Targeted treatment reverses increased left cardiac work in unilateral versus bilateral primary aldosteronism.

BACKGROUND: The incidence of cardiovascular complications may be higher in unilateral than in bilateral primary aldosteronism (PA). We compared non-invasive hemodynamics before and after targeted therapy of bilateral versus unilateral PA. METHODS: Adrenal vein sampling was performed, and cardiovascular variables were recorded using radial artery pulse wave analysis and whole-body impedance cardiography (n=114). In a subset of 40 patients (adrenalectomy n=20, spironolactone-based treatment n=20), hemodynamic recordings were again performed after 33 months of targeted PA treatment. RESULTS: In initial cross-sectional analysis, 51 patients had bilateral and 63 had unilateral PA. The mean ages were 50.6 and 54.3 years (p=0.081), and body mass indexes were 30.3 and 30.6 kg/m2 (p=0.724), respectively. Aortic blood pressure and cardiac output did not significantly differ between the groups, but evaluated left cardiac work was ~10% higher in unilateral PA (p=0.022). In the followup study, initial and final blood pressure levels in the aorta were not significantly different, while initial cardiac output (+13%, p=0.015) and left cardiac work (+17%, p=0.009) were higher in unilateral than in bilateral PA. After a median treatment time of 33 months, the differences in cardiac load were abolished, and extracellular water volume was reduced by 1.3 and 1.4 liters in bilateral versus unilateral PA, respectively (p=0.814). CONCLUSIONS: These results suggest that unilateral PA burdens the heart more than bilateral PA, providing a possible explanation for the higher incidence of cardiac complications in unilateral disease. A similar reduction in aldosterone-induced volume excess was obtained with targeted surgical and medical treatment of PA.

Fixed dose daptomycin: An opportunity for pharmacokinetic/pharmacodynamic optimization in Staphylococcus aureus infections.

BACKGROUND: Daptomycin is a high-use intravenous antimicrobial agent affording the convenience of once-daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight-based dosing but this approach has not been studied prospectively. METHODS: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non-obese adults. At least, three daptomycin concentrations were measured at steady-state for each patient. A population pharmacokinetic model was constructed to evaluate concentration-time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24-h area under the curve (AUC0-24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (C min) ≥24.3 mg/L) targets for fixed (500-1000 mg) and weight-based (6-12 mg/kg) daptomycin doses. RESULTS: Thirty-one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0-24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight-based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight-based regimens. CONCLUSIONS: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy-to-toxicity ratio, transitions of care, and costs compared to weight-based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient-specific basis.

Performance of ePlex® blood culture identification panels in clinical isolates and characterization of antimicrobial stewardship opportunities.

We assessed the performance of GenMark's ePlex® Blood Culture Identification (BCID) Panels for overall agreement of organism identification and resistance mechanism detection with standard microbiologic methods. This study included patients with a positive blood culture from May 2020 to January 2021. The primary outcomes were to assess concordance of ePlex® organism identification with standard identification methods and concordance of ePlex® genotypic resistance mechanism detection with standard phenotypic susceptibility testing. Secondary outcomes included panel specific performance and characterization of antimicrobial stewardship opportunities. The overall identification concordance rate in 1276 positive blood cultures was 98.1%. The overall concordance for the presence of resistance markers was 98.2% and concordance for the absence of resistance markers was 100%. A majority of ePlex® results (69.5%) represented opportunities for potential antimicrobial stewardship intervention. High concordance rates between the ePlex® BCID panels and standard identification and susceptibility methods enable utilization of results to guide rapid antimicrobial optimization.

Volume overload is a major characteristic in primary aldosteronism: a 3-year follow-up study.

OBJECTIVES: We examined haemodynamics, focusing on volume balance and forward and backward wave amplitudes, before and after 2.8 years of targeted treatment of primary aldosteronism. Patients with essential hypertension and normotensive individuals were examined for comparison ( n  = 40 in each group). METHODS: Recordings were performed using radial artery pulse wave analysis and whole-body impedance cardiography. Unilateral aldosteronism was treated with adrenalectomy ( n  = 20), bilateral aldosteronism with spironolactone-based medication ( n  = 20), and essential hypertension with standard antihypertensive agents. RESULTS: Aortic SBP and DBP, forward and backward wave amplitudes, and systemic vascular resistance were equally elevated in primary aldosteronism and essential hypertension. All these haemodynamic variables were similarly reduced by the treatments. Primary aldosteronism presented with 1 litre (∼10%) extracellular water excess ( P  < 0.001) versus the other groups, and this excess was normalized by treatment. Initial pulse wave velocity (PWV) was similarly increased in primary aldosteronism and essential hypertension, but final values remained higher in primary aldosteronism ( P  < 0.001). In regression analyses, significant explanatory factors for treatment-induced forward wave amplitude reduction were decreased systemic vascular resistance ( ß â€Š= 0.380) and reduced extracellular water volume ( ß â€Š= 0.183). Explanatory factors for backward wave amplitude reduction were changes in forward wave amplitude ( ß â€Š= 0.599), heart rate ( ß â€Š= -0.427), and PWV ( ß â€Š= 0.252). CONCLUSION: Compared with essential hypertension, the principal haemodynamic difference in primary aldosteronism was higher volume load. Volume excess elevated forward wave amplitude, which was subsequently reduced by targeted treatment of primary aldosteronism, along with normalization of volume load. We propose that incorporating extracellular water evaluation alongside routine diagnostics could enhance the identification and diagnosis of primary aldosteronism.

Differences in heart rate responses to upright posture are associated with variations in the high-frequency power of heart rate variability.

High resting heart rate is a cardiovascular risk factor, but limited data exist on the underlying hemodynamics and reproducibility of supine-to-upright increase in heart rate. We recorded noninvasive hemodynamics in 574 volunteers [age, 44.9 yr; body mass index (BMI), 26.4 kg/m2; 49% male] during passive head-up tilt (HUT) using whole body impedance cardiography and radial artery tonometry. Heart rate regulation was evaluated using heart rate variability (HRV) analyses. Comparisons were made between quartiles of supine-to-upright heart rate changes, in which heart rate at rest ranged 62.6-64.8 beats/min (P = 0.285). The average upright increases in heart rate in the quartiles 1-4 were 4.7, 9.9, 13.5, and 21.0 beats/min, respectively (P < 0.0001). No differences were observed in the low-frequency power of HRV, whether in the supine or upright position, or in the high-frequency power of HRV in the supine position. Upright high-frequency power of HRV was highest in quartile 1 with lowest upright heart rate and lowest in quartile 4 with highest upright heart rate. Mean systolic blood pressure before and during HUT (126 vs. 108 mmHg) and the increase in systemic vascular resistance during HUT (650 vs. 173 dyn·s/cm5/m2) were highest in quartile 1 and lowest in quartile 4. The increases in heart rate during HUT on three separate occasions several weeks apart were highly reproducible (r = 0.682) among 215 participants. To conclude, supine-to-upright increase in heart rate is a reproducible phenotype with underlying differences in the modulation of cardiac parasympathetic tone and systemic vascular resistance. As heart rate at rest influences prognosis, future research should elucidate the prognostic significance of these phenotypic differences.NEW & NOTEWORTHY Subjects with similar supine heart rates are characterized by variable increases in heart rate during upright posture. Individual heart rate increases in response to upright posture are highly reproducible as hemodynamic phenotypes and present underlying differences in the modulation of cardiac parasympathetic tone and systemic vascular resistance. These results indicate that resting heart rate obtained in the supine position alone is not an optimal means of classifying people into groups with differences in cardiovascular function.

Blood Haemoglobin Concentration Is Directly and Independently Related with Pulse Wave Velocity, a Measure of Large Artery Stiffness.

High haemoglobin level has been associated with metabolic syndrome, elevated blood pressure (BP), and increased mortality risk. In this cross-sectional study, we investigated the association of blood haemoglobin with haemodynamics in 743 subjects, using whole-body impedance cardiography and pulse wave analysis. The participants were allocated to sex-stratified haemoglobin tertiles with mean values 135, 144, and 154 g/L, respectively. The mean age was similar in all tertiles, while body mass index was higher in the highest versus the lowest haemoglobin tertile. The highest haemoglobin tertile had the highest erythrocyte and leukocyte counts, plasma C-reactive protein, uric acid, renin activity, and aldosterone. The lipid profile was less favourable and insulin sensitivity lower in the highest versus the lowest haemoglobin tertile. Aortic BP, cardiac output, and systemic vascular resistance were similar in all tertiles, while the pulse wave velocity (PWV) was higher in the highest versus the lowest haemoglobin tertile. In linear regression analysis, age (Beta 0.478), mean aortic BP (Beta 0.178), uric acid (Beta 0.150), heart rate (Beta 0.148), and aldosterone-to-renin ratio (Beta 0.123) had the strongest associations with PWV (p < 0.001 for all). Additionally, haemoglobin concentration was an explanatory factory for PWV (Beta 0.070, p = 0.028). To conclude, blood haemoglobin concentration had a small direct and independent association with a measure of large artery stiffness.

Ambulatory daytime blood pressure versus tonometric blood pressure measurements in the laboratory: effect of posture.

OBJECTIVE: To compare blood pressure (BP) in tonometric radial artery recordings during passive head-up tilt with ambulatory recordings and evaluate possible laboratory cutoff values for hypertension. METHODS: Laboratory BP and ambulatory BP were recorded in normotensive (n = 69), unmedicated hypertensive (n = 190), and medicated hypertensive (n = 151) subjects. RESULTS: Mean age was 50.2 years, BMI 27.7 kg/m 2 , ambulatory daytime BP 139/87 mmHg, and 276 were male (65%). As supine-to-upright changes in SBP ranged from -52 to +30 mmHg, and in DBP from -21 to +32 mmHg, the mean values of BP supine and upright measurements were compared with ambulatory BP. The mean(supine+upright) systolic laboratory BP was corresponding to ambulatory level (difference +1 mmHg), while mean(supine+upright) DBP was 4 mmHg lower ( P  < 0.05) than ambulatory value. Correlograms indicated that laboratory 136/82 mmHg corresponded to ambulatory 135/85 mmHg. When compared with ambulatory 135/85 mmHg, the sensitivity and specificity of laboratory 136/82 mmHg to define hypertension were 71.5% and 77.3% for SBP, and 71.7% and 72.8%, for DBP, respectively. The laboratory cutoff 136/82 mmHg classified 311/410 subjects similarly to ambulatory BP as normotensive or hypertensive, 68 were hypertensive only in ambulatory, while 31 were hypertensive only in laboratory measurements. CONCLUSION: BP responses to upright posture were variable. When compared with ambulatory BP, mean(supine+upright) laboratory cutoff 136/82 mmHg classified 76% of subjects similarly as normotensive or hypertensive. In the remaining 24% the discordant results may be attributed to white-coat or masked hypertension, or higher physical activity during out-of-office recordings.

The characteristics of elevated blood pressure in abdominal obesity correspond to primary hypertension: a cross-sectional study.

BACKGROUND: Obesity-related hypertension and the associated metabolic abnormalities are considered as a distinct hypertensive phenotype. Here we examined how abdominal fat content, as judged by waist:height ratio, influenced blood pressure and hemodynamic profile in normotensive subjects and never-treated hypertensive patients. METHODS: The 541 participants (20-72 years) underwent physical examination and laboratory analyses and were divided into age and sex-adjusted quartiles of waist:height ratio. Supine hemodynamics were recorded using whole-body impedance cardiography, combined with analyses of radial tonometric pulse wave form and heart rate variability. RESULTS: Mean waist:height ratios in the quartiles were 0.46, 0.51, 0.55 and 0.62. Radial and aortic blood pressure, systemic vascular resistance, pulse wave velocity, markers of glucose and lipid metabolism, leptin levels and C-reactive protein were higher in quartile 4 when compared with quartiles 1 and 2 (p < 0.05 for all). Cardiac index was lower in quartile 4 versus quartile 1, while no differences were seen in heart rate variability, augmentation index, plasma renin activity, and aldosterone concentration between the quartiles. Linear regression analyses showed independent associations of abdominal obesity with higher aortic systolic and diastolic blood pressure, systemic vascular resistance, and pulse wave velocity (p < 0.05 for waist:height ratio in all regression models). CONCLUSION: Higher waist:height ratio was associated with elevated blood pressure, systemic vascular resistance, and arterial stiffness, but not with alterations in cardiac sympathovagal modulation or activation of the circulating renin-angiotensin-aldosterone system. Although obesity-related elevation of blood pressure has distinct phenotypic features, these results suggest that its main characteristics correspond those of primary hypertension. TRIAL REGISTRATION: ClinicalTrails.gov NCT01742702 (date of registration 5th December 2012).

Review of novel ß-lactams and ß-lactam/ß-lactamase inhibitor combinations with implications for pediatric use.

Antimicrobial resistance continues to surmount increasing concern globally, and treatment of difficult-to-treat (DTR) Pseudomonas aeruginosa, carbapenem-resistant (CR) Acinetobacter baumannii (CRAB), and CR Enterobacterales (CRE) remains a challenge for clinicians. Although previously rare, the incidence of multidrug-resistant (MDR) and CR infections in pediatric patients has increased drastically in the last decade and is associated with increased morbidity and mortality. To combat this issue, 14 novel antibiotics, including three ß-lactam/novel ß-lactamase inhibitor combinations (ßL-ßLIs) and two novel ß-lactams (ßLs), have received approval from the United States Food and Drug Administration since 2010. Improving clinician understanding of the utility of these novel therapies is imperative to improve judicious decision-making and prevent societal regression to a pre-penicillin era. In this review, we summarize the pharmacokinetic/pharmacodynamic (PK/PD) properties, clinical efficacy and safety data, dosing considerations, and subsequent role in therapy for ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB), imipenem-cilastatin-relebactam (IMI-REL), ceftolozane-tazobactam (TOL-TAZ), and cefiderocol in pediatric patients.

Resting heart rate predicts cardiac autonomic modulation during passive head-up tilt in subjects without cardiovascular diseases.

Background Resting heart rate (HR) and its variability (HRV) reflects the cardiac sympathovagal balance that is stimulated by head-up tilting. HRV is influenced by the level of HR, but how much HRV offers additional information about cardiac autonomic tone than HR alone remains unresolved. We examined the relation of resting HR with HRV during head-up tilt. Methods. Hemodynamics of 569 subjects without known cardiovascular diseases and medications with direct cardiovascular effects were recorded using whole-body impedance cardiography, radial pulse wave analysis, and electrocardiography-based HRV analysis during passive head-up tilt. Results. Higher low frequency to the high-frequency ratio (LF/HF) of HRV (reflecting sympathovagal balance) was associated with higher HR in supine (p < .05, both linear regression analysis and variance analysis comparing HR tertiles) and upright postures (p < .001, linear regression analysis). The association of HR with HRV during tilt-testing remained significant when the HR dependence of HRV was mathematically weakened by dividing the HRV power spectra with the fourth power of the average RR-interval. Conclusion. Higher resting HR is related to higher LF/HF both supine and upright, reflecting elevated sympathetic influence on cardiac autonomic modulation. Lower resting HR is associated with lower resting LF/HF, while the differences in LF/HF between the HR tertiles were minor during head-up tilt, suggesting a greater change in cardiac sympathovagal balance in response to upright posture in those with lowest resting HR. Altogether, resting HR well predicts HRV levels during head-up tilt.Trial registration: Clinicaltrialsregister.eu 2006-002065-39, first registered 5 May 2006. ClinicalTrials.gov NCT01742702, first registered 5 December 2012.

Cefepime Induced Neurotoxicity Following A Regimen Dose-Adjusted for Renal Function: Case Report and Review of the Literature.

Introduction: Cefepime induced neurotoxicity (CIN) is commonly associated with renal dysfunction, however CIN can occur in patients with normal renal function or renally dose-adjusted regimens. Few reports of this kind have obtained cefepime concentrations to assist in diagnosis. Patient Case: A 42-year old female with a complex past medical history was transferred to our facility with chief complaint of worsening shock and respiratory failure, and the patient was also noted to be hypernatremic, experiencing diabetic ketoacidosis (DKA), and acute kidney injury (AKI). Her DKA resolved and hypernatremia and AKI began to improve. As a result, cefepime was dose-adjusted for renal function estimated by the Cockcroft-Gault (CG) equation. Her hospital course was complicated by persistent altered mental status (AMS), preventing extubation. Cefepime was discontinued due to concern for CIN, and a concentration was obtained 13-hours after the last dose which was elevated at 49 µg/mL. Two days following cefepime discontinuation, the patient's mental status improved allowing for successful extubation. The patient remained stable and was discharged to an acute care floor and then ultimately back to home. Conclusion: CIN should be part of a wider differential diagnosis for patients experiencing encephalopathy, and inaccurate renal function estimation may be a risk factor for developing CIN. Furthermore, therapeutic drug monitoring (TDM) may serve as an important clinical tool in diagnosing and managing CIN.

Extracellular Vesicles: An Important Biomarker in Recurrent Pregnancy Loss?

Recurrent pregnancy loss (RPL) has an estimated incidence of 1-3% of all couples. The etiology is considered to be multifactorial. Extracellular vesicles (EVs) take part in numerous different physiological processes and their contents show the originating cell and pathophysiological states in different diseases. In pregnancy disorders, changes can be seen in the composition, bioactivity and concentration of placental and non-placental EVs. RPL patients have an increased risk of pregnancy complications. The aim of this prospective study was to examine whether measuring different specific EV markers in plasma before and during pregnancy could be used as predictors of pregnancy loss (PL) in women with RPL. Thirty-one RPL patients were included in this study; 25 had a live birth (LB group) and six had a new PL (PL group). Five blood samples were obtained, one before achieved pregnancy and the others in gestational week 6, 8, 10 and 16. Moreover, some of the patients received intravenous immunoglobulin (IVIG) infusions as part of treatment, and it was also examined whether this treatment influenced the EV levels. Seventeen EV markers specific for the immune system, coagulation, placenta and hypoxia were analyzed in the samples with EV Array, a method able to capture small EVs by using an antibody panel targeting membrane proteins. Comparing the LB and PL groups, one EV marker, CD9, showed a significant increase from before pregnancy to gestational week 6 in the PL group. The changes in the other 16 markers were nonsignificant. One case of late-onset PL showed steeply increasing levels, with sudden decrease after gestational week 10 in nine of 17 markers. Moreover, there was an overall increase of all 17 markers after IVIG treatment in the LB group, which was significant in 15 of the markers. Whether increases in EVs positive for CD9 characterize RPL patients who subsequently miscarry should be investigated in future larger studies.

Individual changes of central blood pressure in response to upright posture: different hemodynamic phenotypes.

OBJECTIVES: Most studies about upright regulation of blood pressure have focused on orthostatic hypotension despite the diverse hemodynamic changes induced by orthostatic challenge. We investigated the effect of passive head-up tilt on aortic blood pressure. METHODS: Noninvasive peripheral and central hemodynamics in 613 volunteers without cardiovascular morbidities or medications were examined using pulse wave analysis, whole-body impedance cardiography and heart rate variability analysis. RESULTS: In all participants, mean aortic SBP decreased by -4 (-5 to -3) mmHg [mean (95% confidence intervals)] and DBP increased by 6 (5--6) mmHg in response to upright posture. When divided into tertiles according to the supine-to-upright change in aortic SBP, two tertiles presented with a decrease [-15 (-14 to -16) and -4 (-3 to -4) mmHg, respectively] whereas one tertile presented with an increase [+7 (7-- 8) mmHg] in aortic SBP. There were no major differences in demographic characteristics between the tertiles. In regression analysis, the strongest explanatory factors for upright changes in aortic SBP were the supine values of, and upright changes in systemic vascular resistance and cardiac output, and supine aortic SBP. CONCLUSION: In participants without cardiovascular disease, the changes in central SBP during orthostatic challenge are not uniform. One-third presented with higher upright than supine aortic SBP with underlying differences in the regulation of systemic vascular resistance and cardiac output. These findings emphasize that resting blood pressure measurements give only limited information about the blood pressure status.

Plasma uric acid is related to large arterial stiffness but not to other hemodynamic variables: a study in 606 normotensive and never-medicated hypertensive subjects.

BACKGROUND: Elevated level of plasma uric acid (PUA) has been associated with cardiovascular disease, but whether uric acid is an independent risk factor or merely a marker remains controversial. METHODS: We investigated in a cross-sectional setting the association of PUA with hemodynamics in 606 normotensive and never-medicated hypertensive subjects (295 men, 311 women, age range 19-73 years) without cardiovascular disease or gout. In all except 15 individuals, PUA was within the normal range. Supine hemodynamics were recorded using whole-body impedance cardiography and radial tonometric pulse wave analysis. RESULTS: The mean concentrations of PUA in age, sex and body mass index adjusted quartiles were 234, 278, 314, and 373 µmol/l, respectively. The highest PUA quartile presented with higher aortic to popliteal pulse wave velocity (PWV) than the lowest quartile (8.7 vs. 8.2 m/s, p = 0.026) in analyses additionally adjusted for plasma concentrations of C-reactive protein, low density lipoprotein cholesterol, triglycerides, and mean aortic blood pressure. No differences in radial and aortic blood pressure, wave reflections, heart rate, cardiac output, and systemic vascular resistance were observed between the quartiles. In linear regression analysis, PUA was an independent explanatory factor for PWV (ß = 0.168, p < 0.001, R2 of the model 0.591), but not for systolic or diastolic blood pressure. When the regression analysis was performed separately for men and women, PUA was an independent predictor of PWV in both sexes. CONCLUSIONS: PUA concentration was independently and directly associated with large arterial stiffness in individuals without cardiovascular disease and PUA levels predominantly within the normal range. Trial registration ClinicalTrials.gov NCT01742702.

Perceptions of dementia amongst the general public across Latin America: a systematic review.

Introduction: Perceptions of dementia are important determinants of support, treatment and care received in the dementia community. Understanding these perceptions are vital for regions such as Latin America, where there is a rapid increase in people living with dementia. The aim of this study is to review and synthesise the general public's perceptions of dementia in Latin America, what factors are associated with these perceptions, and how they differ between countries in the region.Methods: Searches were completed across five databases (Medline, SCOPUS, PsychINFO, SciELO, and WoS). Studies were required to capture attitudes or knowledge of dementia in the general public residing within Latin America. English, Spanish and Portuguese search terms were used. Results were synthesised narratively.Results: About 1574 unique records were identified. Following lateral searches, de-duplication and screening, six articles (four studies) met the inclusion criteria for this review. All the studies were quantitative research from Brazil (median, n = 722). There was evidence of a limited to moderate knowledge of dementia, though a significant minority had negative or stigmatising attitudes. Only higher levels of education were consistently associated with better attitudes and knowledge of dementia in the region.Conclusion: There is a need for more in-depth research about attitudes of the general public across Latin America, particularly outside of São Paulo state, Brazil. There appears to be a greater need to raise awareness of dementia amongst less educated Latin American groups.

Interplay of Electronic and Spin Degrees in Ferromagnetic SrRuO_{3}: Anomalous Softening of the Magnon Gap and Stiffness.

The magnon dispersion of ferromagnetic SrRuO_{3} was studied by inelastic neutron scattering experiments on single crystals as a function of temperature. Even at low temperature the magnon modes exhibit substantial broadening pointing to strong interaction with charge carriers. We find an anomalous temperature dependence of both the magnon gap and the magnon stiffness, which soften upon cooling in the ferromagnetic phase. Both effects trace the temperature dependence of the anomalous Hall effect and can be attributed to the impact of Weyl points, which results in the same relative renormalization in the spin stiffness and magnon gap.

The Immunogenetic Conundrum of Preeclampsia.

Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia.

Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance.

We investigated the haemodynamic effects of two-week liquorice exposure (glycyrrhizin dose 290-370 mg/day) in 22 healthy volunteers during orthostatic challenge. Haemodynamics were recorded during passive 10-minute head-up tilt using radial pulse wave analysis, whole-body impedance cardiography, and spectral analysis of heart rate variability. Thirty age-matched healthy subjects served as controls. Liquorice ingestion elevated radial systolic (p < 0.001) and diastolic (p = 0.018) blood pressure and systemic vascular resistance (p = 0.037). During orthostatic challenge, heart rate increased less after the liquorice versus control diet (p = 0.003) and low frequency power of heart rate variability decreased within the liquorice group (p = 0.034). Liquorice intake increased central pulse pressure (p < 0.001) and augmentation index (p = 0.002) supine and upright, but in the upright position the elevation of augmentation index was accentuated (p = 0.007). Liquorice diet also increased extracellular fluid volume (p = 0.024) and aortic to popliteal pulse wave velocity (p = 0.027), and aortic characteristic impedance in the upright position (p = 0.002). To conclude, in addition to increased extracellular fluid volume and large arterial stiffness, two weeks of liquorice ingestion elevated systemic vascular resistance and augmentation index. Measurements performed at rest may underestimate the haemodynamic effects of liquorice ingestion, as enhanced central wave reflection and reduced chronotropic response were especially observed in the upright position.

Haemodynamic Influences of Bisoprolol in Hypertensive Middle-Aged Men: A Double-Blind, Randomized, Placebo-Controlled Cross-Over Study.

Treatment with beta-blockers appears to show inferior reduction in central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta-blockade. Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/day) in a double-blind, randomized, placebo-controlled cross-over trial in never-treated 16 Caucasian males with grade I-II primary hypertension using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p < 0.05 for all). Ejection duration (336 versus 316 ms) and stroke volume (109 versus 98 ml) were increased (p < 0.01 for all), while cardiac output was not significantly changed (6.2 versus 6.6 l/min). Bisoprolol decreased pulse wave velocity (7.8 versus 8.9 m/s, p < 0.001), but after adjustment for blood pressure, the decrease was not significant (8.16 versus 8.52 m/s, p = 0.464). The treatment reduced pulse pressure amplification from central to peripheral circulation (30 versus 38%, p = 0.002). No differences were observed in systemic vascular resistance, augmentation index, aortic characteristic impedance or total arterial stiffness after bisoprolol versus placebo. Bisoprolol decreased central and peripheral blood pressure and pulse wave velocity in male individuals with grade I to grade II hypertension. The decrease in pulse wave velocity was related to the antihypertensive effect. Reduced pulse pressure amplification indicates that peripheral blood pressure was reduced more efficiently than central blood pressure.

Mycobacterium Cytidylate Kinase Appears to Be an Undruggable Target.

New and improved drugs against tuberculosis are urgently needed as multi-drug-resistant forms of the disease become more prevalent. Mycobacterium tuberculosis cytidylate kinase is an attractive target for screening due to its essentiality and different substrate specificity to the human orthologue. However, we selected the Mycobacterium smegmatis cytidylate kinase for screening because of the availability of high-resolution X-ray crystallographic data defining its structure and the high likelihood of active site structural similarity to the M. tuberculosis orthologue. We report the development and implementation of a high-throughput luciferase-based activity assay and screening of 19,920 compounds derived from small-molecule libraries and an in silico screen predicting likely inhibitors of the cytidylate kinase enzyme. Hit validation included a counterscreen for luciferase inhibitors that would result in false positives in the initial screen. Results of this counterscreen ruled out all of the putative cytidylate kinase inhibitors identified in the initial screening, leaving no compounds as candidates for drug development. Although a negative result, this study indicates that this important drug target may in fact be undruggable and serve as a warning for future investigations.