Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs.

BACKGROUND AND PURPOSE: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.

Protective effect of microbiota-derived short chain fatty acids on vascular dysfunction in mice with systemic lupus erythematosus induced by toll like receptor 7 activation.

Our objective was to investigate whether short-chain fatty acids (SCFAs), specifically acetate and butyrate, could prevent vascular dysfunction and elevated blood pressure (BP) in mice with systemic lupus erythematosus (SLE) induced by TLR7 activation using imiquimod (IMQ). Treatment with both SCFAs and dietary fibers rich in resistant starch (RS) or inulin-type fructans (ITF) effectively prevented the development of hypertension and cardiac hypertrophy. Additionally, these treatments improved aortic relaxation induced by acetylcholine and mitigated vascular oxidative stress. Acetate and butyrate treatments also contributed to the maintenance of colonic integrity, reduced endotoxemia, and decreased the proportion of helper T (Th)17 cells in mesenteric lymph nodes (MLNs), blood, and aorta in TLR7-induced SLE mice. The observed changes in MLNs were correlated with increased levels of GPR43 mRNA in mice treated with acetate and increased GPR41 levels along with decreased histone deacetylase (HDAC)- 3 levels in mice treated with butyrate. Notably, the effects attributed to acetate, but not butyrate, were nullified when co-administered with the GPR43 antagonist GLPG-0974. T cell priming and differentiation into Th17 cells in MLNs, as well as increased Th17 cell infiltration, were linked to aortic endothelial dysfunction and hypertension subsequent to the transfer of faecal microbiota from IMQ-treated mice to germ-free (GF) mice. These effects were counteracted in GF mice through treatment with either acetate or butyrate. To conclude, these findings underscore the potential of SCFA consumption in averting hypertension by restoring balance to the interplay between the gut, immune system, and vascular wall in SLE induced by TLR7 activation.

Antibody Content against Epstein-Barr Virus in Blood Extracellular Vesicles Correlates with Disease Activity and Brain Volume in Patients with Relapsing-Remitting Multiple Sclerosis.

We aimed to analyze whether EVs carry antibodies against EBV antigens and the possibility that they could serve as diagnostic and disease activity blood biomarkers in RRMS. This was a prospective and observational study including patients with RRMS with active and inactive disease and healthy controls. Blood EVs were isolated by precipitation. Titers of antibodies against nuclear (anti-EBNA1) and capsid (anti-VCA) EBV antigens in EVs and in plasma, as well as content of myelin antibodies in EVs were determined by ELISA. An exploratory analysis of correlations with clinical and radiological data was performed. Patients with RRMS had higher titers of anti-VCA inside EVs and free in plasma than healthy controls. Patients with active disease showed higher levels of anti-EBNA1 in EVs, but not in plasma, than patients with inactive disease. EV anti-VCA levels correlated with disease duration and with decreased brain volume structures-total brain, white matter, gray matter, cerebellum, hippocampus, -but not with T2/FLAIR lesion volume or EDSS, SDMT, or 9HPT. In addition, EV anti-VCA correlated with EV anti-MBP. The anti-VCA and anti-EBNA1 content in EVs could represent diagnostic and disease activity blood biomarkers, respectively, in RRMS.

Dual role of peripheral B cells in multiple sclerosis: emerging remote players in demyelination and novel diagnostic biomarkers.

Introduction: Multiple sclerosis is an inflammatory and demyelinating disease caused by a pathogenic immune response against the myelin sheath surfaces of oligodendrocytes. The demyelination has been classically associated with pathogenic B cells residing in the central nervous system that release autoreactive antibodies against myelin. The aim of the present study was to investigate whether extracellular vesicles (EVs) mediate delivery of myelin autoreactive antibodies from peripheral B cells against oligodendrocytes in multiple sclerosis (MS) and to analyze whether these EVs could mediate demyelination in vitro. We also studied the role of these EV-derived myelin antibodies as a diagnostic biomarker in MS. Methods: This is a prospective, observational, and single-center study that includes patients with MS and two control groups: patients with non-immune white matter lesions and healthy controls. We isolated B-cell-derived EVs from the blood and cerebrospinal fluid (CSF) and analyzed their myelin antibody content. We also studied whether antibody-loaded EVs reach oligodendrocytes in patients with MS and the effect on demyelination of B-cell-derived EVs containing antibodies in vitro. Results: This study enrolled 136 MS patients, 23 white matter lesions controls, and 39 healthy controls. We found autoreactive myelin antibodies in EVs that were released by peripheral B cells, but not by populations of B cells resident in CSF. We also identified a cut-off of 3.95 ng/mL of myelin basic protein autoantibodies in EVs from peripheral B cells, with 95.2% sensitivity and 88.2% specificity, which allows us to differentiate MS patients from healthy controls. EV-derived myelin antibodies were also detected in the oligodendrocytes of MS patients. Myelin antibody-loaded EVs from B cells induced myelin markers decrease of oligodendrocytes in vitro. Discussion: Peripheral reactive immune cells could contribute remotely to MS pathogenesis by delivering myelin antibodies to oligodendrocytes. EV-derived myelin antibodies could play a role as diagnostic biomarker in MS.

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.

Brain and immune system-derived extracellular vesicles mediate regulation of complement system, extracellular matrix remodeling, brain repair and antigen tolerance in Multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated central nervous system disease whose course is unpredictable. Finding biomarkers that help to better comprehend the disease's pathogenesis is crucial for supporting clinical decision-making. Blood extracellular vesicles (EVs) are membrane-bound particles secreted by all cell types that contain information on the disease's pathological processes. PURPOSE: To identify the immune and nervous system-derived EV profile from blood that could have a specific role as biomarker in MS and assess its possible correlation with disease state. RESULTS: Higher levels of T cell-derived EVs and smaller size of neuron-derived EVs were associated with clinical relapse. The smaller size of the oligodendrocyte-derived EVs was related with motor and cognitive impairment. The proteomic analysis identified mannose-binding lectin serine protease 1 and complement factor H from immune system cell-derived EVs as autoimmune disease-associated proteins. We observed hepatocyte growth factor-like protein in EVs from T cells and inter-alpha-trypsin inhibitor heavy chain 2 from neurons as white matter injury-related proteins. In patients with MS, a specific protein profile was found in the EVs, higher levels of alpha-1-microglobulin and fibrinogen ß chain, lower levels of C1S and gelsolin in the immune system-released vesicles, and Talin-1 overexpression in oligodendrocyte EVs. These specific MS-associated proteins, as well as myelin basic protein in oligodendrocyte EVs, correlated with disease activity in the patients with MS. CONCLUSION: Neural-derived and immune-derived EVs found in blood appear to be good specific biomarkers in MS for reflecting the disease state.

The study of neural antibodies in neurology: A practical summary.

The field of Autoimmune Neurology is expanding rapidly, with new neural antibodies being identified each year. However, these disorders remain rare. Deciding when to test for these antibodies, when and what samples are to be obtained, how to handle and study them correctly, and how to interpret test results, is complex. In this article we review current diagnostic techniques and provide a comprehensive explanation on the study of these patients, in an effort to help with correct diagnosis minimizing false positive and false negative results. We also propose routine storage of samples and referral of certain cases to specialized research laboratories.

Therapeutic plasma exchange for myasthenia gravis, Guillain-Barre syndrome, and other immune-mediated neurological diseases, over a 40-year experience.

BACKGROUND: Therapeutic plasma exchange (TPE) was first used in neurology in the 1980s for myasthenia gravis (MG) and Guillain-Barré syndrome (GBS). Indications have since grown. Fear of complications with this treatment modality limit its use. RESEARCH DESIGN & METHODS: A study of patients undergoing TPE for neurological diseases (1981-2020) in a University Hospital in Madrid, Spain. Clinical indications, complications, procedure number, apheresis technique and replacement fluids were prospectively recorded and retrospectively analyzed. Historical trends were studied. RESULTS: 159 patients (48.69 ±18.15 years, 54.3% females) underwent TPE using central-venous catheter and replacement fluid albumin. We performed 1207 procedures over 189 cycles (6.4 ±3.8 procedures/cycle). Most patients underwent TPE for category I-II indications, mainly GBS and MG (77.7%). Complication rate was low (3.9% procedures), mostly hypotensive/vasovagal reactions (55.3%) and vascular access-related complications (38.3%). Most were mild-moderate (92.9%), permitting TPE completion, and somewhat more frequent during the first procedure (38.3%) and after periods of little TPE use. GBS patients were more prone to complications than MG patients (6.5% vs. 1.2%,p<0.001) mainly hypotensive/vasovagal reactions (3.7% vs. 1.0%,p=0.008). CONCLUSIONS: TPE is well-tolerated with low complication rate (<4% procedures), mainly hypotensive/vasovagal reactions. Patients with GBS seem more prone to them than MG patients. Acquaintance with this technique seems necessary.

Serum glutamate decarboxylase antibodies and neurological disorders: when to suspect their association?

OBJECTIVES: To explore different neurological manifestations with suspicion of being associated to serum glutamate decarboxylase antibodies (GAD-Abs) in order to better characterize anti-GAD neurological syndromes. METHODS: Observational retrospective study including all patients for whom GAD65-Abs titers in serum were requested by the Neurology Department at La Paz University Hospital between 2015 and 2019. GAD-Abs were measured by ELISA. Demographic data, neurological symptoms, comorbidity with diabetes mellitus (DM) or with another autoimmune disease, and GAD-Abs titers were studied. Stiff-person syndrome, ataxia, encephalitis, and epilepsy were considered typical anti-GAD neurological syndromes and were compared to other atypical manifestations. RESULTS: A total of 173 patients (51.7% men, mean age 51.62) were included. A progressive increase in requests of serum GAD-Abs has occurred over the last 5 years, especially in patients with atypical neurological manifestations. GAD-Abs were found in the serum of 22 patients (12.7%); of those, 15 (68.18%) suffered a typical anti-GAD syndrome. Presence of DM or another organ-specific autoimmune disease was predictive of GAD-AB seropositivity (p < 0.001). 6.6% of requested patients with an atypical syndrome had GAD-Abs, but serum levels were significantly lower than those found in patients with a typical syndrome (706.67 vs 1430.23 UI/mL; Mann-Whitney U, p = 0.034), and were finally diagnosed with another neurological disease. CONCLUSION: Serum GAD-Abs were infrequently found in patients with clinical phenotypes other than those classically described as anti-GAD disorders, and with very low titers. In typical anti-GAD syndromes, there is a high comorbidity with DM and with other autoimmune diseases, and high serum GAD-Abs levels are usually present.

Identifying Perceptual, Motor, and Cognitive Components Contributing to Slowness of Information Processing in Multiple Sclerosis with and without Depressive Symptoms.

Increasing findings suggest that different components of the stimulus-response pathway (perceptual, motor or cognitive) may account for slowed performance in Multiple Sclerosis (MS). It has also been reported that depressive symptoms (DS) exacerbate slowness in MS. However, no prior studies have explored the independent and joint impact of MS and DS on each of these components in a comprehensive manner. The objective of this work was to identify perceptual, motor, and cognitive components contributing to slowness in MS patients with and without DS. The study includes 33 Relapsing-Remitting MS patients with DS, 33 without DS, and 26 healthy controls. Five information processing components were isolated by means of ANCOVA analyses applied to five Reaction Time tasks. Perceptual, motor, and visual search components were slowed down in MS, as revealed by ANCOVA comparisons between patients without DS, and controls. Moreover, the compounding effect of MS and DS exacerbated deficits in the motor component, and slowed down the decisional component, as revealed by ANCOVA comparisons between patients with and without DS. DS seem to exacerbate slowness caused by MS in specific processing components. Identifying the effects of having MS and of having both MS and DS may have relevant implications when targeting cognitive and mood interventions.

Identifying perceptual, motor, and cognitive components contributing to slowness of information processing in multiple sclerosis with and without depressive symptoms

Increasing findings suggest that different components of the stimulus-response pathway (perceptual, motor or cognitive) may account for slowed performance in Multiple Sclerosis (MS). It has also been reported that depressive symptoms (DS) exacerbate slowness in MS. However, no prior studies have explored the independent and joint impact of MS and DS on each of these components in a comprehensive manner. The objective of this work was to identify perceptual, motor, and cognitive components contributing to slowness in MS patients with and without DS. The study includes 33 Relapsing-Remitting MS patients with DS, 33 without DS, and 26 healthy controls. Five information processing components were isolated by means of ANCOVA analyses applied to five Reaction Time tasks. Perceptual, motor, and visual search components were slowed down in MS, as revealed by ANCOVA comparisons between patients without DS, and controls. Moreover, the compounding effect of MS and DS exacerbated deficits in the motor component, and slowed down the decisional component, as revealed by ANCOVA comparisons between patients with and without DS. DS seem to exacerbate slowness caused by MS in specific processing components. Identifying the effects of having MS and of having both MS and DS may have relevant implications when targeting cognitive and mood interventions

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The contribution of depressive symptoms to slowness of information processing in relapsing remitting multiple sclerosis.

BACKGROUND: Slowness of information processing has been suggested as a fundamental factor modulating cognitive impairment in multiple sclerosis (MS). However, the contribution of depressive symptoms (DS) to slowness remains unclear. One of the most accepted hypotheses on the impact of depression on the general population suggests that depression interferes only with tasks requiring high cognitive demands. However, no studies have investigated if the same pattern occurs in MS. OBJECTIVE: The aim of this study was to determine the profile of the contribution of DS to slowness. METHODS: Four Reaction Time (RT) tasks requiring an increasing level of cognitive demands were administered to 35 relapsing remitting MS patients with DS, 33 MS patients without DS, 17 depressed non-MS patients and 27 controls. RESULTS: MS patients without DS obtained longer RTs than controls in all the tasks. On the contrary, depressed non-MS patients were slower than controls only in the most demanding task. Finally, MS patients with DS were slower than MS patients without DS not only in the most demanding task but also in the task requiring a lower level of cognitive demands. CONCLUSION: The contribution of DS to slowness depends on the level of cognitive demands. However, its impact on MS is more deleterious than on the general population.

Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon.

BACKGROUND: In the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs' (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon. METHODS: A retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004--September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney's tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation. RESULTS: In total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0%) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3%) had switched therapy: 27 patients (17.4%) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9%) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9%) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4%, 82.5% after 12 months and 72.5% after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 - 4.8] times greater for treatment-naive patients than for patients treated previously with interferon and this was hardly modified after adjusting for sex and age. CONCLUSIONS: Glatiramer acetate was safe and useful with low rates of serious adverse events and low rates of break-through disease. Injection intolerance proved a major limitation to glatiramer acetate use. Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.

Single-port Roux-en-Y gastric bypass: toward a less invasive procedure with the same surgical results and a better cosmesis.

BACKGROUND: The current tendency to use increasingly less aggressive procedures has facilitated the development of new minimally invasive techniques. In this context, single-port (SP) access procedures can become an alternative to the conventional laparoscopic approach. METHODS: A total of 22 morbidly obese patients were submitted to pure SP Roux-en-Y gastric bypass without additional ports. Selection for this approach was based on distance from the xiphoid to the umbilicus less than 28 cm, body mass index (BMI) lower than 50 kg/m(2), and preferably peripheral obesity. Access to the cavity was obtained through a single transverse, transumbilical incision, with placement of a SILS Port device. RESULTS: The mean age of the patients was 41 ± 8.98 years, and 95 % of the patients were women. The mean BMI of the series was 42.68 ± 2.28 kg/m(2), and the mean body weight was 111.34 ± 10.66 kg. Surgery was performed successfully in all cases through a transumbilical incision with a mean length of 26.68 ± 5.27 mm. The mean surgical time was 114.05 ± 21 min, and the mean hospital stay was 3.27 ± 1.01 days. No intraoperative or immediate postoperative deaths or complications occurred. The median postoperative BMI during a mean follow-up period of 12 months was 28 kg/m(2) (range, 18-35 kg/m(2)). The median weight loss was 39 kg, and the percentage loss of excess body weight was 86 %. In relation to improvement of the comorbidities, two of the three patients with arterial hypertension showed normalization of their blood pressure values. Likewise, the blood glucose levels were corrected in two of the three diabetic patients, as well as in the patient with altered fasting blood glucose. CONCLUSIONS: Single-port Roux-en-Y gastric bypass surgery seems to be a safe, viable, and reproducible technique, but randomized studies involving larger patient series and longer follow-up periods are needed to compare the SP access and the multiple-port laparoscopic approach.

Influence of fibrin sealant in preventing postoperative seroma and normalizing the abdominal wall after laparoscopic repair of ventral hernia.

BACKGROUND: Seroma after laparoscopic ventral hernia repair (LVHR) has been related to certain complications of the technique, such as recurrences and postoperative pain. The aim of this study was to assess whether percutaneous application of fibrin sealant in the hernia sac after LVHR reduces the incidence and volume of the postoperative seroma, and to analyze whether the percentage of patients achieving complete normalization of the abdominal wall increases. METHODS: Prospective and comparative study. Patients were distributed into 2 control-case groups. Group 1 comprised patients submitted to LVHR using the double crown technique and a compressing bandage as the only method for prevent seroma. Group 2 comprised patients admitted to LVHR using the same technique together with percutaneous injection of fibrin sealant in the sac, and later applying the same bandage. Patients were examined clinically and radiologically at 7 days, 1 month, and 3 months after surgery. RESULTS: Twenty-five patients were included in each group. There were significant differences in the incidence of seroma by the day 7 after surgery (92% in group 1 vs. 64 % in group 2, p = 0.017) and by 1 month (72% in group 1 vs. 28% in group 2, p = 0.002). The difference was also significant regarding the achievement of normalization of the abdominal wall by day 7 (24% in group 1 vs. 52% in group 2, p = 0.041) and by month 1 (64% in group 1 vs. 88% in group 2, p = 0.047) after operation. Volume of seroma was larger among patients of group 1 after the week (p = 0.002) and 1 month after operation (p = 0.001). CONCLUSIONS: Fibrin sealant application after LVHR reduces the incidence and volume of the seroma 7 days and 1 month after surgery. The treated patients obtain a larger normalization of the abdominal wall 1 week and 1 month after the operation.