Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study.

BACKGROUND: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

In vitro studies of different irradiation conditions for Photodynamic inactivation of Helicobacter pylori.

Helicobacter pylori (HP) infections are considered to be the main cause for chronic gastritis and gastric ulcers, whereby more than half of the world's population is nowadays infected. The increased use of antibiotics is leading to an enhanced resistance. Photodynamic inactivation of bacteria seems to be a potential alternative for antibiotic therapies. In our study we used the photosensitizer Chlorin e6 (Ce6) in combination with red light-emitting diodes to inactivate HP in vitro. Ce6 uptake is determined by spectroscopy. Furthermore diverse experiments of different concentrations in the range of 0-100 µM of the photosensitizer and exposure times up to 300 s are carried out in order to find optimal irradiation parameters (wavelength: 660 nm, power density: 9 mW/cm(2), absorbed dose: up to 2.7 J/cm(2)). The data show a significant reduction after already a few seconds of illumination, even with a low Ce6 concentration in the sub-µM-region. At a concentration of 100 µM a nearly total inactivation (6-log10-reduction) of HP was achieved within 60s of irradiation.

Regulation of soluble VEGFR-2 secreted by microvascular endothelial cells derived from human BPH.

BACKGROUND: Recently, it was reported that the soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) is secreted by microvascular endothelial cells from human BPH (HPECs). The purpose of this study was to investigate the modulation of sVEGFR-2 by common endothelial cell stimulators. In addition, the physiological role of sVEGFR-2 with regard to the VEGF-stimulated proliferation of HPEC was investigated. METHODS: HPECs were isolated and cultured from fresh BPH tissue. After the incubation of HPECs either with adenosine triphosphate (ATP), interleukin (IL)-6, IL-8 or IL-12, the secretion of sVEGFR-2 was measured by enzyme-linked immunosorbent assay. For measurement of HPEC proliferation influenced by sVEGFR-2, VEGF-stimulated HPEC was cultured with/without sVEGFR-2. Cell proliferation was assessed with the Alamar Blue method. RESULTS: The sVEGFR-2 secretion was increased by ATP and decreased by IL-12 and IL-8, respectively. IL-6 did not show any significant effect on sVEGFR-2 secretion of HPECs. HPEC proliferation was significantly inhibited by sVEGFR-2. CONCLUSIONS: In this study, our data suggest that the secretion of sVEGFR-2 by microvascular endothelial cells from prostate origin is influenced by multiple endothelial cell stimulators. Furthermore, our data suggest that sVEGFR-2 acts as an antiangiogenic factor.

Effects of maleimide-polyethylene glycol-modified human hemoglobin (MP4) on tissue necrosis in SKH1-hr hairless mice.

OBJECTIVE: Tissue hypoxia after blood loss, replantation and flap reperfusion remains a challenging task in surgery. Normovolemic hemodilution improves hemorheologic properties without increasing oxygen carrying capacity. Red blood cell transfusion is the current standard of treatment with its attendant risks. The aim of this study was to investigate the potential of the chemically modified hemoglobin, MP4, to reduce skin flap necrosis and its effect on selected blood markers and kidneys. MATERIALS AND METHODS: Tissue ischemia was induced in the ear of hairless mice (n=26). Hemodilution was performed by replacing one third of blood volume with the similar amount of MP4, dextran, or blood. The extent of non-perfused tissue was assessed by intravital fluorescent microscopy. RESULTS: Of all groups, MP4 showed the smallest area of no perfusion (in percentage of the ear +/- SEM: 16.3% +/- 2.4), the control group the largest (22.4% +/- 3.5). Leukocytes showed a significant increase in the MP4 and dextran group (from 8.7 to 13.6 respectively 15.4*109/l). On histology no changes of the kidneys could be observed. CONCLUSION: MP4 causes an increase of leukocytes, improves the oxygen supply of the tissue and shows no evidence of renal impairment.

Estimation of the mortality risk of surgical intensive care patients based on routine laboratory parameters.

BACKGROUND: In established risk score models the collection and documentation of clinical data is time-consuming, causes labor-related costs, and is dependent on the examiner. MATERIAL AND METHODS: Based on low-cost laboratory parameters that are routinely measured at admission to the intensive care unit, a new score was developed (n = 271, study sample) and validated in an independent group of patients (n = 283, validation sample). Parameters were selected by a stepwise logistic regression analysis. This new score was compared to established risk models (APACHE II, SAPS II). RESULTS: Mean age was 61.3 +/- 1.2 years (study sample) and 63.1 +/- 1.1 years (validation sample), respectively. In-hospital mortality was 24.7% (67/271, study sample) and 23.3% (66/283, validation sample). The following parameters were used to build the new score called Dense Laboratory Whole Blood Applied Risk Estimation (DELAWARE): alanine aminotransferase, C-reactive protein, cholesterol, creatine kinase MB, leukocytes, potassium, thrombocytes, triglycerides, and age. The areas under the curves were 0.853/0.813 (study sample/validation sample). In the study sample DELAWARE correlated with APACHE II (r = 0.586) and SAPS II (r = 0.614; p < 0.001), respectively. CONCLUSIONS: A general admission risk score for surgical intensive care patients solely based on quality controlled low-cost routine laboratory parameters is feasible.

[The cortisol awakening response in patients with acute and chronic low back pain. Relations with psychological risk factors of pain chronicity]. / Die Cortisol-Aufwachreaktion bei Patienten mit akuten und chronischen Rückenschmerzen. Zusammenhänge mit psychologischen Risikofaktoren der Schmerzchronifizierung.

BACKGROUND: Peculiarities of the hypothalamic-pituitary-adrenal axis activity in stress-related pain-disorders and potential relations with psychological risk factors of pain chronicity have been discussed controversially. MATERIAL AND METHODS: The cortisol awakening responses of 31 low back pain patients (14 acute, 17 chronic) and 14 healthy controls were compared. In addition the interrelations between awakening response and chronic stress as well as depressive mood and - for the first time - maladaptive painprocessing and -copingstrategies were investigated. RESULTS: The groups did not differ in their cortisol awakening responses. Chronic stress, depressive mood and maladaptive cognitive painprocessing did not correlate with the awakening response. There were, however, significant interrelations between awakening responses and the behavioral paincoping-strategies. CONCLUSIONS: Behavioral paincoping-strategies should be considered as a potentially important contributing psychological factor in the relation between the activity of the hypothalamic-pituitary-adrenal axis and stress-related pain disorders.

[Significance of the PSA-concentration for the detection of prostate cancer]. / Bedeutung des PSA-Wertes für die Diagnostik des Prostatakarzinoms.

Prostate cancer among adult males is the most common neoplasm in western countries. Prostate specific antigen (PSA) is now a well established tumor marker that aids in the early detection of localized prostate cancer. Increased PSA concentrations are found in the serum of patients with benign prostatic hyperplasia or patients with prostate cancer, respectively. Therefore, in general the specificity of this test is low. The diagnostic value of PSA can be improved in consideration of clinical data, patients age, the measurement of free or complexed PSA, and the measurement of PSA velocity, respectively. Furthermore, there is a high variability between commercial PSA assays. Finally, the pre-analytical laboratory procedures have a high impact on the PSA measurement.

Making the case for adapting the abbreviated burn severity index to include erythroblast count.

The presence of erythroblasts is an accurate predictor of a poor prognosis. This study investigates whether this should be taken into account when assessing patients with burn injuries as traditional protocols may underestimate the level of risk.

Primary culture of microvascular endothelial cells from human benign prostatic hyperplasia.

BACKGROUND: Prostate growth seems to be influenced by paracrine factors like IL-6 originating from the microvascular endothelium. Therefore, our efforts were focused on the primary culture and behavior of microvascular endothelial cells (HPEC) derived from tissue of human benign prostatic hyperplasia (BPH). Until now, the isolation and culture of HPEC from BPH have not been reported. METHODS: BPH tissue was cut into small cubes and gently squeezed after incubation with dispase. HPEC were cultured from the resulting cell suspension after a stepwise selection by use of superparamagnetic beads coated with antibodies against endothelial specific antigens. HPEC were characterized by flow cytometry and immunohistochemistry. gamma-Glutamyl transpeptidase activity (specific for microvascular endothelium) was measured after dissolution of the HPEC with Triton X-100. After the incubation of HPEC either with ATP, VEGF, or TNF-alpha, the release of IL-6 was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: HPEC showed a typical endothelial morphology. They were positive for von Willebrand factor, CD31, CD62E (after stimulation with TNF-alpha), alpha-actin and were negative for fibroblastic antigens and PSA. Proliferation was stimulated by vascular endothelial growth factor (VEGF). gamma-Glutamyl transpeptidase activity in HPEC was 6.3 microIU/microg protein, whereas in human umbilical vein endothelial cells (HUVEC) no gamma-glutamyl transpeptidase activity was detectable. The IL-6 secretion of HPEC was stimulated by VEGF and TNF-alpha, but not by ATP and bradykinin. CONCLUSIONS: For the first time, the primary culture of microvascular endothelial cells from BPH tissue was successfully performed. Our results suggest that HPEC may be actively involved in prostate growth, due to the secretion of regulatory factors such as IL-6.

Prognostic significance of the presence of erythroblasts in blood after cardiothoracic surgery.

In patients suffering from a variety of severe diseases the detection of erythroblasts in peripheral blood is associated with poor prognosis. However, as yet the prognostic significance of erythroblasts in the blood of patients after cardiothoracic surgery has not been assessed. In a retrospective study we analyzed the database of 2074 patients, of whom 87 died in hospital during the postoperative period. All patients underwent cardiothoracic surgery using a heart-lung machine. Together with erythroblasts in blood, age, sex, body mass index, preoperative ejection fraction, smoking, diabetes mellitus, type of operation, emergency surgery, renal deficiency, pulmonary hypertension, and endocarditis were considered. The postoperative mortality of patients with erythroblasts in peripheral blood (n=57) was 45.6% (n=26), being significantly higher (p<0.001) than the mortality of patients without erythroblasts (3.0%). None of six patients with more than 2000 erythroblasts x 10(6)/l survived. The postoperative detection of erythroblasts is highly predictive of death, the odds ratio after adjustment for the other known prognostic factors being 7.2 (95% confidence interval 3.4-15.1). Erythroblasts were detected for the first time on average 11 +/- 2 days (median: 7 days; n=57) after surgery and 8 +/- 2 days (median: 6 days; n=26) before death. The detection of erythroblasts in blood after cardiothoracic surgery has a high prognostic significance in terms of in-hospital mortality, helping physicians to identify patients at high risk of death. This finding has to be confirmed by a prospective study with the use of a more sensitive and reliable technology and prospectively defined time intervals for counting blood cells.

Prognostic significance of low serum cholesterol after cardiothoracic surgery.

BACKGROUND: The precise prognostic significance of critically low cholesterol concentrations in patients undergoing cardiothoracic surgery is unknown. METHODS: In a retrospective case-control study, we analyzed the database of 2074 patients, of whom 87 died postoperatively in hospital. All patients underwent cardiothoracic surgery using a heart-lung machine. Age, sex, body mass index, preoperative ejection fraction, smoking, diabetes mellitus, type of operation, emergency surgery, renal deficiency, pulmonary hypertension, and endocarditis were considered together with serum concentrations of cholesterol, C-reactive protein, alanine aminotransferase, and triglycerides. The statistics included sensitivity, specificity, predictive value, odds ratio, and the ROC curve. RESULTS: Cholesterol decreased sharply immediately after surgery in both the deceased and the survivors. In the deceased, the mean cholesterol concentration (+/- SE) remained rather low between days 4 and 7 after surgery [2.46 +/- 0.16 mmol/L (95 +/- 6 mg/dL)]. In the survivors at that time, the mean cholesterol concentration was significantly (P <0.001) higher [4.37 +/- 0.03 mmol/L (169 +/- 1 mg/dL)]. The positive predictive value of a critically low cholesterol concentration [<3.10 mmol/L (<120 mg/dL)] was 25.4%, increasing to 66.6% at a cutoff value of 1.55 mmol/L (60 mg/dL). The odds ratio under those circumstances was 15.5, and the area under curve (C-statistic) was 0.90. CONCLUSIONS: The cholesterol concentration between days 4 and 7 after cardiothoracic surgery possesses a high prognostic significance in terms of in-hospital mortality.

Effects of diadenosine polyphosphates on the intracellular Ca2+ concentration in endothelial cells.

Diadenosine polyphosphates have differential hemodynamic effects. The role of the endothelium in the vascular effects of these agonists is still unclear. Primary cultures of rat aortal endothelial cells and Ea.hy 926 cells (a continuous endothelial cell line) were used to investigate the effects of Ap3A-Ap6A, adenosine triphosphate (ATP), and for comparison, arginine vasopressin (AVP) and angiotensin II (A II) on the intracellular Ca2+ concentration, [Ca2+]i. Fura-2 was used as Ca2+ indicator. In rat aortal endothelial cells, ATP and Ap4A concentration dependently increased [Ca2+]i with an initial peak followed by an elevated plateau. The half-maximal effects were reached at approximately 7 micromol/l for ATP and at approximately 10 micromol/l for Ap4A. The maximal peak effects at 100 micromol/l were 1,035 +/- 413 nmol/l (n = 3) and 437 +/- 271 nmol/l (n = 8) for ATP and Ap4A, respectively. At 100 micromol/l Ap3A and Ap6A slightly increased [Ca2+]i, while Ap5A had no significant effect. The known endothelial agonists AVP (100 nmol/l) and A II (10 nmol/l) increased [Ca2+]i initially by 1,549 +/- 913 nmol/l (n = 7) and 209 +/- 45 nmol/l (n = 9), respectively. In Ea.hy 926 cells an increase in [Ca2+]i was obtained only with ATP (10 micromol/l) and with Ap4A (100 micromol/l). Ap3A, Ap5A, and Ap6A (each 100 micromol/l) and also AVP (100 nmol/l) and A II (10 nmol/l) had no significant effects in these cells. These results show that a considerable increase in [Ca2+]i in endothelial cells can only be induced by Ap4A among the diadenosine polyphosphates, indicating that the vasoactive effects of only this polyphosphate could at least partly be mediated via Ca2+-dependent mechanisms in endothelial cells, comparable to the known effects of AVP, A II, and ATP. The fact that A II and AVP did not influence [Ca2+]i in Ea.hy 926 cells is probably due to the loss of the respective receptors in this cell line.

Regulation of organic cation transport in IHKE-1 and LLC-PK1 cells. Fluorometric studies with 4-(4-dimethylaminostyryl)-N-methylpyridinium.

The regulation of transport of the fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP+) by renal proximal tubular organic cation transport was studied in IHKE-1 and LLC-PK1 cells with a recently established fluorometric technique (Stachon et al., 1996, 1997). Stimulation of Ca++/diacylglycerol-dependent protein kinase by 1,2-dioctanoyl glycerol (DOG; 0.01-1 mumol/l, n = 7), ATP (0.1 mmol/l, n = 9), oxytocin (0.1 mumol/l, n = 6) and bradykinin (1 mumol/l, n = 7) resulted in an increase of ASP+ accumulation in IHKE-1 cells by 35 +/- 9% (DOG), 65 +/- 30% (ATP), 66 +/- 14% (bradykinin) and 70 +/- 20% (oxytocin) as compared with basal conditions, whereas ASP+ accumulation was slightly reduced in LLC-PK1 cells after stimulation with DOG (1 mumol/l, -20 +/- 7%, n = 10) and angiotensin II (0.1 nmol/l, -20 +/- 5%, n = 6). ASP+ accumulation in IHKE-1 cells also was increased by 0.5 mumol/l (20 +/- 8%, n = 8) and 1 mumol/l forskolin (35 +/- 13%, n = 19), and by 8-bromo-cAMP (1 mumol/l, 125 +/- 25%, n = 9), both activators of the cAMP-dependent protein kinase (PKA). Activation of the cGMP-dependent protein kinase (PKG) by human atrial natriuretic peptide (10 nmol/l, n = 10) or 8-bromo-cGMP (0.1 mmol/l, n = 12) resulted in an increase of 35 +/- 5% and 28 +/- 6%, respectively. Activation of PKA and PKG had no influence on ASP+ transport in LLC-PK1 cells. Regulation of ASP+ uptake by these two cell lines may be caused by direct phosphorylation of the organic cation transporters involved or by regulation of trafficking of the transporters to the membrane. Differences in the organic cation transporter isoforms or alternatively, in the trafficking may contribute to the distinct regulation of ASP+ transport in IHKE-1 and LLC-PK1 cells.

[Acute tetraplegia, diabetes mellitus (clin conference)]. / Akute Tetraparese, Diabetes mellitus.

A 48-year-old patient with massive obesity developed a dramatic increase of serum glucose and sodium concentration as first symptom of a so far unknown diabetes mellitus. A treatment with intravenous insulin infusion and administration of free water was initiated. Two weeks after this event he became comatose, developed dysphagia, a speech disorder and ocular bobbing; finally, he showed the picture of a complete tetraparesis. Computertomographic findings of the brain were unremarkable. Two weeks later physical findings of the patient showed a significant improvement. Dysphagia, speech disorder and even the tetraparesis disappeared. Computertomography of the brain now yielded a hypodense area within the pons. The symptoms can be understood as signs of central pontine myelinolysis, which may be due to hypo-osmolarity or fast equilibration of a hypo-osmolarity. The history of this patient is a rare example of a central pontine myelinolysis with spontaneous remission.