Tim Holland-Letz

Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double‐blind placebo‐controlled study

Background:  Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double‐blind placebo‐controlled study in children with grass pollen allergy using high dose allergen extracts.

High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients

BACKGROUND Vitamin D has emerged as an important survival factor in patients with chronic kidney disease. Non-activated vitamin D may also have beneficial effects on bone, cardiovascular and immune functions. Cholecalciferol is the prevalent non-activated vitamin D in Europe, but there is no valid prospective data available about its use in haemodialysis patients. Thus, we initiated a prospective study to evaluate dosing, safety and tolerability of cholecalciferol supplementation in haemodialysis patients. METHODS The prospective study included 64 haemodialysis patients. During replenishment phase patients received 20 000 IU cholecalciferol/week for 9 months. In the open maintenance phase (15 months), patients were randomized to a treated group (20 000 IU cholecalciferol/month) and an untreated group, which did not receive cholecalciferol. RESULTS Calcidiol [25(OH)D] deficiency (<37.5 nmol/l; <15 microg/l) was detected in 61/64 patients (95%). During the replenishment phase, calcidiol increased significantly from 16.65 +/- 9.6 to 79.48 +/- 27.15 nmol/l (6.66 +/- 3.84 microug/l to 31.79 +/- 10.86 microg/l) (P < 0.001). Recommended levels (>75 nmol/l; >30 microg/l; K/DOQI) were achieved in 57% of patients. Calcium increased from 2.28 +/- 0.17 to 2.37 +/- 0.19 mmol/l (9.1 +/- 0.69 mg/dl to 9.49 +/- 0.75 mg/dl) (P<0.01). Phosphorus, calcium-phosphorus product and parathyroid hormone showed no significant changes. Fifty-nine patients progressed to the maintenance phase. Analysis per protocol showed a significant drop of calcidiol in the treated [83.98 +/- 31.73 versus 78.5 +/- 38.75 nmol/l (33.59 +/- 12.69 versus 31.4 +/- 15.5 microg/l) (P < 0.001)] and untreated groups [86.35 +/- 40.75 versus 53.4 +/- 26.2 nmol/l (34.54 +/- 16.3 versus 21.36 +/- 10.48 microg/l) (P < 0.001)]. The comparison of the treated and the untreated groups showed no significant differences at the beginning of the maintenance phase: 83.98 +/- 31.73 versus 86.35 +/- 40.75 nmol/l (33.59 +/- 12.69 versus 34.54 +/- 16.3 microg/l). At the end they differed significantly: 78.5 +/- 38.75 versus 53.4 +/- 26.2 nmol/l (31.4 +/- 15.5 versus 21.36 +/- 10.48 microg/l) (P < 0.001). CONCLUSION Vitamin D deficiency is present in a majority of haemodialysis patients. Supplementation with cholecalciferol is safe, well tolerated and reasonable to replenish vitamin D stores in haemodialysis patients. However, only 57% of patients achieved recommended calcidiol levels, thus favouring additional dose-finding studies.

Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis

BACKGROUND Appendiceal perforation in patients with acute appendicitis may cause a variety of potentially life-threatening complications. Escherichia coli endotoxin has been shown to impact physiological bile flow in vivo. This had led to the theory that hyperbilirubinemia in patients with appendicitis may have a predictive potential for the preoperative diagnosis of appendiceal perforation. The aim of this retrospective study was to investigate the diagnostic value of hyperbilirubinemia as a preoperative laboratory marker for appendiceal perforation in patients with acute appendicitis. METHODS We identified 538 patients (306 female; 232 male, mean age, 35.6 y) with histologically proved acute appendicitis who underwent laparoscopic or conventional appendectomy between January 2004 and December 2007 in a surgical department of an academic teaching hospital. A retrospective multiple chart review of the medical records including laboratory values and histologic results was conducted. RESULTS The mean bilirubin level of all patients was .9 mg/dL (+/-.6 SD mg/dL; range, .1-4.3 mg/dL; median, .7 mg/dL). Patients with appendiceal perforation, however, had a mean bilirubin level of 1.5 mg/dL (+/-.9 SD mg/dL; range, .4-4.3 mg/dL; median, 1.4 mg/dL), which was significantly higher than those with a nonperforated appendicitis (P < .05). The specificity of hyperbilirubinemia for appendiceal perforation was .86 compared with .55 for white blood count and .35 for C-reactive protein. Sensitivity was .7 compared with .81 for white blood count and .96 for C-reactive protein. CONCLUSIONS Patients with hyperbilirubinemia and clinical symptoms of appendicitis should be identified as having a higher probability of appendiceal perforation than those with normal bilirubin levels.

Pancreatitis risk in primary hyperparathyroidism: relation to mutations in the SPINK1 trypsin inhibitor (N34S) and the cystic fibrosis gene.

OBJECTIVEPrimary hyperparathyroidism (pHPT)-related hypercalcemia is considered to represent a risk factor for the development of pancreatitis. We therefore explored whether mutations in genes that were previously identified to increase the risk for pancreatitis coexist in a cohort of 826 patients with pHPT prospectively studied between 1987 and 2002.METHODSAmong 826 patients with pHPT, 38 patients were identified with pancreatitis (4.6%). DNA was available from 25 patients (13 women/12 men, 16 acute pancreatitis/9 chronic pancreatitis). These individuals and 50 patients with pHPT without pancreatitis were analyzed for mutations in the serine protease inhibitor Kazal type I (SPINK1) gene (N34S) and the cationic trypsinogen gene (PRSS1) (N29I, R122H) by melting curve analysis and DNA sequencing. Sequence analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was carried out for the detection of 36 mutations and the Tn polymorphism.RESULTSFour of 25 patients with pHPT and pancreatitis carried the N34S missense mutation in the SPINK1 gene (16%), while all 50 controls (pHPT without pancreatitis) showed no mutation in SPINK1 or PRSS1 genes (P < 0.05 vs controls, P < 0.001 vs general population). CF-causing CFTR mutations were present in four patients (P < 0.05 vs general population), while one patient carried a 5T allele. One patient was transheterozygous (SPINK1: N34S/CFTR: R553X). Mean serum calcium levels in pancreatitis patients (3.1 mmol/L) did not differ significantly from the mean of the entire cohort (3.0 mmol/L) or pHPT patients without pancreatitis (3.1 mmol/L).CONCLUSIONPancreatitis risk is approximately 10-fold elevated in pHPT, but pancreatitis occurs infrequently. This indicates an existing but minor impact of pHPT-related hypercalcemia. If pancreatitis occurs, it seems associated with genetic risk factors such as mutations in the SPINK1 and CFTR genes. In contrast, a combination of both hypercalcemia and genetic variants in SPINK1 or CFTR increases the risk to develop pancreatitis in patients with pHPT.

High in-hospital mortality of intensive care patients with nucleated red blood cells in blood

Abstract The detection of nucleated red blood cells (NRBCs) in blood of patients suffering from a variety of severe diseases is known to be highly associated with increased mortality. Blood analyzers to routinely measure NRBC concentrations are now available. However, the diagnostic and prognostic significance of this parameter for intensive care patients has not been evaluated. Using a Sysmex XE-2100 analyzer, NRBC concentrations were determined in blood samples from 421 patients treated in intensive care units (general and accident surgery, cardiothoracic surgery, and internal medicine) of a university hospital. NRBCs were found at least once in 19.2% of all patients. The mortality of NRBC-positive patients (n = 81) was 42.0% (n = 34); this was significantly higher (p < 0.001) than the mortality of NRBC-negative patients (5.9%, n = 340). The NRBC concentration was 115 ± 4 × 106/l (median 40 × 106/l; range 20–2930 × 106/l) at initial detection of NRBCs in the blood. Mortality increased with increasing NRBC concentration and increasing frequency of occurrence. With regard to in-hospital mortality, NRBCs in blood showed sensitivity and specificity of 63.0% and 87.2%, respectively. The detection of NRBCs is highly predictive of death, the odds ratio after adjustment for other laboratory prognostic indicators being 1.01 (p < 0.01) for each increase in the NRBC concentration of +1 × 106/l. NRBCs were detected for the first time, on average, 13 days (median 8 days) before death. The routine analysis of NRBCs in blood is of high prognostic power with regard to in-hospital mortality of critically ill patients. Therefore, this parameter may serve as an early indicator for patients at increased mortality risk.

CT Angiography in Suspected Pulmonary Embolism: Impact of Patient Characteristics and Different Venous Lines on Vessel Enhancement and Image Quality

OBJECTIVE The objective of our study was to compare image quality, patient characteristics, and different catheters in pulmonary CT angiography (CTA) performed with bolus tracking and z-axis automated tube current modulation (ATCM) in patients with suspected pulmonary embolism. SUBJECTS AND METHODS One hundred twenty-six patients were referred to undergo pulmonary CTA with bolus tracking and ATCM. Besides patient characteristics, the type, position, size, and side of venous catheters were documented. Pulmonary vessel enhancement and image noise were quantified; signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Subjective vessel contrast was assessed by two radiologists in consensus. RESULTS Patient age showed a moderate but significant positive correlation to vessel enhancement (r = 0.244, p = 0.006), CNR (r = 0.178, p = 0.046), and subjective image quality (r = 0.344, p < 0.001). Patient weight revealed a significant negative correlation to vessel enhancement (r = -0.496, p < 0.001), SNR (r = -0.446, p < 0.001), CNR (r = -0.425, p < 0.001), and subjective image quality (r = -0.422, p < 0.001). In univariate analysis, SNR and CNR were significantly higher in patients who received contrast medium through peripheral catheters (30 +/- 13 and 27 +/- 13, respectively) than in those in whom central catheters were used (22 +/- 8 and 19 +/- 7, p = 0.041 and p = 0.029, respectively). Neither patient sex nor catheter size, position, or side had any significant impact on image quality. CONCLUSION Patient age and weight showed significant impact on vascular attenuation and image quality in pulmonary CTA with bolus tracking and ATCM, whereas patient sex and different peripheral catheters did not significantly influence image parameters.

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile

BackgroundCytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolises arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11, 12-epoxyeicosatrienoic acid, has several vasoprotective effects. The CYP2J2-G-50T-promotor polymorphism decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease. In the present study, we investigated the influence of this polymorphism on survived myocardial infarction in two study groups of patients with on average high cardiovascular risk profile.MethodsThe CYP2J2 polymorphism was genotyped in two groups of patients that were collected with the same method of clinical data collection. Data from 512 patients with sleep apnoea (group: OSA) and on average high cardiovascular risk profile and from another 488 patients who were admitted for coronary angiography (CAR-group) were evaluated for a potential correlation of the CYP2J2 polymorphism G-50T and a history of myocardial infarction. The G-50T polymorphism of the CYP2J2 gene was genotyped by allele specific restriction and light cycler analysis.ResultsThe T-allele of the polymorphism was found in 111 (11.1%; CAR-group: N = 65, 13.3%; OSA: N = 46, 9.0%). 146 patients had a history of myocardial infarction (CAR: N = 120, 24.6%; OSA: N = 26, 5.1%). Cardiovascular risk factors were equally distributed between the different genotypes of the CYP2J2 G-50T polymorphism. In the total group of 1000 individuals, carriers of the T-allele had significantly more myocardial infarctions compared to carriers of the wild type (T/T or G/T: 21.6%; G/G: 13.7%; p = 0.026, odds ratio 1.73, 95%-CI [1.06–2.83]). In the multivariate logistic regression analysis the odds ratio for a history of myocardial infarction in carriers of the T-allele was 1.611, 95%-CI [0.957–2.731] but this trend was not significant (p = 0.073).ConclusionIn presence of other risk factors, the CYP2J2 G-50T failed to show a significant role in the development of myocardial infarction. However, since our result is close to the border of significance, this question should be clarified in larger, prospective studies in the future.

A new efficient trial design for assessing reliability of ankle-brachial index measures by three different observer groups

BackgroundThe usual method of assessing the variability of a measure such as the ankle brachial index (ABI) as a function of different observer groups is to obtain repeated measurements. Because the number of possible observer-subject combinations is impractically large, only a few small studies on inter- and intraobserver variability of ABI measures have been carried out to date. The present study proposes a new and efficient study design. This paper describes the study methodology.MethodsUsing a partially balanced incomplete block design, six angiologists, six primary-care physicians and six trained medical office assistants performed two ABI measurements each on six individuals from a group of 36 unselected subjects aged 65–70 years. Each test subject is measured by one observer from each of the three observer groups, and each observer measures exactly six of the 36 subjects in the group. Each possible combination of two observers occurs exactly once per patient and is not repeated on a second subject. The study involved four groups of 36 subjects (144), plus standbys.ResultsThe 192 volunteers present at the study day were similar in terms of demographic characteristics and vascular risk factors: mean age 68.6 ± 1.7; mean BMI 29.1 ± 4.6; mean waist-hip ratio 0.92 ± 0.09; active smokers 12%; hypertension 60.9%; hypercholesterolemia 53.4%; diabetic 17.2%. A complete set of ABI measurements (three observers performing two Doppler measurements each) was obtained from 108 subjects. From all other subjects at least one ABI measurement was obtained. The mean ABI was 1.08 (± 0.13), 15 (7.9%) volunteers had an ABI <0.9, and none had an ABI >1.4, i.e. a ratio that may be associated with increased stiffening of the arterial walls.ConclusionThis is the first large-scale study investigating the components of variability and thus reliability in ABI measurements. The advantage of the new study design introduced here is that only one sixth of the number of theoretically possible measurements is required to obtain information about measurement errors. Bland-Altman plots show that there are only small differences and no systematic bias between the observers from three occupational groups with different training backgrounds.

Clinical Outcome Following Conservative vs Revascularization Therapy in Patients With Stable Coronary Artery Disease and Borderline Fractional Flow Reserve Measurements

Fractional flow reserve (FFR) measurements in the so‐called gray‐zone range of ≥ 0.75 and ⩽0.80 are associated with uncertainty concerning the guidance of patient therapy. It is unclear whether any difference in clinical outcome exists when revascularization treatment of FFR‐evaluated lesions in this borderline range is deferred or performed. The objective of this study is to compare the clinical outcome of these patients with respect to their recommended treatment strategy.

ASSOCIATION BETWEEN NUCLEATED RED BLOOD CELLS IN BLOOD AND THE LEVELS OF ERYTHROPOIETIN, INTERLEUKIN 3, INTERLEUKIN 6, AND INTERLEUKIN 12p70

The appearance of nucleated red blood cells (NRBC) in the circulation is associated with a variety of severe diseases, and indicates a relatively poor prognosis. Whether a malfunction of the bone marrow leads to this phenomenon is as unknown as the possible role that cytokines could play in this process. We analyzed erythropoietin, interleukin (IL)-3, IL-6, and IL-12p70 in the blood of 301 patients with circulating NRBCs. Two hundred fifty NRBC-negative patients served as controls. Multiple logistic regression revealed a significant association between the appearance of NRBCs in the blood and erythropoietin (odds ratio, 1.017; 95% confidence limits, 1.007-1.027; P < 0.001), IL-3 (odds ratio, 1.293; 95% confidence limits, 1.180-1.417; P < 0.001), IL-6 (odds ratio, 1.138; 95% confidence limits, 1.016-1.275; P < 0.05), and age (odds ratio, 1.019; 95% confidence limits, 1.009-1.030; P < 0.001), respectively. Gender and IL-12p70 were not significantly associated with the appearance of NRBC in the blood. To estimate the RBC production in the bone marrow, the increase in the reticulocyte concentration in blood was measured. The reticulocyte concentration in NRBC-positive patients was 69 ± 2/nL, which was significantly higher than in NRBC-negative patients (60 ± 2/nL; P < 0.01). Taken together, NRBC could be a marker that sums up hypoxic and inflammatory injuries. Thus, generally, the appearance of NRBC in blood is a valid parameter to identify patients at high mortal risk. Moreover, the increased number of reticulocytes in the blood of NRBC-positive patients may indicate that the appearance of NRBC is not associated with disturbed bone marrow function as far as the erythropoiesis is concerned.