Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Firing properties of single axons with cardiac rhythmicity in the human cervical vagus nerve.

Microneurographic recordings of the human cervical vagus nerve have revealed the presence of multi-unit neural activity with measurable cardiac rhythmicity. This suggests that the physiology of vagal neurones with cardiovascular regulatory function can be studied using this method. Here, the activity of cardiac rhythmic single units was discriminated from human cervical vagus nerve recordings using template-based waveform matching. The activity of 44 cardiac rhythmic neurones (22 with myelinated axons and 22 with unmyelinated axons) was isolated. By consideration of each unit's firing pattern with respect to the cardiac and respiratory cycles, the functional identification of each unit was attempted. Of note is the observation of seven cardiac rhythmic neurones with myelinated axons whose activity was recruited or enhanced by slow, deep breathing, was maximal during the nadir of respiratory sinus arrhythmia, and showed an expiratory peak. This is characteristic of cardioinhibitory efferent neurones, which are responsible for respiratory sinus arrhythmia. The remaining 15 cardiac rhythmic neurones with myelinated axons were categorised as cardiopulmonary receptors or arterial baroreceptors based on the position of their peak in firing with respect to the R-wave of the cardiac cycle. This latter method is not viable for neurones with unmyelinated axons due to their slow and unknown conduction velocities. With the exception of three neurones whose expiratory modulation implicates them as cardiac-projecting efferent neurones, this population is likely dominated by arterial baroreceptors. In conclusion, the activity of single units with cardiovascular function has been discriminated within the human cervical vagus, enabling their systematic study. KEY POINTS: Recordings of the electrical activity of the vagus nerve have recently been made at the level of the neck in humans. Examination of the gross activity of this nerve reveals subpopulations of neurones whose activity fluctuates in time with the heart's beat, suggesting that the neurones that monitor or modify cardiac function can be studied using this method. Here, the activity of individual cardiac rhythmic neurones was isolated from human vagus nerve recordings using template-based spike sorting. The relationship between this activity and the cardiac and respiratory cycles was used as a means of classifying each neurone. Neuronal firing patterns that are consistent with that of neurones that modify cardiac function, including heart-slowing 'cardioinhibitory' neurones, as well as neurones that inform the brain of cardiovascular status were observed. This approach enables, for the first time, the systematic study of the function of these neurones in humans in both health and disease.

A general O-glycosylation system important to the physiology of a major human intestinal symbiont.

The Bacteroides are a numerically dominant genus of the human intestinal microbiota. These organisms harbor a rare bacterial pathway for incorporation of exogenous fucose into capsular polysaccharides and glycoproteins. The infrequency of glycoprotein synthesis by bacteria prompted a more detailed analysis of this process. Here, we demonstrate that Bacteroides fragilis has a general O-glycosylation system. The proteins targeted for glycosylation include those predicted to be involved in protein folding, protein-protein interactions, peptide degradation as well as surface lipoproteins. Protein glycosylation is central to the physiology of B. fragilis and is necessary for the organism to competitively colonize the mammalian intestine. We provide evidence that general O-glycosylation systems are conserved among intestinal Bacteroides species and likely contribute to the predominance of Bacteroides in the human intestine.

Borderline Personality Disorder: A Review.

Importance: Borderline personality disorder (BPD) affects approximately 0.7% to 2.7% of adults in the US. The disorder is associated with considerable social and vocational impairments and greater use of medical services. Observations: Borderline personality disorder is characterized by sudden shifts in identity, interpersonal relationships, and affect, as well as by impulsive behavior, periodic intense anger, feelings of emptiness, suicidal behavior, self-mutilation, transient, stress-related paranoid ideation, and severe dissociative symptoms (eg, experience of unreality of one's self or surroundings). Borderline personality disorder is typically diagnosed by a mental health specialist using semistructured interviews. Most people with BPD have coexisting mental disorders such as mood disorders (ie, major depression or bipolar disorder) (83%), anxiety disorders (85%), or substance use disorders (78%). The etiology of BPD is related to both genetic factors and adverse childhood experiences, such as sexual and physical abuse. Psychotherapy is the treatment of choice for BPD. Psychotherapy such as dialectical behavior therapy and psychodynamic therapy reduce symptom severity more than usual care, with medium effect sizes (standardized mean difference) between -0.60 and -0.65. There is no evidence that any psychoactive medication consistently improves core symptoms of BPD. For discrete and severe comorbid mental disorders, eg, major depression, pharmacotherapy such as the selective serotonin reuptake inhibitors escitalopram, sertraline, or fluoxetine may be prescribed. For short-term treatment of acute crisis in BPD, consisting of suicidal behavior or ideation, extreme anxiety, psychotic episodes, or other extreme behavior likely to endanger a patient or others, crisis management is required, which may include prescription of low-potency antipsychotics (eg, quetiapine) or off-label use of sedative antihistamines (eg, promethazine). These drugs are preferred over benzodiazepines such as diazepam or lorazepam. Conclusions and Relevance: Borderline personality disorder affects approximately 0.7% to 2.7% of adults and is associated with functional impairment and greater use of medical services. Psychotherapy with dialectical behavior therapy and psychodynamic therapy are first-line therapies for BPD, while psychoactive medications do not improve the primary symptoms of BPD.

Common carotid artery responses to the cold-pressor test are impaired in individuals with cervical spinal cord injury.

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the three- to fourfold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascular and CCA responses to the CPT may provide insight into cardiovascular autonomic dysfunction and cardiovascular disease risk in individuals with cervical SCI. Here, we used CPT to perturb the autonomic nervous system in 14 individuals with cervical SCI and 12 uninjured controls, while measuring cardiovascular responses and CCA diameter. The CCA diameter responses were 55% impaired in those with SCI compared with uninjured controls (P = 0.019). The CCA flow, velocity, and shear response to CPT were reduced in SCI by 100% (P < 0.001), 113% (P = 0.001), and 125% (P = 0.002), respectively. The association between mean arterial pressure and CCA dilation observed in uninjured individuals (r = 0.54, P = 0.004) was absent in the SCI group (r = 0.22, P = 0.217). Steady-state systolic blood pressure (P = 0.020), heart rate (P = 0.003), and cardiac contractility (P < 0.001) were reduced in those with cervical SCI, whereas total peripheral resistance was increased compared with uninjured controls (P = 0.042). Relative cerebral blood velocity responses to CPT were increased in the SCI group and reduced in controls (middle cerebral artery, P = 0.010; posterior cerebral artery, P = 0.026). The CCA and cardiovascular responsiveness to CPT are impaired in those with cervical SCI.NEW & NOTEWORTHY This is the first study demonstrating that CCA responses during CPT are suppressed in SCI. Specifically, CCA diameter, flow, velocity, and shear rate were reduced. The relationship between changes in MAP and CCA dilatation in response to CPT was absent in individuals with SCI, despite similar cardiovascular activation between SCI and uninjured controls. These findings support the notion of elevated cardiovascular disease risk in SCI and that the cardiovascular responses to environmental stimuli are impaired.

Development and Validation of the Interview of Personality Organization Processes in Adolescence (IPOP-A).

The assessment of personality and personality pathology in adolescence represents a critical topic to understand adolescent's difficulties, predict long-term outcome in adulthood, and indicate adequate treatment. Personality Organization, and its underlying dimensions, plays an essential role in shaping how adolescents face their developmental tasks as they are connected with psychosocial functioning and psychopathological severity. However, few measures are available to assess personality organization during adolescence. The aim of the present research is to investigate the psychometric properties of the Interview of Personality Organization Processes in Adolescence (IPOP-A), a semi-structured interview designed for the assessment of the main personality organization dimensions in adolescence. Three studies were performed to explore the psychometric properties of the IPOP-A, in terms of factor structure, reliability, convergent, and discriminant validity. Exploratory and confirmatory factor analysis supported the IPOP-A construct validity. Furthermore, IPOP-A showed good reliability and evidenced a convergent and discriminant validity with DSM-oriented personality patterns, emotion dysregulation, identity disturbance, and psychopathology. Our results provide evidence of IPOP-A validity to assess emerging personality organization in adolescence. Furthermore, the IPOP-A is a promising tool to use in the clinical consultation and treatment planning for the adolescent.

Challenges for the Future of Psychoanalysis.

This paper summarizes the current crisis of psychoanalysis in its relations to the scientific and cultural environment. It proposes tasks to assure the survival and contributions of psychoanalysis as science, profession, and humanistic discipline. It proposes emphasis on empirical research in the boundaries with the neurosciences and social psychology, and the development of an infrastructure for research linked to its educational program. It proposes renovation in training, abolishment of the training analysis system, and systematic teaching and research on the psychoanalytic psychotherapies focused on specific pathologies. This overall proposal stresses the need to collaborate and potentially integrate psychoanalytic institutions within university settings, and the development of active interdisciplinary engagements with other sciences and the community at large. Finally, it stresses the role of contemporary object relations theory to reunify the presently diverging schools of psychoanalytic theory and technique.

Effects of circulating extracellular microvesicles from spinal cord-injured adults on endothelial cell function.

People with spinal cord injury (SCI) have three- to four-fold greater risk of cardiovascular disease (CVD) compared with those without SCI. Although circulating extracellular microvesicles are key effectors of vascular health and disease, how their functional phenotype might be altered with SCI is unknown. The aim of the present study was to determine the effects of microvesicles isolated from SCI adults on endothelial cell inflammation and oxidative stress as well as endothelial nitric oxide (NO) synthase (eNOS) activation and tissue-type plasminogen activator (t-PA) expression. Eighteen young and middle-aged adults were studied: 10 uninjured (7M/3F; age: 39 ± 3 years) and 8 cervical level spinal cord injured (SCI; 7M/1F; 46 ± 4 years; cervical injury: C3: n=1; C5: n=4; C6: n=3). Circulating microvesicles were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were cultured and treated with microvesicles from either the uninjured or SCI adults. Microvesicles from SCI adults did not affect cellular markers or mediators of inflammation and oxidative stress. However, microvesicles from the SCI adults significantly blunted eNOS activation, NO bioavailability and t-PA production. Intercellular expression of phosphorylated eNOS at Ser1177 and Thr495 sites, specifically, were ∼65% lower and ∼85% higher, respectively, in cells treated with microvesicles from SCI compared with uninjured adults. Decreased eNOS activity and NO production as well as impaired t-PA bioavailability renders the vascular endothelium highly susceptible to atherosclerosis and thrombosis. Thus, circulating microvesicles may contribute to the increased risk of vascular disease and thrombotic events associated with SCI.

Alterations in resting cerebrovascular regulation do not affect reactivity to hypoxia, hyperoxia or neurovascular coupling following a SCUBA dive.

NEW FINDINGS: What is the central question of this study? What are the characteristics of cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. What is the main finding and its importance? Acute alterations in CBF regulation at rest, including extra-cranial vasodilatation, reductions in shear patterns and elevations in intra-cranial blood velocity were observed at rest following a single SCUBA dive. These subtle changes in CBF regulation did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or neurovascular coupling following a single SCUBA dive. ABSTRACT: Reductions in vascular function during a SCUBA dive - due to hyperoxia-induced oxidative stress, arterial and venous gas emboli and altered endothelial integrity - may also extend to the cerebrovasculature following return to the surface. This study aimed to characterize cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18 m sea water with a 47 min bottom time. Prior to and following the dive, participants (n = 11) completed (1) resting CBF in the internal carotid (ICA) and vertebral (VA) arteries (duplex ultrasound) and intra-cranial blood velocity (v) of the middle and posterior cerebral arteries (MCAv and PCAv, respectively) (transcranial Doppler ultrasound); (2) cerebrovascular reactivity to acute poikilocapnic hypoxia (i.e. FIO2 , 0.10) and hyperoxia (i.e. FIO2 , 1.0); and (3) neurovascular coupling (NVC; regional CBF response to local increases in cerebral metabolism). Global CBF, cerebrovascular reactivity to hypoxia and hyperoxia, and NVC were unaltered following a SCUBA dive (all P > 0.05); however, there were subtle changes in other cerebrovascular metrics post-dive, including reductions in ICA (-13 ± 8%, P = 0.003) and VA (-11 ± 14%, P = 0.021) shear rate, lower ICAv (-10 ± 9%, P = 0.008) and VAv (-9 ± 14%, P = 0.028), increases in ICA diameter (+4 ± 5%, P = 0.017) and elevations in PCAv (+10 ± 19%, P = 0.047). Although we observed subtle alterations in CBF regulation at rest, these changes did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or NVC. Whether prolonged exposure to hyperoxia and hyperbaria during longer, deeper, colder and/or repetitive SCUBA dives would provoke changes to the cerebrovasculature requires further investigation.

Vascular dysfunction following breath-hold diving.

The pathogenesis of predominantly neurological decompression sickness (DCS) is multifactorial. In SCUBA diving, besides gas bubbles, DCS has been linked to microparticle release, impaired endothelial function, and platelet activation. This study focused on vascular damage and its potential role in the genesis of DCS in breath-hold diving. Eleven breath-hold divers participated in a field study comprising eight deep breath-hold dives with short surface periods and repetitive breath-hold dives lasting for 6 h. Endothelium-dependent vasodilation of the brachial artery, via flow-mediated dilation (FMD), and the number of microparticles (MPs) were assessed before and after each protocol. All measures were analyzed by two-way within-subject ANOVA (2 × 2 ANOVA; factors: time and protocol). Absolute FMD was reduced following both diving protocols (p < 0.001), with no interaction (p = 0.288) or main effect of protocol (p = 0.151). There was a significant difference in the total number of circulating MPs between protocols (p = 0.007), where both increased post-dive (p = 0.012). The number of CD31+/CD41- and CD66b+ MP subtypes, although different between protocols (p < 0.001), also increased by 41.0% ± 56.6% (p = 0.050) and 60.0% ± 53.2% (p = 0.045) following deep and repetitive breath-hold dives, respectively. Both deep and repetitive breath-hold diving lead to endothelial dysfunction that may play an important role in the genesis of neurological DCS.

Assessment of the applicability of HLB values for natural phospholipid emulsifiers for preparation of stable emulsions.

Natural phospholipid (PL) excipients are native, biocompatible and relatively inexpensive alternatives to synthetic emulsifiers. A well-known PL excipient is lecithin, which primarily contains phosphatidylcholine (PC) and (depending on the purity grade) also contains a well-defined mixture of other PLs with a fatty acid composition, which reflects their natural source. Since all of these lipid species are emulsifiers, natural PLs can be considered as a mixture of (co-) emulsifiers. Many different HLB values for lecithins are given in the literature, which is why this needs to be clarified. To assess this, HLB values of thirteen different plant derived PLs differing in PC content were determined using a centrifugation stress method to determine the relative stability of an emulsion with the respective emulsifier and different oil phases. It could be shown that the studied PLs can be characterized by a broad HLB range, which may be linked to the composition of the PLs and the oil used. In order to emphasize the results of the HLB determination, it could be demonstrated that stable emulsions could be prepared with a wide range of oils using the plant-based PLs and that the preparation method of the emulsions is important in order to obtain stable emulsions. Therefore, assigning a specific exact HLB value to natural PLs instead of a wider range is inappropriate. The broad HLB ranges indicate the suitability of the studied PL emulsifiers for the preparation of oil-in-water emulsions for a wide range of oils: It is recommended to experimentally evaluate the suitability of these natural emulsifiers for the preparation of stable emulsions and to benefit from the wide range of HLB values of these emulsifiers instead of relying on inaccurate and confusing HLB values in the literature.

Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury.

Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b-) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (-93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.

Strong impact of MammaPrint and BluePrint on treatment decisions in luminal early breast cancer: results of the WSG-PRIMe study.

PURPOSE: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer. METHODS: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires. RESULTS: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in "discordant" groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients' State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients. CONCLUSIONS: MammaPrint and BluePrint test results strongly impacted physicians' therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

Competitive apnea and its effect on the human brain: focus on the redox regulation of blood-brain barrier permeability and neuronal-parenchymal integrity.

Static apnea provides a unique model that combines transient hypertension, hypercapnia, and severe hypoxemia. With apnea durations exceeding 5 min, the purpose of the present study was to determine how that affects cerebral free-radical formation and the corresponding implications for brain structure and function. Measurements were obtained before and following a maximal apnea in 14 divers with transcerebral exchange kinetics, measured as the product of global cerebral blood flow (duplex ultrasound) and radial arterial to internal jugular venous concentration differences ( a-vD). Apnea increased the systemic (arterial) and, to a greater extent, the regional (jugular venous) concentration of the ascorbate free radical, resulting in a shift from net cerebral uptake to output ( P < 0.05). Peroxidation (lipid hydroperoxides, LDL oxidation), NO bioactivity, and S100ß were correspondingly enhanced ( P < 0.05), the latter interpreted as minor and not a pathologic disruption of the blood-brain barrier. However, those changes were insufficient to cause neuronal-parenchymal damage confirmed by the lack of change in the a-vD of neuron-specific enolase and human myelin basic protein ( P > 0.05). Collectively, these observations suggest that increased cerebral oxidative stress following prolonged apnea in trained divers may reflect a functional physiologic response, rather than a purely maladaptive phenomenon.-Bain, A. R., Ainslie, P. N., Hoiland, R. L., Barak, O. F., Drvis, I., Stembridge, M., MacLeod, D. M., McEneny, J., Stacey, B. S., Tuaillon, E., Marchi, N., De Maudave, A. F., Dujic, Z., MacLeod, D. B., Bailey, D. M. Competitive apnea and its effect on the human brain: focus on the redox regulation of blood-brain barrier permeability and neuronal-parenchymal integrity.

Cerebrovascular function is preserved during mild hyperthermia in cervical spinal cord injury.

STUDY DESIGN: Experimental study. OBJECTIVES: Compromised cerebrovascular function likely contributes to elevated neurological risk in spinal cord injury (SCI). Passive heating offers many cardiovascular and neurological health benefits; therefore, we aimed to determine the effects of an acute bout of heating on cerebrovascular function in chronic SCI. METHODS: Persons with cervical SCI (n = 15) and uninjured controls (CON; n = 15) completed 60 min of lower limb hot water immersion (40 °C). Assessments of middle cerebral (MCA) and posterior cerebral artery (PCA) velocities, pulsatilities, and neurovascular coupling (NVC) were performed using transcranial Doppler ultrasound. Duplex ultrasonography was used to index cerebral blood flow via the internal carotid artery (ICA), and carotid-femoral pulse-wave velocity (PWV) was measured using tonometry. The NVC response was quantified as the peak hyperemic value during 30-s cycles of visual stimulation. RESULTS: Mean arterial pressure changed differentially with heating [mean (standard deviation); SCI: +6(14) mmHg, CON: -8(12) mmHg; P = 0.01]. There were no differences in any intracranial artery measures (all P > 0.05), except for small (~10%) increases in MCA conductance in CON after heating vs. SCI (interaction P = 0.006). Resting ICA flow was greater in SCI vs. CON (P = 0.03) but did not change with heating in either group (interaction P = 0.34). There were also no between-group differences in the NVC response (ΔPCA conductance) pre- [SCI: 29(19)% vs. CON: 30(9)%] or post-heating [SCI 30(9)% vs. 25(9)%; interaction P = 0.22]. CONCLUSIONS: Mild acute heating does not impair or improve cerebrovascular function in SCI or CON. Thus, further study of the effects of chronic heating interventions are warranted.

Reflections on Supervision.

This paper explores basic tasks involved in the supervisory process, and frequent problems in carrying out these tasks. Basic tasks include clarification of mutual expectations of supervisor and supervisee; the establishment of mutual trust as fundamental for countertransference analysis; "parallel process" exploration and clarification of explicit and implicit theoretical assumptions by both supervisor and supervisee. Frequent problems include the extent of initial evaluation of patients; problems of intervening "without memory or desire"; transference and countertransference diagnoses and interpretive consequences; clarification of affective dominance; interventive shifts with severe psychopathology, and realistic goals of patient, supervisee and supervisor. Limitations to supervision include specific psychopathologies, cognitive limitations, and a generally restricted capacity for empathy by the supervisee.

Wavelet decomposition analysis is a clinically relevant strategy to evaluate cerebrovascular buffering of blood pressure after spinal cord injury.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) is crucial to prevent stroke, the incidence of which is three- to fourfold elevated after spinal cord injury (SCI). Disruption of descending sympathetic pathways within the spinal cord due to cervical SCI may result in impaired cerebrovascular buffering. Only linear analyses of cerebrovascular buffering of BP, such as transfer function, have been used in SCI research. This approach does not account for inherent nonlinearity and nonstationarity components of cerebrovascular regulation, often depends on perturbations of BP to increase the statistical power, and does not account for the influence of arterial CO2 tension. Here, we used a nonlinear and nonstationary analysis approach termed wavelet decomposition analysis (WDA), which recently identified novel sympathetic influences on cerebrovascular buffering of BP occurring in the ultra-low-frequency range (ULF; 0.02-0.03Hz). WDA does not require BP perturbations and can account for influences of CO2 tension. Supine resting beat-by-beat BP (Finometer), middle cerebral artery blood velocity (transcranial Doppler), and end-tidal CO2 tension were recorded in cervical SCI ( n = 14) and uninjured ( n = 16) individuals. WDA revealed that cerebral blood flow more closely follows changes in BP in the ULF range ( P = 0.0021, Cohen's d = 0.89), which may be interpreted as an impairment in cerebrovascular buffering of BP. This persisted after accounting for CO2. Transfer function metrics were not different in the ULF range, but phase was reduced at 0.07-0.2 Hz ( P = 0.03, Cohen's d = 0.31). Sympathetically mediated cerebrovascular buffering of BP is impaired after SCI, and WDA is a powerful strategy for evaluating cerebrovascular buffering in clinical populations.

Differential influence of vitamin C on the peripheral and cerebral circulation after diving and exposure to hyperoxia.

We examined if the diving-induced vascular changes in the peripheral and cerebral circulation could be prevented by oral antioxidant supplementation. Fourteen divers performed a single scuba dive to eighteen meter sea water for 47 min. Twelve of the divers participated in a follow-up study involving breathing 60% of oxygen at ambient pressure for 47 min. Before both studies, participants ingested vitamin C (2 g/day) or a placebo capsule for 6 days. After a 2-wk washout, the study was repeated with the different condition. Endothelium-dependent vasodilator function of the brachial artery was assessed pre- and postintervention using the flow-mediated dilation (FMD) technique. Transcranial Doppler ultrasound was used to measure intracranial blood velocities pre- and 90 min postintervention. FMD was reduced by ∼32.8% and ∼21.2% postdive in the placebo and vitamin C trial and posthyperoxic condition in the placebo trial by ∼28.2% ( P < 0.05). This reduction in FMD was attenuated by ∼10% following vitamin C supplementation in the hyperoxic study ( P > 0.05). Elevations in intracranial blood velocities 30 min after surfacing from diving were reduced in the vitamin C study compared with the placebo trial ( P < 0.05). O2 breathing had no postintervention effects on intracranial velocities ( P > 0.05). Prophylactic ingestion of vitamin C effectively abrogated peripheral vascular dysfunction following exposure to 60% O2 but did not abolish the postdive decrease in FMD. Transient elevations of intracranial velocities postdive were reduced by vitamin C. These findings highlight the differential influence of vitamin C on peripheral and cerebral circulations following scuba diving, which are only partly mediated via hyperoxia.

Highs and lows of hyperoxia: physiological, performance, and clinical aspects.

Molecular oxygen (O2) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O2 delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O2, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O2 delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O2 toxicity and future research directions are also considered.

Oxygen therapy improves cerebral oxygen delivery and neurovascular function in hypoxaemic chronic obstructive pulmonary disease patients.

NEW FINDINGS: What is the central question of this study? How does oxygen therapy influence cerebral blood flow, cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients? What is the main finding and its importance? Oxygen therapy improves cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients. This improvement in cerebral oxygen delivery and neurovascular function might provide a physiological link between oxygen therapy and a reduced risk of cerebrovascular disease (e.g. stroke, mild cognitive impairment and dementia) in chronic obstructive pulmonary disease. ABSTRACT: We investigated the role of hypoxaemia in cerebral blood flow (CBF), oxygen delivery (CDO2 ) and neurovascular coupling (coupling of CBF to neural activity; NVC) in hypoxaemic chronic obstructive pulmonary disease (COPD) patients (n = 14). Resting CBF (duplex ultrasound), peripheral oxyhaemoglobin saturation (SpO2; pulse-oximetry) and NVC (transcranial Doppler) were assessed before and after a 20 min wash-in of supplemental oxygen (∼3 l min-1 ). The peripheral oxyhaemoglobin saturation increased from 91.0 ± 3.3 to 97.4 ± 3.0% (P < 0.01), whereas CBF was unaltered (593.0 ± 162.8 versus 590.1 ± 138.5 ml min-1 ; P = 0.91) with supplemental O2 . In contrast, both CDO2 (98.1 ± 25.7 versus 108.7 ± 28.4 ml dl-1 ; P = 0.02) and NVC were improved. Specifically, the posterior cerebral artery cerebrovascular conductance was increased to a greater extent after O2 normalization (+40%, from 20.4 ± 9.9 to 28.0 ± 10.4% increase in conductance; P = 0.04), whereas the posterior cerebral artery cerebrovascular resistance decreased to a greater extent during O2 normalization (+22%, from -16.7 ± 7.3 to -21.4 ± 6.6% decrease in resistance; P = 0.04). The cerebral vasculature of COPD patients appears insensitive to oxygen, because CBF was unaltered in response to O2 supplementation leading to improved CDO2 . In patients, the improvements in CDO2 and neurovascular function with supplemental O2 may underlie the cognitive benefits associated with O2 therapy.