Hyponatremia in the emergency department.

Hyponatremia, defined as a serum sodium <135 mmol/L, is frequently encountered in patients presenting to the emergency department. Symptoms are often unspecific and include a recent history of falls, weakness and vertigo. Common causes of hyponatremia include diuretics, heart failure as well as Syndrome of Inappropriate Antidiuresis (SIAD) and correct diagnosis can be challenging. Emergency treatment of hyponatremia should be guided by presence of symptoms and focus on distinguishing between acute and chronic hyponatremia.

Restoration of renal function does not correct impairment of uremic HDL properties.

Cardiovascular disease remains the leading cause of death in renal transplant recipients, but the underlying causative mechanisms for this important problem remain elusive. Recent work has indicated that qualitative alterations of HDL affect its functional and compositional properties in ESRD. Here, we systematically analyzed HDL from stable renal transplant recipients, according to graft function, and from patients with ESRD to determine whether structural and functional properties of HDL remain dysfunctional after renal transplantation. Cholesterol acceptor capacity and antioxidative activity, representing two key cardioprotective mechanisms of HDL, were profoundly suppressed in kidney transplant recipients independent of graft function and were comparable with levels in patients with ESRD. Using a mass spectroscopy approach, we identified specific remodeling of transplant HDL with highly enriched proteins, including α-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, surfactant protein B, and serum amyloid A. In conclusion, this study demonstrates that HDL from kidney recipients is uniquely altered at the molecular and functional levels, indicating a direct pathologic role of HDL that could contribute to the substantial cardiovascular risk in the transplant population.

Molecular regulation of the renin-angiotensin system in haemodialysis patients.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) exerts beneficial effects in patients with mild-to-moderate chronic kidney disease, yet evidence suggesting a similar benefit in haemodialysis (HD) patients is not available. Furthermore, knowledge of the effects of RAS blockade on systemic RAS components in HD patients is limited. Analysis of the quantity and dynamics of all known peripheral constituents of the RAS may yield important pathomechanistic information of a widespread therapeutic measure in HD patients. METHODS: Fifty-two HD patients from the following groups were analysed cross-sectionally: patients without RAS blockade (n = 16), angiotensin-converting enzyme inhibitor (ACEi) users (n = 8), angiotensin receptor blocker (ARB) users (n = 11), patients on ACEi plus ARB (dual blockade, n = 8) and anephric patients (n = 9). Ten healthy volunteers served as controls. Angiotensin metabolites were quantified by mass spectrometry. RESULTS: In general, HD patients showed a broad variability of RAS activity. Patients without RAS blockade displayed angiotensin metabolite patterns similar to healthy controls. ACEi therapy increased plasma Ang 1-10 and Ang 1-7 concentrations, whereas ARB treatment increased both Ang 1-8 and Ang 1-5, while suppressing Ang 1-7 to minimal levels. Dual RAS blockade resulted in high levels of Ang 1-10 and suppressed levels of other angiotensins. Anephric patients were completely devoid of detectable levels of circulating angiotensins. CONCLUSION: In HD patients, the activity status of the systemic RAS is highly distorted with the emergence of crucial angiotensin metabolites upon distinct RAS blockade. The characterization of molecular RAS patterns associated with specific RAS interfering therapies may help to individualize future clinical studies and therapies.

Histopathology and prognosis of de novo bladder tumors following solid organ transplantation.

BACKGROUND: Patients following solid organ transplantation have an increased risk of developing de novo bladder tumors, but their biology is poorly characterized. METHODS: We studied 1743 patients who underwent a transurethral resection of a newly diagnosed bladder tumor at a single institution. The histopathology, treatment, recurrence-free survival and overall survival were evaluated and compared between transplant and non-transplant patients. RESULTS: We identified 74 transplant patients who developed a de novo bladder tumor after a median post-transplantation interval of 62 months. The tumor was malignant in 29 patients (39 %). The most common benign lesion was nephrogenic adenoma (84 %), which neither coexisted with nor developed into malignant tumors during follow-up. Compared with non-transplant patients (n = 1669), transplant patients were significantly younger (median 55 vs 69 years, P < 0.001) and had a 9.0-fold higher odds of benign tumors (P < 0.001), while there were no differences in pathology among patients with urothelial carcinoma of the bladder (UCB). In a multivariable analysis for non-muscle-invasive UCB that was adjusted for the risk group, patients with a transplant had a 1.8-fold increased risk of recurrence (P = 0.048). Four of five transplant patients did not respond to Bacillus Calmette-Guérin instillations. There were no differences in overall survival after radical cystectomy (P = 0.87). CONCLUSIONS: The majority of bladder tumors in transplant patients are benign, and they neither coexist with nor develop into malignant tumors. Transplant patients with non-muscle-invasive UCB show an increased risk of disease recurrence, while those treated with radical cystectomy have similar outcomes to patients without a transplant.

Severe hypocalcemia in the emergency department: a retrospective cohort study of prevalence, etiology, treatment and outcome.

The aim of this study was to evaluate the prevalence of severe hypocalcemia in patients attending the emergency department. Symptoms, causes, treatment, and outcome of severe hypocalcemia as well as course of calcium concentrations were assessed. This retrospective case series included all adult patients with measurements of serum calcium concentrations presenting to the emergency department of the Bürgerspital Solothurn between January 01 in 2017 and December 31 in 2020. Medical record reviews were performed of all patients with severe hypocalcemia, defined by a serum calcium concentration < 1.9 mmol/L, to assess clinical presentation and management. 1265 (3.95%) patients had a serum calcium concentration of < 2.1 mmol/L of which 139 (11%) had severe hypocalcemia of < 1.9 mmol/L. 113 patients had at least one measurement of albumin. Of these, 43 (3.4%) had an albumin-corrected serum calcium < 1.9 mmol/L defining true, severe hypocalcemia. Hypocalcemia was identified and documented in 35% of all cases. The mean serum calcium concentration was 1.74 ± 0.14 mmol/L. Calcium concentrations in malignancy-related hypocalcemia were similar to non-malignancy-related hypocalcemia. The main symptoms attributed to hypocalcemia were cardiac and neurologic. 12% of patients with severe hypocalcemia received intravenous and 23% oral calcium replacement. Active malignancy was the main cause of severe hypocalcemia in 28%, while in most cases, the main cause remained unclear. 41.9% of severely hypocalcemic patients reattended the emergency department for another episode of hypocalcemia within 1 year. Hypocalcemia is common in patients attending the emergency department, however, appears to be neglected frequently. The disorder is often a manifestation of severe disease, triggered by multiple causes. Calcium replacement was administered in less than half of the patients with severe hypocalcemia in this study. Due to frequent readmissions to the emergency department and a high mortality, increased awareness of the disorder and careful follow-up are desirable.

Renal function-adapted D-dimer cutoffs in combination with a clinical prediction rule to exclude pulmonary embolism in patients presenting to the emergency department.

D-dimer levels significantly increase with declining renal function and hence, renal function-adjusted D-dimer cutoffs to rule out pulmonary embolism were suggested. Aim of this study was to "post hoc" validate previously defined renal function-adjusted D-dimer levels to safely rule out pulmonary embolism in patients presenting to the emergency department. In this retrospective, observational analysis, all patients with low to intermediate pre-test probability receiving D-dimer measurement and computed tomography angiography (CTA) to rule out pulmonary embolism between January 2017 and December 2020 were included. Previously defined renal function-adjusted D-dimer cutoffs (1306 µg/l for moderate and 1663 µg/l for severe renal function impairment) were applied to determine sensitivity, specificity, negative and positive predictive values. One thousand, three hundred sixty-nine patients were included of which 229 (17%) were diagnosed with pulmonary embolism. The estimated glomerular filtration rate (eGFR) was ≥ 60 ml/min in 1079 (79%), 30-59 ml/min in 266 (19%) and < 30 ml/min in 24 (2%) patients. Only three patients (1.1%) with an eGFR < 60 ml/min had a D-dimer level < 500 µg/l. There was a significant correlation between D-dimer and eGFR (R = - 0.159, p < 0.001). Calculated on the standard D-dimer cutoff value of 500 µg/l, sensitivity of D-dimer testing was 97% for patients with an eGFR ≥ 60 ml/min and 100% for those with 30-60 ml/min, while specificity decreased in patients with renal function impairment. A negative predictive value of 0.99 as a premise to safely rule out pulmonary embolism was achieved by applying a D-dimer cutoff of 1480 µg/l for eGFR 30-59 ml/min and 1351 µg/l for eGFR < 30 ml/min. The findings of this study underline that application of renal function-adapted D-dimer levels in combination with a clinical prediction rule appears feasible to rule out pulmonary embolism. Out of the current dataset, renal function-adjusted D-dimer cutoffs to rule out pulmonary embolism were slightly different compared to previously defined cutoffs. Further studies on a larger scale are needed to validate possible renal function-adjusted D-dimer cutoffs.

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.

A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-κB and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. Renal transplant patients receiving rapamycin but not those receiving calcineurin inhibitors displayed a state of innate immune cell hyper-responsiveness despite the concurrent use of GC. Finally, mTOR inhibition was able to override the healing phenotype of dexamethasone in a murine lipopolysaccharide shock model. Collectively, these data identify a novel link between the glucocorticoid receptor and mTOR in innate immune cells, which is of considerable clinical importance in a variety of disorders, including allogeneic transplantation, autoimmune diseases, and cancer.

Novel views on new-onset diabetes after transplantation: development, prevention and treatment.

New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.

Fluid overload in hemodialysis patients: a cross-sectional study to determine its association with cardiac biomarkers and nutritional status.

BACKGROUND: Chronic fluid overload is associated with higher mortality in dialysis patients; however, the link with cardiovascular morbidity has not formally been established and may be influenced by subclinical inflammation. We hypothesized that a relationship exists between fluid overload and [i] cardiovascular laboratory parameter as well as between fluid overload and [ii] inflammatory laboratory parameters. In addition, we aimed to confirm whether volume status correlates with nutritional status. METHODS: We recorded baseline characteristics of 244 hemodialysis patients at three hemodialysis facilities in Vienna (Austria) and determined associations with volume measurements using the body composition monitor (Fresenius/Germany). In one facility comprising 126 patients, we further analyzed cardiovascular, inflammatory and nutritional parameters. RESULTS: We detected predialysis fluid overload (FO) in 39% of all patients (n = 95) with FO defined as ≥15% of extracellular water (ECW). In this subgroup, the absolute FO was 4.4 +/-1.5 L or 22.9 ± 4.8% of ECW. A sub-analysis of patients from one center showed that FO was negatively associated with body mass index (r = -0.371; p = <0.001), while serum albumin was significantly lower in fluid overloaded patients (p = 0.001). FO was positively associated with D-Dimer (r = 0.316; p = 0.001), troponin T (r = 0.325; p < 0.001), and N-terminal pro-B-type natriuretic peptide (r = 0.436; p < 0.001), but not with investigated inflammatory parameters. CONCLUSIONS: Fluid overload in HD patients was found to be lower in patients with high body mass index, indicating that dry weight was inadequately prescribed and/or difficult to achieve in overweight patients. The association with parameters of cardiovascular compromise and/or damage suggests that fluid overload is a biomarker for cardiovascular risk. Future studies should determine if this applies to patients prior to end-stage renal disease.

Serum amyloid A in uremic HDL promotes inflammation.

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.

Early basal insulin therapy decreases new-onset diabetes after renal transplantation.

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better ß-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of ß cells.

Gender Equality in National Cardiology Societies: A Cross-Sectional Study.

BACKGROUND: Higher productivity and team stability have been shown for gender-diverse teams. However, there is a relevant and well-known gender gap in clinical and academic cardiovascular medicine. So far, no data concerning gender distribution in presidents and executive boards of national cardiology societies exist. METHODS: In this cross-sectional analysis, gender equality in presidents and representatives of all national cardiology societies, which were members of, or affiliated with, the European Society of Cardiology (ESC) in 2022, was analyzed. In addition, representatives of the American Heart Association (AHA) were evaluated. RESULTS: A total of 106 national societies were screened, of which 104 were included in the final analysis. Overall, 90 of 106 (85%) presidents were men, while 14 (13%) were women. In the analysis of board members and executives, a total of 1128 individuals were included. Overall, 809 (72%) board members were men, 258 (23%) women, and 61 (5%) of unknown gender. Except for society presidents in Australia, women were relevantly outnumbered by men in all world regions. CONCLUSION: Women were underrepresented in leading positions of national cardiology societies in all world regions. As national societies are important regional stakeholders, improving gender equality in executive boards might create women role models, help foster careers, and narrow the global cardiology gender gap.

Characteristics and outcome of severe hypercalcemia on admission to the emergency department: a retrospective cohort study.

AIMS OF THE STUDY: To investigate the prevalence of hypercalcemia (>2.60 mmol/l) and severe hypercalcemia (≥2.80 mmol/l) on admission. Symptoms, causes, course of serum calcium, treatment and outcome of severe hypercalcemia were evaluated and compared to historical data from previous studies. METHODS: In this retrospective cohort study, all patients presenting to the interdisciplinary emergency department of the Buergerspital Solothurn between 01 January 2017 and 31 December 2020 with measurements of serum calcium were included. Chart reviews were performed for patients with calcium ≥2.80 mmol/l to assess clinical presentation, course of disease and treatment for severe hypercalcemia. RESULTS: Of 31,963 tested patients, 869 patients (2.7%) had hypercalcemia on the admission, of which 161 had severe hypercalcemia. Non-albumin corrected calcium was 3.07 (0.32) while albumin corrected calcium was 3.34 (0.44). Calcium was higher in patients with malignancy-related hypercalcemia (3.18 [0.34] versus 3.00 [0.3], p <0.001). Neuropsychiatric (35%) and gastrointestinal (24%) were the leading symptoms. Malignancy was the most common identifiable cause of hypercalcemia (40%), with lung cancer (20%), multiple myeloma (14%) and renal cell carcinoma (11%) being the main cancer types. 36% of patients with severe hypercalcemia took calcium supplements. Bisphosphonate treatment was an independent predictor of a fall in calcium until day 5 (regression coefficient: -0.404, standard error 0.11, p <0.001). Hypercalcemia was not mentioned in the final discharge report in 38% of cases. CONCLUSION: Severe hypercalcemia is common and malignancy-related in almost half of the cases. Neuropsychiatric and gastrointestinal symptoms were most prevalent. Awareness of hypercalcemia, particularly in cancer patients and those with known triggering factors, should be raised in order to identify and treat this harmful disorder early.

A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation.

The mammalian target of rapamycin (mTOR) regulates cell growth and survival and exists as rapamycin-sensitive mTOR complex (mTORC) 1 and as rapamycin-insensitive mTORC2. Although mTOR is a well-known regulator of diverse immune cells, its detailed role in human dendritic cell (DC) function and differentiation is only incompletely understood. In this study, we demonstrate divergent roles of mTOR during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. Inhibition of mTORC1 or mTORC1/2 during moDC differentiation decreased moDC survival and markedly hampered its immunostimulatory phenotype. Analyzing the fate of DCs in vivo, we found that kidney transplant patients treated with rapamycin displayed an increased immunostimulatory potential of mDCs compared with patients treated with calcineurin inhibitors. Furthermore, rapamycin did not interfere with mDC differentiation in these patients. Collectively, mTOR exerts divergent immunoregulatory functions during DC activation and differentiation depending on the DC type that lead to opposing T cell responses, which might be of clinical importance in transplantation, cancer, and also for novel vaccination strategies.

Emergency medicine in Switzerland: an analysis of physician workforce, gender equality and academics.

BACKGROUND: Globally, emergency medicine is continuously evolving and in numerous countries, societies and colleges help develop the specialty on a professional and academic level. However, there are countries, including Switzerland, where emergency medicine is not a fully recognised specialty and there is a historical gender gap. AIMS OF THE STUDY: It was the aim of this study to investigate the trends and developments in Swiss emergency medicine in terms of physician workforce, gender equality and academic posts over time. METHODS: In this observational longitudinal analysis, the number and gender distribution of Swiss Society of Emergency and Rescue Medicine (SSERM) members as well as SSERM-certified physicians were analysed in 2011, 2016 and 2021. Additionally, head and leading physicians of SSERM-certified emergency departments of category 1 and 2 were analysed in 2021 with special regard to gender distribution. Finally, an analysis of Swiss academic emergency medicine including Swiss academic tracks, professors in emergency medicine as well as committees, chairs and speakers of the annual SSERM conference was performed. RESULTS: From 2011 to 2021, there was an increase in SSERM members of 52% and a growing proportion of women from 26% to 35%. Similarly, there was a rise of 66% in physicians certified in in-hospital and 79% certified in prehospital emergency medicine. The proportion of women increased by 153% and 131%, respectively. In the analysed emergency departments, 69% of all head physicians were men whereas 50% of senior consultants and consultants with extended responsibility were women in 2021. Concerning academics, emergency medicine was a mandatory subject at all Swiss universities offering a master's degree in medical studies in 2021. However, 11 Swiss universities reported only six full professors, of whom only one was a woman, and three associate professors in emergency medicine in 2021. The analysis of the annual SSERM conferences from 2016 to 2019 revealed that men outnumbered women at every conference in terms of committees, chairs and speakers. CONCLUSIONS: The number of SSERM members and board-certified emergency physicians, women in particular, remarkably increased in 10 years. Equality appears to be within reach for clinical emergency physicians, but women continue to be underrepresented in academic positions, at scientific conferences and among professors. In Switzerland, academic emergency medicine appears to be lagging behind in view of the growing emergency physician and women workforce, which might complicate further progress in and development of Swiss emergency medicine on a scientific and professional level..

The versatility of HDL: a crucial anti-inflammatory regulator.

BACKGROUND: Low levels of plasma high-density lipoprotein (HDL) represent a major cardiovascular risk factor and therefore raising HDL has been proposed to positively affect patients with atherosclerotic heart disease. However, the current evidence that raising HDL per se will reduce atherosclerosis and thereby cardiovascular events still remains controversial. AIMS: In this review, we discuss the diverse anti-atherogenic and anti-inflammatory properties of HDL in the light of recent findings indicating that the quality rather than the mere quantity of HDL determines its beneficial effects against atherosclerosis. More specifically, we will focus on the conspicuous anti-inflammatory properties of HDL as this might contribute to the overall beneficial effects of HDL in diseased patients such as modulation of costimulatory/adhesion molecule expression, cytokine production and inhibition of the prototypical proinflammatory transcription factor NF-κB. RESULTS: A range of clinical disorders share permanent inflammation as a characteristic hallmark including coronary artery disease, chronic kidney disease, diabetes mellitus or rheumatoid arthritis and also display distinct qualitative changes in the HDL compartment. Loss of anti-inflammatory functions of HDL is emerging as an important risk factor for disease progression and survival in these clinical entities. CONCLUSIONS: It will be important to define the anti-inflammatory effects of HDL at the molecular level and to dissect the manifold functional implications to develop both novel functional assays that enable meaningful outcome studies and foster new therapeutic concepts in patients with altered HDL function.

Sirolimus in renal transplant recipients with tuberous sclerosis complex: clinical effectiveness and implications for innate immunity.

Tuberous sclerosis complex (TSC) is caused by constitutively activated mammalian target of rapamycin (mTOR) resulting in nonmalignant tumours of several organs and consequently renal failure. Recent reports suggest a possible beneficial role of the mTOR-inhibitor (mTOR-I) sirolimus for TSC; however, safety and efficiency of sirolimus in TSC patients after renal transplantation, both as primary immunosuppressant as well as anti-proliferative agent, are still undefined. Moreover, it is currently unknown whether the TSC mutation affects the primary immune response in these patients. In this article, we report on three TSC patients after renal transplantation who have been converted from a calcineurin-inhibitor (CNI)-based immunosuppression to sirolimus. During 2 years of follow-up, renal allograft function was stable or even improved, and no significant sirolimus-associated side-effects were noted. Beneficial effects of sirolimus against TSC were detected in the skin, along with improved spirometric measurements and an arrest of astrocytoma progression. We show that the inflammatory immune response was significantly altered in TSC patients as compared with controls and sirolimus potently affected both inflammatory cytokine production and vascular endothelial growth factor levels in these patients. Larger studies are warranted to further examine the relationship between clinical parameters and the molecular response to mTOR-inhibition in TSC patients after renal transplantation.