increases of 6% above base line after both moderate and low doses were significantly greater than the 3% increase after the placebo. Subsequent examination of the effects of smoking a nonnicotine cigarette suggested that the small placebo effect was due to acute metabolic consequences of inhalation. These results confirm that intake of nicotine, isolated from tobacco smoke, significantly increases RMR in humans. However, the results also indicate that non-pharmacological, behavioral aspects of smoking may also contribute to acutely increasing RMR in smokers.

Metabolic effects of nicotine after consumption of a meal in smokers and nonsmokers.

The thermogenic effect of nicotine intake after calorie consumption was investigated to determine if nicotine influences metabolic response to a calorie challenge. Smokers and nonsmokers (10 males in each group), matched for body weight, age, and physical fitness, each participated in four sessions that involved consuming a liquid calorie load (4.77 kcal/kg body wt) or water, followed by nicotine (15 micrograms/kg body wt) or placebo via nasal spray every 20 min for 2 h. Energy expenditure was significantly increased above baseline resting metabolic rate (RMR) over the 2 h by nicotine alone (6.5% of RMR, p less than 0.01). However, the combined effect of nicotine after calorie load (20.1% of RMR, p less than 0.001) was not significantly greater than the effect of calorie load alone (18.4% of RMR, p less than 0.001). Smokers and nonsmokers did not differ in baseline RMR or in response to nicotine or calorie load. These results confirm the thermogenic effect of nicotine but suggest that the effect of nicotine after calorie consumption is less than additive.

Acute thermogenic effects of nicotine combined with caffeine during light physical activity in male and female smokers.

The thermogenic effects of nicotine and caffeine during physical activity compared with rest were examined in male and female smokers (n = 10 each). During eight sessions, nicotine (15 micrograms/kg) or placebo was given via measured-dose nasal spray intermittently after consumption of decaffeinated coffee with or without added caffeine (5 mg/kg), followed by assessment of energy expenditure by indirect calorimetry while subjects engaged in standardized, low-intensity cycle ergometer riding (activity) or remained at quiet rest. Results indicated significant thermogenic effects of nicotine and caffeine individually, with the combination of nicotine and caffeine producing additive effects. Expenditure attributable to nicotine, caffeine, or their combination was significantly enhanced during activity compared with rest, but only for males and not females. Plasma nicotine concentrations were influenced by activity and caffeine, but these pharmacokinetic changes did not appear to explain the differences in expenditure. These findings suggest a sex difference in thermogenic effects of nicotine and caffeine during casual physical activity and potentially explain some of the apparent individual variability in expenditure due to tobacco smoking.