Pilot Study to Gain First Indications for the Impact of a 3-Month's Oral Intake of a Sucrosomial Iron Supplement on Hemoglobin in Iron-Deficient Blood Donors.

Introduction: Regular whole blood donors often suffer from iron deficiency (ID) or iron deficiency anemia due to the loss of 200-300 mg of iron with each donation. Hemoglobin (Hb) as donor eligibility criterion reflects iron stores only poorly. ID in blood donors is typically prevented or treated with orally administered ferrous salts, which frequently cause gastrointestinal side effects. A high daily oral iron dose is counterproductive due to hepcidin upregulation. Oral sucrosomial iron (sucriron) is encapsulated ferric pyrophosphate that may be an option for blood donors due to its supposed high bioavailability and good tolerability. Methods: This monocentric single-cohort pilot study included fifty whole blood donors (divided into premenopausal women, postmenopausal women, and men) who did not meet Hb donation criteria. Participants aged 18-65 years with ferritin <30 ng/mL and venous Hb <12.5 g/dL in women and Hb <13.5 g/dL in men received oral sucriron (30 mg iron) for 90-120 days. Primary endpoints were the increase of Hb and ferritin. Results: Forty-seven participants completed the study. With the limitation that no control group was included, there was a substantial overall median increase of 0.94 g/dL Hb and 4.97 ng/mL ferritin (standardized on 90 days of iron intake). These value improvements were likewise observed in each of the subgroups. sucriron was very well tolerated, with almost no gastrointestinal side effects identified. Conclusion: A clear increase of Hb and ferritin was observed after the intake of sucriron, so it may be a reasonable and useful alternative to traditional oral iron therapy. The ease of administration, pleasant taste, dietary supplement status, and, most importantly, good tolerability highlight the value of sucriron supplementation.

Retrospective Analysis of the Blood Component Utilization in a University Hospital of Maximum Medical Care.

BACKGROUND: Demographic data illustrate clearly that people in highly developed countries get older, and the elderly need more blood transfusions than younger patients. Additionally, special extensive therapies result in an increased consumption of blood components. Beyond that the aging of the population reduces the total number of preferably young and healthy blood donors. Therefore, Patient Blood Management will become more and more important in order to secure an increasing blood supply under fair-minded conditions. METHODS: At the University Hospital of Münster (UKM) a comprehensive retrospective analysis of the utilization of all conventional blood components was performed including all medical and surgical disciplines. In parallel, a new medical reporting system was installed to provide a monthly analysis of the transfusional treatments in the whole infirmary, in every department, and in special blood-consuming cases of interest, as well. RESULTS: The study refers to all UKM in-patient cases from 2009 to 2011. It clearly demonstrates that older patients (>60 years, 35.2-35.7% of all cases, but 49.4-52.6% of all cases with red blood cell (RBC) transfusions, 36.4-41. 6% of all cases with platelet (PTL, apheresis only) transfusions, 45.2-48.0% of all cases with fresh frozen plasma (FFP) transfusions) need more blood products than younger patients. Male patients (54.4-63.9% of all cases with transfusions) are more susceptible to blood transfusions than female patients (36.1-45.6% of all cases with transfusions). Most blood components are used in cardiac, visceral, and orthopedic surgery (49.3-55.9% of all RBC units, 45.8-61.0% of all FFP units). When regarding medical disciplines, most transfusions are administered to hematologic and oncologic patients (12.9-17.7% of all RBC units, 9.2-12.0% of all FFP units). The consumption of PTL in this special patient cohort (40.6-50.9% of all PTL units) is more pronounced than in all other surgical or in non-surgical disciplines. CONCLUSION: The results obtained from our retrospective analysis may help to further optimize the responsible and medical indication-related utilization of blood transfusions as well as the recruitment of blood donors and their timing. It may be also a helpful tool in order to avoid needless transfusions and transfusionassociated adverse events.

Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder.

Calcium-binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH-SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH-SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH-SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein.

Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder.

Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

Risk variants in the S100B gene predict elevated S100B serum concentrations in healthy individuals.

Several lines of evidence suggest an important role of the S100B protein and its coding gene in different neuropathological and psychiatric disorders like dementia, bipolar affective disorders and schizophrenia. To clarify whether a direct link exists between gene and gene product, that is, whether S100B variants directly modulate S100B serum concentration, 196 healthy individuals were assessed for S100B serum concentrations and genotyped for five potentially functional S100B SNPs. Functional variants of the serotonergic genes 5-HT1A and 5-HTT possibly modulating S100B serum levels were also studied. Further, publicly available human postmortem gene expression data were re-analyzed to elucidate the impact of S100B, 5-HT1A and 5-HTT SNPs on frontal cortex S100B mRNA expression. Several S100B SNPs, particularly rs9722, and the S100B haplotype T-G-G-A (including rs2186358-rs11542311-rs2300403-rs9722) were associated with elevated S100B serum concentrations (Bonferroni corrected P < 0.05). Of these, rs11542311 was also associated with S100B mRNA expression directly (Bonferroni corrected P = 0.05) and within haplotype G-A-T-C (rs11542311-rs2839356-rs9984765-rs881827; P = 0.004), again with the G-allele increasing S100B expression. Our results suggest an important role of S100B SNPs on S100B serum concentrations and S100B mRNA expression. It hereby links recent evidence for both, the impact of S100B gene variation on various neurological or psychiatric disorders like dementia, bipolar affective disorders and schizophrenia and the strong relation between S100B serum levels and these disorders.

Association analysis of Rgs7 variants with panic disorder.

Following our recent finding of Rgs2 playing a role in the development of human panic disorder (PD), we examine another positional and functional candidate from the functionally interwoven Rgs (regulator of G-protein signaling) family, Rgs7, in the pathogenesis of PD. A German PD sample (N = 224) was compared with matched controls (N = 224) for seven SNPs within and flanking the gene. The intronic SNP3 (rs11805657) and its corresponding haplotypes were found to be associated with PD, particularly PD with comorbid agoraphobia (PDAgP), with the effect originating from the female subgroup (P values 0.008-0.047). The rare A-allele was underrepresented in patients, suggesting a protective effect with carriers possessing an about 2-fold lower risk for developing the disorder compared to G/G homozygotes. Our results argue against a major role of Rgs7 gene variants in the pathogenesis of PD, but are consistent with a minor gender-specific effect on PD, particularly PDAgP.

Chromosome 4q31-34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants.

There is strong evidence for a genetic contribution to the pathogenesis of panic disorder, with a recent linkage study pointing toward a risk locus on chromosome 4q31-q34 [Kaabi et al., 2006]. Since the neuropeptide Y (NPY) system has been reported to be involved in the pathophysiology of anxiety and in particular panic disorder and the genes coding for NPY Y1, Y2, and Y5 receptors are located in the suggested risk region (4q31-q32), variants in the NPY, NPY Y1, Y2, and Y5 genes were investigated for association with panic disorder in a sample of 230 German patients with panic disorder and matched healthy controls. A synonymous (Gly-426-Gly) NPY Y5 coding variant (rs11946004) as well as haplotypes including rs11946004 and an intronic NPY Y5 variant (rs11724320) were significantly associated with panic disorder (P = 0.027), with the effect originating from the subgroup of female patients (P = 0.030), particularly with concurrent agoraphobia (P = 0.002-0.019). No association was observed for any variants located in the genes coding for NPY, NPY Y1, or Y2. The present results provide preliminary support for an influence of NPY Y5 receptor variants on the etiology of panic disorder in a potentially gender-specific manner further strengthening the evidence for a risk locus on chromosome 4q31-q34 in anxiety disorders. However, in order to allow for conclusive evaluation of the present finding and to exclude a false positive result, further studies in larger, independent, preferably family based samples are warranted.

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder.

Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality.

Adenosine A(2A) receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. A variant within the corresponding ADORA2A gene (rs5751876) increased the risk for panic disorder (PD), for elevated anxiety during challenge tests in healthy probands and for anxiety-related arousal in blood-injury phobia. These multiple effects may mirror a more general effect of the SNP on basic personality traits. In the present study we therefore aimed to replicate the original finding in a large PD sample and extend it by investigating an additional proband sample characterized for different anxiety-related personality scores. In addition, as rs5751876 is assumed not to be the disease variant itself but to be in linkage disequilibrium (LD) with the true functional polymorphism other SNPs of potentially functional relevance were identified by re-sequencing the whole gene including several newly identified regions of putative regulatory potential and analysed for their impact on PD and anxious personality. We were indeed able to replicate rs5751876 as risk factor for PD, particularly PD with agoraphobia. Rs5751876 and several other variants in high LD (rs5751862, rs2298383 and rs3761422) as well as the corresponding haplotypes were also associated with different anxiety-related personality scores (Bonferroni corrected P(all) < 0.05). Of these variants, rs2298383 shows functional potential based on in silico analyses and might therefore represent the true underlying causal variant. Our data provide further support for an important role of ADORA2A variants in the pathogenesis of anxiety disorders and anxious personality reflecting their potential as basic susceptibility factors.

Processing of peripheral blood progenitor cell components in improved clean areas does not reduce the rate of microbial contamination.

BACKGROUND: Microbial contamination of peripheral blood progenitor cell components (PBPCs) may cause severe complications in immunosuppressed recipients. Therefore, principles of Good Manufacturing Practice (GMP) are applicable for processing of PBPC components to reduce potential risks of contamination. STUDY DESIGN AND METHODS: It was investigated in a retrospective study whether the microbial contamination of PBPC components could be reduced after processing in improved clean areas according to the "Manufacture of Sterile Medicinal Products." Starting in 1994, a total of 1478 autologous and allogeneic PBPC components have been collected and processed into 3149 cryopreservation bags at the Department of Transfusion Medicine. Sterility testing was performed for all bags. Until December 1998, 783 PBPC components were processed at a clean bench only (group I). Thereafter, 695 PBPC components have been processed at a clean bench located in a clean area with an airlock system for personnel and equipment (group II). RESULTS: In group I, 16 of 1555 bags (1.03%) showed positive results in the first sterility testing. In group II, 21 of 1594 bags (1.32%) were positive (p = NS). The clinical follow-up was inconspicuous. CONCLUSION: Microbial contamination of PBPC components could not be reduced by installation of improved clean area conditions.