Dynamic spatiotemporal variability of alpha-BOLD relationships during the resting-state and task-evoked responses.

Accurate characterization of the spatiotemporal relationship between two of the most prominent neuroimaging measures of neuronal activity, the 8-13Hz, occipito-parietal EEG alpha oscillation and the BOLD fMRI signal, must encompass the intrinsically dynamic nature of both alpha power and brain function. Here, during the eyes-open resting state, we use a 16s sliding-window analysis and demonstrate that the mean spatial network of dynamic alpha-BOLD correlations is highly comparable to the static network calculated over six minutes. However, alpha-BOLD correlations showed substantial spatiotemporal variability within-subjects and passed through many different configurations such that the static network was fully represented in only ~10% of 16s epochs, with visual and parietal regions (coherent on average) often opposingly correlated with each other or with alpha. We find that the common assumption of static-alpha BOLD correlations greatly oversimplifies temporal variation in brain network dynamics. Fluctuations in alpha-BOLD coupling significantly depended upon the instantaneous amplitude of alpha power, and primary and lateral visual areas were most strongly negatively correlated with alpha during different alpha power states, possibly suggesting the action of multiple alpha mechanisms. Dynamic alpha-BOLD correlations could not be explained by eye-blinks/movements, head motion or non-neuronal physiological variability. Individual's mean alpha power and frequency were found to contribute to between-subject variability in alpha-BOLD correlations. Additionally, application to a visual stimulation dataset showed that dynamic alpha-BOLD correlations provided functional information pertaining to the brain's response to stimulation by exhibiting spatiotemporal fluctuations related to variability in the trial-by-trial BOLD response magnitude. Significantly weaker visual alpha-BOLD correlations were found both preceding and following small amplitude BOLD response trials compared to large response trials.

Post-stimulus fMRI and EEG responses: Evidence for a neuronal origin hypothesised to be inhibitory.

Post-stimulus undershoots, negative responses following cessation of stimulation, are widely observed in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) data. However, the debate surrounding whether the origin of this response phase is neuronal or vascular, and whether it provides functionally relevant information, that is additional to what is contained in the primary response, means that undershoots are widely overlooked. We simultaneously recorded electroencephalography (EEG), BOLD and cerebral blood-flow (CBF) [obtained from arterial spin labelled (ASL) fMRI] fMRI responses to hemifield checkerboard stimulation to test the potential neural origin of the fMRI post-stimulus undershoot. The post-stimulus BOLD and CBF signal amplitudes in both contralateral and ipsilateral visual cortex depended on the post-stimulus power of the occipital 8-13Hz (alpha) EEG neuronal activity, such that trials with highest EEG power showed largest fMRI undershoots in contralateral visual cortex. This correlation in post-stimulus EEG-fMRI responses was not predicted by the primary response amplitude. In the contralateral visual cortex we observed a decrease in both cerebral rate of oxygen metabolism (CMRO2) and CBF during the post-stimulus phase. In addition, the coupling ratio (n) between CMRO2 and CBF was significantly lower during the positive contralateral primary response phase compared with the post-stimulus phase and we propose that this reflects an altered balance of excitatory and inhibitory neuronal activity. Together our data provide strong evidence that the post-stimulus phase of the BOLD response has a neural origin which reflects, at least partially, an uncoupling of the neuronal responses driving the primary and post-stimulus responses, explaining the uncoupling of the signals measured in the two response phases. We suggest our results are consistent with inhibitory processes driving the post-stimulus EEG and fMRI responses. We therefore propose that new methods are required to model the post-stimulus and primary responses independently, enabling separate investigation of response phases in cognitive function and neurological disease.

Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of average responses.

Perceptions and Experiences of Integrated Service Delivery Among Women Living with HIV Attending Reproductive Health Services in Kenya: A Mixed Methods Study.

This is one of the few studies that explores preferences of and experiences with integrated sexual and reproductive health (SRH)-HIV care among users of mainstream family planning and postnatal care services who are women living with HIV (WLWH). This paper reports on the quantitative data from 179 clients attending public sector clinics and from 30 qualitative in-depth interviews with WLHIV in Kenya. Quantitative data show that integration is happening for the vast majority of these clients at their last HIV visit. However, qualitative data show that very often the care received by WLWH is fragmented as providers do not offer multiple same-day appointments for FP and ARV refills. Our study has shown factors that could either prevent or enable receipt of integrated SRH and HIV care for WLWH. To address these factors, management systems need to be able to support providers to make flexible decisions and facilitate better coordination and communication across clinics within facilities.

Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG-BOLD-CBF study in humans.

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n=0.91±0.04, M=10.45%) than in the contralateral S1/M1 (n=0.65±0.03, M=10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8-13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR.

Investigating intrinsic connectivity networks using simultaneous BOLD and CBF measurements.

When the sensory cortex is stimulated and directly receiving afferent input, modulations can also be observed in the activity of other brain regions comprising spatially distributed, yet intrinsically connected networks, suggesting that these networks support brain function during task performance. Such networks can exhibit subtle or unpredictable task responses which can pass undetected by conventional general linear modelling (GLM). Additionally, the metabolic demand of these networks in response to stimulation remains incompletely understood. Here, we recorded concurrent BOLD and CBF measurements during median nerve stimulation (MNS) and compared GLM analysis with independent component analysis (ICA) for identifying the spatial, temporal and metabolic properties of responses in the primary sensorimotor cortex (S1/M1), and in the default mode (DMN) and fronto-parietal (FPN) networks. Excellent spatial and temporal agreement was observed between the positive BOLD and CBF responses to MNS detected by GLM and ICA in contralateral S1/M1. Values of the change in cerebral metabolic rate of oxygen consumption (Δ%CMRO2) and the Δ%CMRO2/Δ%CBF coupling ratio were highly comparable when using either GLM analysis or ICA to extract the contralateral S1/M1 responses, validating the use of ICA for estimating changes in CMRO2. ICA identified DMN and FPN network activity that was not detected by GLM analysis. Using ICA, spatially coincident increases/decreases in both BOLD and CBF signals to MNS were found in the FPN/DMN respectively. Calculation of CMRO2 changes in these networks during MNS showed that the Δ%CMRO2/Δ%CBF ratio is comparable between the FPN and S1/M1 but is larger in the DMN than in the FPN, assuming an equal value of the parameter M in the DMN, FPN and S1/M1. This work suggests that metabolism-flow coupling may differ between these two fundamental brain networks, which could originate from differences between task-positive and task-negative fMRI responses, but might also be due to intrinsic differences between the two networks.

An exploratory study of eating disorder psychopathology among Overeaters Anonymous members.

Overeaters Anonymous (OA) is a widely available, 12-step, self-help treatment program primarily used for weight loss that also offers to address eating disorder (ED) symptoms. However, because of OA's tradition of avoiding contact with "outside enterprises," little research has examined eating pathology among OA members. The present, uncontroled study examined current, self-reported ED psychopathology with the Eating Disorder Examination Questionnaire among 20 self-selected OA members. Consistent with OA's aim to address compulsive overeating, rates of subjective and objective bulimic episodes and eating concern were significantly elevated among OA members relative to norms for adult women, demonstrating medium effects, and restraint showed a significant, small effect. Other ED symptoms, including weight concern and compensatory behaviors, were not statistically different from norms, yet demonstrated small effect sizes. We conclude that many OA members may experience ED psychopathology that extends beyond binge eating.

Political feasibility of scaling-up five evidence-informed HIV interventions in Pakistan: a policy analysis.

BACKGROUND: Drawing on policy theories, an assessment was made of the perceived political feasibility of scaling-up five evidence-based interventions to curb Pakistan's HIV epidemic: needle and syringe exchange programmes; targeted behaviour change communication; sexual health care for male and transgender sex workers; sexual and reproductive health care for female sex workers; and promoting and protecting the rights of those at greatest risk. METHOD: A questionnaire was emailed to 40 stakeholders and completed by 22. They expressed their level of agreement with 15 statements for each intervention (related to variables associated with policy success). Semi-structured interviews were conducted with 12 respondents. RESULTS: The interventions represent considerable change from the status quo, but are perceived to respond to widely acknowledged problems. These perceptions, held by the HIV policy elite, need to be set in the context of the prevailing view that the AIDS response is not warranted given the small and concentrated nature of the epidemic and that the interventions do not resonate closely with values held by society. The interventions were perceived to be evidence-based, supported by at least one donor and subject to little resistance from frontline staff as they will be implemented by contracted non-government organisations. The results were mixed in terms of other factors determining political feasibility, including the extent to which interventions are easy to explain, exhibit simple technical features, require few additional funds, are supported and not opposed by powerful stakeholders. CONCLUSION: The interventions stand a good chance of being implemented although they depend on donor support. The prospects for scaling them would be improved by ongoing policy analysis and strengthening of domestic constituencies among the target groups.

Prevalence of HIV, HCV and sexually transmitted infections among injecting drug users in Rawalpindi and Abbottabad, Pakistan: evidence for an emerging injection-related HIV epidemic.

OBJECTIVES: To measure the prevalence of hepatitis C virus (HCV), HIV and sexually transmitted infections (STI) among injecting drug users (IDUs) in Rawalpindi and Abbottabad and to examine risk factors associated with HIV and HCV. METHODS: Two cross-sectional surveys were performed of community-recruited IDUs with collection of clinical specimens for testing of HCV, HIV and other STIs. Behavioural data were collected through interviewer-administered questionnaires. Characteristics and risk behaviours were compared across cities. Univariate and multivariate analyses explored risk factors associated with HIV and HCV. RESULTS: The prevalence of HIV was 2.6% (95% CI 0.83% to 4.5%) in Rawalpindi (n = 302) and zero in Abbottabad (n = 102). The prevalence of HCV was significantly higher in Rawalpindi at 17.3% (95% CI 13.0% to 21.6%) than in Abbottabad at 8% (95% CI 2.6% to 13.4%). The prevalence of other STIs was low in both cities, with <2% of participants having current gonorrhoea or Chlamydia and <3% with active syphilis. Injecting risk behaviours were greater in Rawalpindi. An increased risk of HCV was associated with using informal sources as a main source of new needles/syringes (OR 2.8, 95% CI 1.3 to 6.0) compared with pharmacies and a history of drug treatment (OR 3.7, 95% CI 0.9 to 11.6). Reporting symptoms of an STI was associated with decreased odds of HIV in Rawalpindi (OR 0.02, 95% CI 0.03 to 0.9). CONCLUSIONS: The findings suggest recent transmission of HIV and HCV and point to the urgent need for the provision of clean needles/syringes to IDUs and a review of how needles/syringes are currently provided via healthcare establishments.

Understanding the context of male and transgender sex work using peer ethnography.

OBJECTIVES: To distinguish between three distinct groups of male and transgender sex workers in Pakistan and to demonstrate how members of these stigmatized groups need to be engaged in the research process to go beyond stated norms of behaviour. METHODS: A peer ethnography study was undertaken in a major city in Pakistan. 15 male and 15 transgender sex workers were trained as peer researchers to each interview three peers in their network. Analysis was based on interviews with peer researchers as well as observation of dynamics during training and analysis workshops. RESULTS: The research process revealed that, within the epidemiological category of biological males who sell sex, there are three sociologically different sexual identities: khusras (transgender), khotkis (feminized males) and banthas (mainstream male identity). Both khusras and khotkis are organised in strong social structures based on a shared identity. While these networks provide emotional and material support, they also come with rigid group norms based on expected "feminine" behaviours. In everyday reality, sex workers showed fluidity in both behaviour and identity according to the situational context, transgressing both wider societal and group norms. The informal observational component in peer ethnography was crucial for the accurate interpretation of interview data. Participant accounts of behaviour and relationships are shaped by the research contexts including who interviews them, at what stage of familiarity and who may overhear the conversation. CONCLUSIONS: To avoid imposing a "false clarity" on categorisation of identity and assumed behaviour, it is necessary to go beyond verbal accounts to document the fluidity of everyday reality.

Protecting the unprotected: mixed-method research on drug use, sex work and rights in Pakistan's fight against HIV/AIDS.

OBJECTIVES: To investigate the nature and extent of human rights abuses against three vulnerable groups (injecting drug users (IDUs) and male and female sex workers), to understand the social and sexual linkages between them and to examine how protecting their rights could enhance the impact of HIV prevention policies. METHODS: In-depth interviews were carried out with 38 high-risk respondents (IDUs and female, male and transgender sex workers) and a bio-behavioural survey was performed of 813 IDU/sex worker respondents in Rawalpindi. RESULTS: People in all vulnerable groups interacted both sexually and socially. All groups experienced human rights abuses by state and non-state actors which increased their HIV risk. Non-state actors, including relations and sex worker clients, are responsible for verbal, physical and sexual violence. State actors (particularly police) perpetrate harassment, exploitation and abuse of all vulnerable groups with impunity. Health service providers fail to provide adequate services for vulnerable groups. CONCLUSIONS: High levels of discrimination and abuse of human dignity of all groups studied were revealed. This violates their physical and mental integrity and also leads to an increased risk of HIV. The sexual and social interactions between groups mean that human rights abuses experienced by one high-risk group can increase the risk of HIV both for them and other groups. The protection of human rights needs to become an integral part of a multisector response to the risk of HIV/AIDS by state and non-state agencies. The Government of Pakistan should work at both legal and programme levels to protect the rights of, and minimise discrimination against, groups vulnerable to HIV in order to reduce the potential for the spread of HIV before the epidemic takes hold.

Understanding low adherence to an exercise program for adolescents with obesity: the HEARTY trial.

INTRODUCTION: Despite efforts to improve adherence to physical activity interventions in youth with obesity, low adherence and attrition remain areas of great concern. OBJECTIVE: The study was designed to determine which physiological and/or psychological factors predicted low adherence in adolescents with obesity enrolled in a 6-month exercise intervention study aimed to improve body composition. METHODS: Three hundred four adolescents with obesity aged 14-18 years who volunteered for the HEARTY (Healthy Eating Aerobic and Resistance Training in Youth) randomized controlled trial completed physiological (body mass index, waist circumference, per cent body fat, resting metabolic rate and aerobic fitness) and psychological (body image, mood, self-esteem and self-efficacy) measures. RESULTS: One hundred forty-one out of 228 (62%) randomized to exercise groups had low adherence (completed <70% of the prescribed four exercise sessions per week) to the intervention protocol. Logistic regression revealed that there were no baseline demographic or physiological variables that predicted low adherence in the participants. Appearance concern (a subscale of body image) (odds ratio [OR] 1.46, 95% confidence interval [CI]: 1.01, 2.1, P = 0.04), depressive mood (OR 1.12, 95% CI: 1.01, 1.23, P = 0.03) and confused mood (OR 1.16, 95% CI: 1.05, 1.27, P = 0.003) (two subscales of mood) were significant predictors of low adherence. CONCLUSIONS: Adolescents with obesity who had higher appearance concerns and depressive and confused moods were less likely to adhere to exercise. Body image and mood should be screened to identify adolescents who may be at high risk of poor adherence and who may need concurrent or treatment support to address these psychological issues to derive maximal health benefits from an exercise programme.

Cultural expectations of thinness in women: a partial replication and update of magazine content.

OBJECTIVE: To determine if magazine articles in mainstream women's magazines, continue to emphasize weight reduction. METHOD: Articles devoted to diet, exercise, and cosmetic surgery were tabulated from January 1989 to April 2007 in eight popular women's magazines. RESULTS: The number of cosmetic surgery articles has substantially increased since 1989, while exercise articles continue to decline. Diet for weight loss articles have progressively decreased since 1989, with a marginal increase between 2003-2007. CONCLUSION: The upward trend in cosmetic surgery articles indicates that cosmetic surgery is now viewed as an alternate means to diet and exercise that women may choose to alter their physical appearance. One of the implications of moving to cosmetic surgery as a means to conform is that when it comes to female beautification, there are few extremes.

Addressing weight bias and discrimination: moving beyond raising awareness to creating change.

Weight discrimination is the unjust treatment of individuals because of their weight. There have been very few interventions to address weight discrimination, due in part to the lack of consensus on key messages and strategies. The objective of the third Canadian Weight Bias Summit was to review current evidence and move towards consensus on key weight bias and obesity discrimination reduction messages and strategies. Using a modified brokered dialogue approach, participants, including researchers, health professionals, policy makers and people living with obesity, reviewed the evidence and moved towards consensus on key messages and strategies for future interventions. Participants agreed to these key messages: (1) Weight bias and obesity discrimination should not be tolerated in education, health care and public policy sectors; (2) obesity should be recognized and treated as a chronic disease in health care and policy sectors; and (3) in the education sector, weight and health need to be decoupled. Consensus on future strategies included (1) creating resources to support policy makers, (2) using personal narratives from people living with obesity to engage audiences and communicate anti-discrimination messages and (3) developing a better clinical definition for obesity. Messages and strategies should be implemented and evaluated using consistent theoretical frameworks and methodologies.

Automated single-trial measurement of amplitude and latency of laser-evoked potentials (LEPs) using multiple linear regression.

OBJECTIVE: Laser stimulation of Adelta-fibre nociceptors in the skin evokes nociceptive-specific brain responses (laser-evoked potentials, LEPs). The largest vertex complex (N2-P2) is widely used to assess nociceptive pathways in physiological and clinical studies. The aim of this study was to develop an automated method to measure amplitudes and latencies of the N2 and P2 peaks on a single-trial basis. METHODS: LEPs were recorded after Nd:YAP laser stimulation of the left hand dorsum in 7 normal volunteers. For each subject, a basis set of 4 regressors (the N2 and P2 waveforms and their respective temporal derivatives) was derived from the time-averaged data and regressed against every single-trial LEP response. This provided a separate quantitative estimate of amplitude and latency for the N2 and P2 components of each trial. RESULTS: All estimates of LEP parameters correlated significantly with the corresponding measurements performed by a human expert (N2 amplitude: R2=0.70; P2 amplitude: R2=0.70; N2 latency: R2=0.81; P2 latency: R2=0.59. All P<0.0001). Furthermore, regression analysis was able to extract an LEP response from a subset of the trials that had been classified by the human expert as without response. CONCLUSIONS: This method provides a simple, fast and unbiased measurement of different components of single-trial LEP responses. SIGNIFICANCE: This method is particularly desirable in several experimental conditions (e.g. drug studies, correlations with experimental variables, simultaneous EEG/fMRI and low signal-to-noise ratio data) and in clinical practice. The described multiple linear regression approach can be easily implemented for measuring evoked potentials in other sensory modalities.

Weight bias reduction in health professionals: a systematic review.

Innovative and coordinated strategies to address weight bias among health professionals are urgently needed. We conducted a systematic literature review of empirical peer-reviewed published studies to assess the impact of interventions designed to reduce weight bias in students or professionals in a health-related field. Combination sets of keywords based on three themes (1: weight bias/stigma; 2: obesity/overweight; 3: health professional) were searched within nine databases. Our search yielded 1447 individual records, of which 17 intervention studies satisfied the inclusion criteria. Most studies (n = 15) included medical, dietetic, health promotion, psychology and kinesiology students, while the minority included practicing health professionals (n = 2). Studies utilized various bias-reduction strategies. Many studies had methodological weaknesses, including short assessment periods, lack of randomization, lack of control group and small sample sizes. Although many studies reported changes in health professionals' beliefs and knowledge about obesity aetiology, evidence of effectiveness is poor, and long-term effects of intervention strategies on weight bias reduction remain unknown. The findings highlight the lack of experimental research to reduce weight bias among health professionals. Although changes in practice will likely require multiple strategies in various sectors, well-designed trials are needed to test the impact of interventions to decrease weight bias in healthcare settings.

A continuous fluorometric assay for flavokinase. Properties of flavokinase from Peptostreptococcus elsdenii.

A continuous fluorometric assay that utilizes apoflavodoxin as a trapping agent for riboflavin 5'-phosphate (FMN) has been developed for flavokinase (ATP:riboflavin 5'-phosphotransferase, EC 2.7.1.26). Use of this assay is illustrated in a procedure for the partial purification of flavokinase from the strict anaerobe Peptostreptococcus elsdenii. The purified enzyme catalyzed the formation of 8.3 nmol FMN - min-1 - mg-1 at 37 degrees C and had apparent Km values for riboflavin and ATP of 10 and 4.7 micronM, respectively. ATP could be replaced by ADP (22% of the rate observed with ATP) but not by GTP. The enzyme also phosphorylated 5-deaza- and 8-bromoriboflavin with activities of 15 and 70%, respectively, of that with riboflavin; it was inactive with iso riboflavin and deoxyriboflavin.

Studies on the binding of FMN by apoflavodoxin from Peptostreptococcus elsdenii, pH and NaCl concentration dependence.

1. The pH and ionic strength dependence of the interaction of FMN with apoflavodoxin has been studied by fluorometry in the pH region 2-5, at 22 degrees C. 2. The rate constant of dissociation and the dissociation constant were experimentally determined; the rate constants of association were claculated at a given pH value. These constants depend on the ionic strength. The plots of these constants against the square root of the ionic strength are straight. 3. Our data have been interpreted in terms of the Brönsted theory, which relates chemical reaction rates to ionic strength. The data indicate that the apoenzyme reaches its maximum net positive charge at pH 2.0-2.6. The calculated net charge in this pH region is between 11 and 12 and is in agreement with the theoretical value of 12 as deduced from the primary structure of the protein. The isoelectric point of the holoenzyme is about 4. 4. The rate constant of association extrapolated to zero ionic strength is 3.2-10(5)M-1-s-1 and is pH-independent. 5. The rate constant of dissociation and the dissociation constant extrapolated to zero ionic strength depend on the pH. The results are explained by assuming that there are two protein ionizations with a pK value of 3.4; these ionizing groups are possibly close to the FMN binding site.

A photo-CIDNP study of the active sites of Megasphaera elsdenii and Clostridium MP flavodoxins.

Megasphaera elsdenii and Clostridium MP flavodoxins have been investigated by photo-CIDNP techniques. Using time-resolved spectroscopy and external dyes carrying different charges it was possible to assign unambiguously the resonance lines in the NMR-spectra to tyrosine, tryptophan and methionine residues in the two proteins. The results show that Trp-91 in M.elsdenii and Trp-90 in Cl.MP flavodoxin are strongly immobilized and placed directly above the benzene subnucleus of the prosthetic group. The data further indicate that the active sites of the two flavodoxins are extremely similar.

A dose-response study of atenolol in mild to moderate hypertension in general practice.

A double-blind, crossover, multicentre study of 98 previously untreated patients with mild to moderate essential hypertension was carried out in general practice to assess the effect of 50 mg, 100 mg, and 200 mg atenolol, given once daily, compared with that of placebo over a period of 4 weeks each. At the end of the double-blind phase, all patients took 100 mg atenolol daily for a further 8 weeks. All three doses of atenolol produced statistically significant falls in systolic and diastolic pressure and pulse rate (p less than 0.001). The lowest pressures were achieved with 100 mg daily; a difference of 22/15 mmHg at the end of the double-bling phase, and a difference of 25/16 mmHg at the final observation. Body weight, blood urea, blood uric acid, and serum electrolytes remained within normal limits throughout the study. The incidence of side-effects with 50 mg and 100 mg atenolol was not significantly different from that caused by placebo, but the incidence of tiredness at the 200 mg dose level was greater than that caused by placebo and by the lower doses. The incidence of possible side-effects elicited by a questionnaire was low, the greatest number being volunteered by patients taking placebo. It is concluded that the optimal dose of atenolol for treating patients with mild to moderate hypertension in general practice is 100 mg daily.