Obstructive sleep apnoea and 12-month weight loss in adults with class 3 obesity attending a multidisciplinary weight management program.

BACKGROUND: Although there is a strong association between obesity and obstructive sleep apnoea (OSA), the effects of OSA and CPAP therapy on weight loss are less well known. The aim of this study in adults with class 3 obesity attending a multidisciplinary weight management program was to assess the relationship between OSA and CPAP usage, and 12-month weight change. METHODS: A retrospective cohort study of all patients commencing an intensive multidisciplinary publicly funded weight management program in Sydney, Australia, between March 2018 and March 2019. OSA was diagnosed using laboratory overnight sleep studies. Demographic and clinical data, and use of CPAP therapy was collected at baseline and 12 months. CPAP use was confirmed if used ≥4 h on average per night on download. RESULTS: Of the 178 patients who joined the program, 111 (62.4 %) completed 12 months in the program. At baseline, 63.1 % (n=70) of patients had OSA, of whom 54.3 % (n=38) were using CPAP. The non-OSA group had more females compared to the OSA with CPAP group and OSA without CPAP group (90.2 % vs. 57.9 % and 62.5 %, respectively; p=0.003), but there were no significant baseline differences in BMI (50.4±9.3 vs. 52.1±8.7 and 50.3±9.5 kg/m2, respectively; p=0.636). There was significant weight loss across all three groups at 12 months. However, there were no statistically significant differences across groups in the percentage of body weight loss (OSA with CPAP: 6.3±5.6 %, OSA without CPAP: 6.8±6.9 %, non-OSA: 7.2±6.5 %; p=0.844), or the proportion of patients who achieved ≥5 % body weight loss (OSA with CPAP: 57.9 %, OSA without CPAP: 59.4 %, non-OSA: 65.9 %; p=0.743). In patients with T2DM, there was a significant reduction in HbA1c from baseline to 12 months (7.8±1.7 % to 7.3±1.4 %, p=0.03), with no difference between groups (p=0.997). CONCLUSIONS: This multidisciplinary weight management program resulted in significant weight loss at 12 months, regardless of OSA diagnosis or CPAP use in adults with class 3 obesity. Larger studies are needed to further investigate the effects of severity of OSA status and CPAP use in weight management programs. Until completed, this study suggests that the focus should remain on implementing lifestyle changes and weight management regardless of OSA status.

Differences in regional grey matter volume of the brain are related to mean blood pressure and muscle sympathetic nerve activity in normotensive humans.

OBJECTIVES: The brainstem plays a critically important role in the beat-to-beat control of blood pressure, as well as setting mean blood pressure (MBP). We recently showed that regional cerebral blood flow to specific brainstem nuclei is inversely related to resting MBP in healthy normotensive individuals. Here we tested the hypothesis that grey matter volume in these same nuclei, and areas above the brainstem to which they are connected, is also associated with resting MBP and muscle sympathetic nerve activity (MSNA). METHODS: Structural MRI of the brain and recordings of MSNA and BP were collected in 54 healthy participants. Subjects were divided into a lower MBP group (mean ±â€ŠSEM 78.8 ±â€Š1.5 mmHg, n=27) and higher MBP group (96.6 ±â€Š1.2 mmHg, n = 27), as well as into a lower MSNA (9.5 ±â€Š0.8 bursts/min, n = 27) and higher MSNA (25.4 ±â€Š1.2 bursts/min, n = 27) group. RESULTS: Regional grey matter volume was higher in the region of the rostral ventrolateral medulla, nucleus tractus solitarius, and medullary raphe in the group with higher MBP and correlated significantly with mean MBP across all participants. Grey matter volume was significantly higher in the dorsomedial hypothalamus and anterior and posterior cingulate cortices in the group with lower MSNA and was inversely related to MSNA across all participants. CONCLUSION: We conclude that small differences in MBP and MSNA are associated with significant differences in grey matter volume in cortical and subcortical regions known to be involved in blood pressure regulation, suggesting that these structural differences contribute to resting MBP and MSNA and can predict the establishment of hypertension.

Resting regional brain activity and connectivity vary with resting blood pressure but not muscle sympathetic nerve activity in normotensive humans: An exploratory study.

Blood pressure is tightly controlled by the central nervous system, particularly the brainstem. The aim of this study was to investigate the relationship between mean blood pressure (MBP), muscle sympathetic nerve activity (MSNA) and resting regional brain activity in healthy human subjects. Pseudocontinuous arterial spin labeling and functional magnetic resonance imaging of the brain were performed immediately following a laboratory microneurography recording of MSNA and BP measurement in 31 young, healthy normotensive subjects. Regional cerebral blood flow (CBF) correlated significantly with resting MBP levels in the region encompassing the rostroventrolateral medulla (RVLM), dorsolateral pons, and insular, prefrontal and cingulate cortices. Functional connectivity analysis revealed that the ventrolateral prefrontal cortex displayed greater resting connectivity strength within the RVLM in the lower compared with the higher MBP group. No significant differences in CBF were found when subjects were divided based on their MSNA levels. These results suggest that even subtle differences in resting MBP are associated with significant differences in resting activity in brain regions, which are well known to play a role in cardiovascular function. These data raise the question of the potential long-term consequences of differences in regional brain activity levels and their relationship with systemic blood pressure.

The effects of audiovisual distraction on the muscle sympathetic responses to experimental muscle pain.

Pain elicited by intramuscular infusion of hypertonic saline solution causes muscle sympathetic nerve activity (MSNA) to increase in some subjects, yet decrease in others. Although the direction of the response is not predictable based on baseline physiological and psychological parameters, we know that it results from sustained functional changes in specific brain regions that are responsible for the behavioral and cardiovascular responses to psychological stressors, as well as those involved in attention. The aim of this study was to investigate whether MSNA responses to experimental muscle pain in humans could be altered with an audiovisual stimulus that served to distract them from the pain. MSNA was recorded from the left common peroneal nerve of 20 young healthy individuals during a 45-min intramuscular infusion of hypertonic saline solution into the ipsilateral tibialis anterior muscle. The distracting stimulus commenced 15 min after the start of the infusion and lasted for 15 min. Fifteen subjects showed an increase in mean burst amplitude of MSNA (to 176.4 ± 7.9% of baseline), while five showed a decrease (to 73.1 ± 5.2% of baseline); distraction had no effect on these profiles. These results indicate that even though the subjects were attending to the audiovisual stimulus, and were presumably distracted from the pain, it failed to alter the MSNA responses to muscle pain.

Muscle sympathetic nerve activity-coupled changes in brain activity during sustained muscle pain.

Introduction: Long-lasting experimental muscle pain elicits divergent muscle sympathetic responses, with some individuals exhibiting a persistent increase in muscle sympathetic nerve activity (MSNA), and others a decrease. These divergent responses are thought to result from sustained functional changes in specific brain regions that modulate the cardiovascular responses to pain. Aim: The aim of this study was to investigate brain regions that are functionally coupled to the generation of an MSNA burst at rest and to determine their behavior during tonic muscle pain. Methods: Functional magnetic resonance imaging of the brain was performed concurrently with microelectrode recording of MSNA from the common peroneal nerve during a 40 min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle of 37 healthy human subjects. Results: At rest, blood oxygen level-dependent signal intensity coupled to bursts of MSNA increased in the rostral ventrolateral medulla, insula, dorsolateral prefrontal cortex, posterior cingulate cortex, and precuneus and decreased in the region of the midbrain periaqueductal gray. During pain, MSNA-coupled signal intensity was greater in the region of the nucleus tractus solitarius, midbrain periaqueductal gray, dorsolateral prefrontal, medial prefrontal, and anterior cingulate cortices, than at rest. Conversely, MSNA-coupled signal intensity decreased during pain in parts of the prefrontal cortex. Conclusions: These results suggest that multiple brain regions are recruited in a burst-to-burst manner, and the magnitude of these signal changes is correlated to the overall change in MSNA amplitude during tonic muscle pain.

Central circuitry responsible for the divergent sympathetic responses to tonic muscle pain in humans.

Experimentally induced tonic muscle pain evokes divergent muscle vasoconstrictor responses, with some individuals exhibiting a sustained increase in muscle sympathetic nerve activity (MSNA), and others a sustained decrease. These patterns cannot be predicted from an individual's baseline physiological or psychological measures. The aim of this study was to investigate whether the different muscle sympathetic responses to tonic muscle pain were associated with differential changes in regional brain activity. Functional magnetic resonance imaging (fMRI) of the brain was performed concurrently with microelectrode recording of MSNA from the peroneal nerve during a 40-min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle. MSNA increased in 26 and decreased in 11 of 37 subjects during tonic muscle pain. Within the prefrontal and cingulate cortices, precuneus, nucleus accumbens, caudate nucleus, and dorsomedial hypothalamus, blood oxygen level dependent (BOLD) signal intensity increased in the increasing-MSNA group and remained at baseline or decreased in the decreasing-MSNA group. Similar responses occurred in the dorsolateral pons and in the region of the rostral ventrolateral medulla. By contrast, within the region of the dorsolateral periaqueductal gray (dlPAG) signal intensity initially increased in both groups but returned to baseline levels only in the increasing-MSNA group. These results suggest that the divergent sympathetic responses to muscle pain result from activation of a neural pathway that includes the dlPAG, an area thought to be responsible for the behavioral and cardiovascular responses to psychological rather than physical stressors. Hum Brain Mapp 38:869-881, 2017. © 2016 Wiley Periodicals, Inc.

Inter-individual responses to experimental muscle pain: Baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans.

We have recently shown that intramuscular infusion of hypertonic saline, causing pain lasting ~60min, increases muscle sympathetic nerve activity (MSNA) in one group of subjects, yet decreases it in another. Across subjects these divergent sympathetic responses to long-lasting muscle pain are consistent over time and cannot be foreseen on the basis of baseline MSNA, blood pressure, heart rate or sex. We predicted that differences in anxiety or attitudes to pain may account for these differences. Psychometric measures were assessed prior to the induction of pain using the State and Trait Anxiety Inventory (STAI), Pain Vigilance and Awareness Questionnaire (PVAQ), Pain Anxiety Symptoms Scale (PASS) and Pain Catastrophising Scale (PCS); PCS was also administered after the experiment. MSNA was recorded from the common peroneal nerve, before and during a 45-minute intramuscular infusion of hypertonic saline solution into the tibialis anterior muscle of 66 awake human subjects. Forty-one subjects showed an increase in mean burst amplitude of MSNA (172.8±10.6%) while 25 showed a decrease (69.9±3.8%). None of the measured psychological parameters showed significant differences between the increasing and the decreasing groups. We conclude that inter-individual anxiety or pain attitudes do not determine whether MSNA increases or decreases during long-lasting experimental muscle pain in healthy human subjects.

Inter-Individual Responses to Experimental Muscle Pain: Baseline Physiological Parameters Do Not Determine Whether Muscle Sympathetic Nerve Activity Increases or Decreases During Pain.

We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 min, increases muscle sympathetic nerve activity (MSNA)-as well as blood pressure and heart rate-in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-min intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 ± 7.3%), while 26 showed a sustained decrease (55.1 ± 3.5%). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 ± 1.5 vs. 18.9 ± 1.2 bursts/min), mean BP (88.1 ± 5.2 vs. 88.0 ± 3.8 mmHg), HR (74.7 ± 2.0 vs. 72.8 ± 1.8 beats/min) or heart rate variability (LF/HF 1.8 ± 0.2 vs. 2.2 ± 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pain.

Antibody and T cell responses in reciprocal prime-boost studies with full-length and truncated merozoite surface protein 1-42 vaccines.

The P. falciparum Merozoite Surface Protein 1-42 (MSP1-42) is one of the most studied malaria subunit vaccine candidates. The N-terminal fragment of MSP1-42, MSP1-33, is primarily composed of allelic sequences, and has been shown to possess T helper epitopes that influence protective antibody responses toward the C-terminal region, MSP1-19. A truncated MSP1-42 vaccine, Construct 33-I, consisting of exclusively conserved T epitope regions of MSP1-33 expressed in tandem with MSP1-19, was previously shown to be a more effective immunogen than the full-length MSP1-42 vaccine. Here, by way of reciprocal priming/boosting immunization regimens, we studied the immunogenicity of Construct 33-I in the context of recognition by immune responses induced by the full-length native MSP1-42 protein, in order to gauge the effects of pre- and post-exposures to MSP1-42 on vaccine induced responses. Judging by immune responsiveness, antibody and T cell responses, Construct 33-I was effective as the priming antigen followed by full-length MSP1-42 boosting, as well as the boosting antigen following full-length MSP1-42 priming. In particular, Construct 33-I priming elicited the broadest responsiveness in immunized animals subsequently exposed to MSP1-42. Moreover, Construct 33-I, with its conserved MSP1-33 specific T cell epitopes, was equally well recognized by homologous and heterologous allelic forms of MSP1-42. Serum antibodies raised against Construct 33-I efficiently inhibited the growth of parasites carrying the heterologous MSP1-42 allele. These results suggest that Construct 33-I maintains and/or enhances its immunogenicity in an allelic or strain transcending fashion when deployed in populations having prior or subsequent exposures to native MSP1-42s.

Iron oxide nanoparticles as a clinically acceptable delivery platform for a recombinant blood-stage human malaria vaccine.

This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10 vs. 1.6×10; respectively). Only rMSP1-1O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery.