Detection of large-scale X-ray bubbles in the Milky Way halo.

The halo of the Milky Way provides a laboratory to study the properties of the shocked hot gas that is predicted by models of galaxy formation. There is observational evidence of energy injection into the halo from past activity in the nucleus of the Milky Way1-4; however, the origin of this energy (star formation or supermassive-black-hole activity) is uncertain, and the causal connection between nuclear structures and large-scale features has not been established unequivocally. Here we report soft-X-ray-emitting bubbles that extend approximately 14 kiloparsecs above and below the Galactic centre and include a structure in the southern sky analogous to the North Polar Spur. The sharp boundaries of these bubbles trace collisionless and non-radiative shocks, and corroborate the idea that the bubbles are not a remnant of a local supernova5 but part of a vast Galaxy-scale structure closely related to features seen in γ-rays6. Large energy injections from the Galactic centre7 are the most likely cause of both the γ-ray and X-ray bubbles. The latter have an estimated energy of around 1056 erg, which is sufficient to perturb the structure, energy content and chemical enrichment of the circumgalactic medium of the Milky Way.

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

The Nasal Microbiome in ANCA-Associated Vasculitis: Picking the Nose for Clues on Disease Pathogenesis.

PURPOSE OF REVIEW: The onset and progression of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies has been linked to microbial infections. Here, we provide a brief overview of the association of nasal colonization of Staphylococcus aureus with ANCA-associated vasculitis (AAV) and discuss several recent studies mapping the nasal microbiome in AAV patients in particular. RECENT FINDINGS: Nasal microbiome studies revealed dysbiosis as a common trait in active AAV which tends to normalize upon immunosuppressive treatment and quiescent disease. However, due to differences in study design, patient selection, and methodology, the reported microbiome profiles differ considerably precluding conclusions on causal relationships. The microbiome is an emerging area of research in AAV warranting further investigation. Ideally, such studies should be combined with mechanistic studies to unravel key elements related to host-microbe interactions and their relevance for AAV pathogenesis.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Turbulent heating in galaxy clusters brightest in X-rays.

The hot (10(7) to 10(8) kelvin), X-ray-emitting intracluster medium (ICM) is the dominant baryonic constituent of clusters of galaxies. In the cores of many clusters, radiative energy losses from the ICM occur on timescales much shorter than the age of the system. Unchecked, this cooling would lead to massive accumulations of cold gas and vigorous star formation, in contradiction to observations. Various sources of energy capable of compensating for these cooling losses have been proposed, the most promising being heating by the supermassive black holes in the central galaxies, through inflation of bubbles of relativistic plasma. Regardless of the original source of energy, the question of how this energy is transferred to the ICM remains open. Here we present a plausible solution to this question based on deep X-ray data and a new data analysis method that enable us to evaluate directly the ICM heating rate from the dissipation of turbulence. We find that turbulent heating is sufficient to offset radiative cooling and indeed appears to balance it locally at each radius-it may therefore be the key element in resolving the gas cooling problem in cluster cores and, more universally, in the atmospheres of X-ray-emitting, gas-rich systems on scales from galaxy clusters to groups and elliptical galaxies.

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

Characterization of urinary CD4⁺ and CD8⁺ T cells in kidney transplantation patients with polyomavirus BK infection and allograft rejection.

BACKGROUND AND OBJECTIVES: The objective of this study was to characterize CD4(+) and CD8(+) T-cell populations in blood and urine of renal transplant patients with BK virus (BKV) infection or allograft rejection. MATERIALS AND METHODS: Percentages and absolute numbers of CD4(+) and CD8(+) effector memory T-cell subtype (TEM ) and terminal differentiated T cells (TTD ) in renal transplant patients with BKV infection (n = 14), with an episode of allograft rejection (n = 9), and in uncomplicated renal transplant patients with a stable kidney function (n = 12) were measured and compared using 4-color fluorescence-activated cell sorting. Results were correlated with the number of CD4(+) and CD8(+) T cells in renal biopsies. RESULTS: In patients with allograft rejection, the number of urinary CD4(+) TEM and CD8(+) TEM cells was significantly increased compared to patients with BKV infection or patients without complications. Positive correlation was found between the number of CD4(+) and CD8(+) cells in the renal biopsies and the number of CD4(+) and CD8(+) cells in urine. In patients with rejection, after 2 months of immunosuppressive therapy, a reduction in urinary CD8(+) TEM cells was found. CONCLUSIONS: CD4(+) TEM and CD8(+) TEM cells in urine could be a marker to distinguish allograft rejection from BKV-associated nephropathy and to monitor therapy effectiveness in renal transplant patients with allograft rejection.

Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis and potential targets for biologic treatment.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.

Magnetic support of the optical emission line filaments in NGC 1275.

The giant elliptical galaxy NGC 1275, at the centre of the Perseus cluster, is surrounded by a well-known giant nebulosity of emission-line filaments, which are plausibly in excess of 10(8) years old. The filaments are dragged out from the centre of the galaxy by radio-emitting 'bubbles' rising buoyantly in the hot intracluster gas, before later falling back. They act as markers of the feedback process by which energy is transferred from the central massive black hole to the surrounding gas. The mechanism by which the filaments are stabilized against tidal shear and dissipation into the surrounding extremely hot (4 x 10(7) K) gas has been unclear. Here we report observations that resolve thread-like structures in the filaments. Some threads extend over 6 kpc, yet are only 70 pc wide. We conclude that magnetic fields in the threads, in pressure balance with the surrounding gas, stabilize the filaments, so allowing a large mass of cold gas to accumulate and delay star formation.

Patient engagement as a collaborative process in a large Dutch COVID-19 vaccination study (RECOVAC) - insight into the contribution of patient engagement and learnings for the future.

BACKGROUND: The need for patient engagement in health research has been increasingly acknowledged and accepted in recent years. However, implementation is still limited due to lack of evidence on its value and lack of guidance on how to implement patient engagement. This study aims to provide insight into the contribution of patient engagement in the RECOVAC project, which studied COVID-19 vaccination in kidney patients, and formulate concrete practice-based action perspectives for patient engagement. METHODS: We used a qualitative participatory mixed methods approach, based on the Patient Engagement Monitoring and Evaluation (PEME) framework. Patient engagement and data collection were based on the Reflexive Monitoring in Action (RMA) approach. Data collection included participant observations, open ended questionnaires and interactive reflection sessions. Qualitative analysis was done via a thematic approach. RESULTS: We have described the process of patient engagement systematically, provided insight in its value and found that there is a need for clear aims, expectations and preparations from the start of the engagement process. We have shown that reflection throughout the process is of utmost importance and the same applies to clear communication between researchers and patient representatives. By being part of the consortium patient representatives had direct access to information, straight from the source, on for example the vaccination schedule and medication availability and had indirect influence on decisions made by the National Institute for Public Health and the Environment (RIVM) on preventive measures and treatment against COVID-19. Having experienced patient representatives is important, otherwise training needs to be provided. We also found that patient engagement had impact on conduct and outcomes of research activities itself and may have impact on future research and patient engagement activities in general. CONCLUSION: Patient engagement has changed the course of the project. Concrete practice-based action perspectives have been formulated, which are already being implemented by the Dutch Kidney Patients Association (NVN). Studying patient engagement in a high pace project with high public interest has resulted in lessons learned and will help prepare and implement patient involvement in future research projects. CLINICAL TRIAL REGISTRATION: The RECOVAC studies in which the patient engagement took place are registered at clinicialtrial.gov (NCT04741386 registration date 2021-02-04, NCT04841785 registration date 2021-03-22 and NCT05030974 registration date 2021-08-20).

This article is about the extensive engagement of patients in a scientific research project and what that engagement adds to the project. Although researchers acknowledge the importance of engagement of patients in research projects, it is not happening very often, Because there is not enough scientific evidence on the value of patient engagement and not enough guidance for researcher on how to implement it in their research. We used the Patient Engagement Monitoring and Evaluation (PEME) framework and qualitative participatory mixed methods research to provide insight into patient involvement in the RECOVAC project, which studied COVID-19 vaccination in kidney patients. We also formulated practical guidance for researchers who want to engage patients in their research. We describe the process of patient engagement in the RECOVAC project; what went well and what could be improved. We found that it is important to prepare well, keep reflecting on the engagement process throughout the project with all stakeholders of the project, communicate clearly and have experienced patient representatives involved or have training available for them. Patient engagement had impact on the conduct and outcome of the research activities itself and on activities outside of the project (e.g., doctors changing their conversations with their patients). We can conclude that involving patients changed the project and its outcomes to better fit with the needs of patients. A guideline has been made and is already implemented by the Dutch Kidney Patients Association. The lessons learned from this project will help researchers involve patients in their future projects.

Fasting before living-kidney donation: effect on donor well-being and postoperative recovery: study protocol of a multicenter randomized controlled trial.

BACKGROUND: One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated. METHODS: We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery. DISCUSSION: Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions. TRIAL REGISTRATION: Netherlands Trial Register NL9262 . EudraCT 2020-005445-16 . MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21.

Renal scintigraphy for post-transplant monitoring after kidney transplantation.

BACKGROUND: Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities. METHODS: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391. RESULTS: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes. CONCLUSIONS: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results.

How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.

Cardiopulmonary baroreflexes fail to modulate sympathetic responses during isometric exercise in humans: direct evidence from microneurographic studies.

To further evaluate the reported interaction in animals and humans between cardiopulmonary baroreflexes and the somatic pressor reflex, studies were performed in 16 normal men using direct measurements of efferent sympathetic nerve activity to muscle (microneurography) during sustained isometric handgrip (30% maximal voluntary contraction). Forearm vasoconstrictor (plethysmography) and muscle sympathetic nerve activity responses to sustained handgrip were measured during cardiopulmonary baroreceptor deactivation (lower body negative pressure, n = 8) and activation (volume expansion, n = 8). In addition, responses to posthandgrip muscle ischemia were studied during these perturbations of cardiopulmonary baroreflexes. No evidence of an interaction between these two reflex pathways was found. When handgrip was performed during lower body negative pressure, the percent increase in muscle sympathetic nerve activity (+115 +/- 17%) was not different from the sum of the individual sympathetic responses to handgrip and lower body negative pressure performed separately (+106 +/- 19%, p = NS). Likewise, the change in forearm vascular resistance (+3.9 +/- 0.8 U) for sustained handgrip performed during lower body negative pressure was not different from the algebraic sum of the responses to handgrip and lower body negative pressure when these were performed separately (+4.7 +/- 2.7 U, p = NS). No difference was noted in forearm vasoconstrictor and sympathetic nerve activity responses to posthandgrip muscle ischemia and lower body negative pressure when these were performed alone or in combination. Volume expansion also failed to uncover an inhibitory interaction. Handgrip performed before volume expansion resulted in forearm vascular resistance responses (-1.2 +/- 0.9 U) that were not different from the responses when such handgrip was performed after volume infusion (+0.9 +/- 0.9 U, p = NS). Rather than producing the predicted inhibition of muscle sympathetic nerve activity responses to sustained handgrip, volume infusion actually increased these responses. During prevolume sustained handgrip, the increase in sympathetic nerve activity (+64.5 +/- 15.7%) was significantly less than the increase when handgrip was performed after volume infusion (+105.6 +/- 20.1%, p less than 0.01). A similar lack of inhibitory modulation was seen during posthandgrip muscle ischemia performed before and after volume expansion. These data indicate that the efferent sympathetic responses to the somatic pressor reflex are not modulated by the cardiopulmonary baroreflexes in normal humans.

Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings.

To characterize the neural excitatory state of heart failure, simultaneous measurements of efferent sympathetic nerve activity to muscle (by microneurography) and rest hemodynamics were obtained in 10 normal subjects (age 25 +/- 2 years, mean +/- SEM) and 29 patients with heart failure (age 49 +/- 2 years; New York Heart Association functional class II to IV; left ventricular ejection fraction 21 +/- 1%; cardiac index = 2.16 +/- 0.13 liters/min per m2; pulmonary capillary wedge pressure 23 +/- 2 mm Hg). Sympathetic nerve activity was significantly higher in the patients with heart failure (54.7 +/- 4.5 bursts/min) than in normal subjects (16.7 +/- 2.2 bursts/min, p less than 0.001). Multiple linear regression analyses indicated that sympathetic activity in these human subjects was most strongly and inversely correlated with left ventricular stroke work index (r = -0.86, p less than 0.0001) and stroke volume index (r = -0.85, p less than 0.0001). There was a strong positive correlation between sympathetic nerve activity and pulmonary artery diastolic (r = 0.82, p less than 0.0001) and mean (r = 0.81, p less than 0.0001) pressures. Similar correlations were seen when patients with heart failure were analyzed separately. There was no significant correlation between sympathetic nerve activity and mean arterial pressure, left ventricular ejection fraction (by radionuclide ventriculography), cardiac chamber size (by echocardiography) or arterial oxygen tension in the patients with heart failure. Direct measurements of sympathetic nerve activity correlated closely with plasma norepinephrine (r = 0.72, p less than 0.0001) in patients with heart failure. Thus, sympathetic nerve activity at rest parallels impairment of cardiac performance in patients with heart failure.

Pathophysiologic levels of atrial natriuretic factor do not alter reflex sympathetic control: direct evidence from microneurographic studies in humans.

To determine if circulating levels of atrial natriuretic factor comparable with those seen in pathophysiologic states alter autonomic control of the circulation, direct recordings of hemodynamic variables and efferent sympathetic nerve activity to muscle (microneurography) were obtained during two separate protocols in a total of 21 normal men (age 25 +/- 1 years). In protocol 1, the responses of 10 men were compared during incremental mechanical unloading of cardiopulmonary baroreceptors with lower body negative pressure versus responses to comparable unloading during infusion of alpha-human atrial natriuretic factor. Lower body negative pressure decreased pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure or heart rate and increased muscle sympathetic nerve activity from 205.2 +/- 36.3 to 438.7 +/- 100.2 units/min (p less than 0.01). Intravenous infusion of atrial natriuretic factor (25 ng/kg per min) increased plasma levels of the hormone from 24 +/- 4 to 322 +/- 34 pg/ml (p less than 0.01, n = 6), produced similar decreases in pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure, increased heart rate and increased sympathetic nerve activity from 233.1 +/- 35.6 to 387.2 +/- 64.9 units/min (p less than 0.05). Thus, during similar hemodynamic perturbations produced by lower body negative pressure or infusion of atrial natriuretic factor at the dose used in this study, these subjects exhibited comparable sympathoexcitatory responses, with a 109 +/- 23% increase in sympathetic activity during lower body negative pressure and a 76 +/- 19% increase during atrial natriuretic factor infusion (p = NS). In protocol 2, the responses of 11 additional men were examined during lower body negative pressure performed before and again during infusion of atrial natriuretic factor (12.5 ng/kg per min). During baseline (prehormone) trials, lower body negative pressure (-14.5 +/- 1.6 mm Hg) decreased central venous pressure, did not change arterial pressure or heart rate and increased sympathetic nerve activity from 215 +/- 47.7 to 372.3 +/- 64.3 units/min (p less than 0.001). Infusion of atrial natriuretic factor increased plasma levels of the hormone from 39 +/- 8 to 313 +/- 18 pg/ml (p less than 0.01, n = 7); central venous pressure was held constant during hormone infusion by intravenous infusion of saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Chyloptysis (chylous sputum) due to thoracic lymphangiectasis with successful surgical correction.

A 73-year-old woman with a two-year history of recurrent episodes of respiratory distress is described. The finding of an elevated triglyceride value of 23.4 mmol/L (2072 mg/dL) and a normal cholesterol value in her sputum led to the correct diagnosis of chyloptysis after lymphangiography was performed. It is thought that congenital incompetence of the lymphatic valves was the cause of chyloptysis.