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We describe a patient who received an unintentionally prolonged epidural infusion of phenylephrine. The patient experienced no major morbidity. However, this case highlights the continuing problem of wrong-route drug administration and the urgent need to adopt route-specific connections.

The reaction of the ortho-amide 1,1,1-tris-(di-methyl-amino)-4-methyl-4-(tri-methyl-sil-yloxy)pent-2-yne with bromine in benzene, yields the title salt, C15H33BrN3OSi(+)·Br(-). The C-N bond lengths in the amidinium unit are 1.319 (6) and 1.333 (6) Å, indicating double-bond character, pointing towards charge delocalization within the NCN plane. The C-Br bond length of 1.926 (5) Å is characteristic for a C-Br single bond. Additionally, there is a bromine-bromine inter-action [3.229 (3) Å] present involving the anion and cation. In the crystal, weak C-H⋯Br inter-actions between the methyl H atoms of the cation and the bromide ions are present.

Supramolecular columnar assemblies are known to form intrinsic macrodipoles, which play an important role in intercolumnar interactions and govern the self-assembly on the mesoscale. A prominent class that provides this feature are trisamide derivatives, namely, 1,3,5-benzenetrisamides and 1,3,5-cyclohexanetrisamides. The understanding of how subtle changes in the chemical structure influence the columnar order and consequently the macrodipole formation is of fundamental interest. Here we report on the theoretical investigation of trisamide derivatives and how the formed macrodipole is related to the properties of the columnar aggregates. Calculations were carried out on a semiempirical level using the PM6 approximation, which is able to treat weak interactions like hydrogen bonding and dispersion forces with a sufficient accuracy. We have compared the influence of a benzene core with a cyclohexane core on the macrodipole formation. It was revealed that columnar aggregates based on 1,3,5-cyclohexanetrisamides have much higher dipole moments than those formed with aromatic cores. A cooperative effect was found during aggregation, as longer aggregates show stronger hydrogen bonding, thereby facilitating the addition of the next molecule. We have also investigated the influence of the amide connection on the strength of the formed macrodipole. The trends observed for the macrodipole strength correlate with the calculated heat of formation. If the amide groups are inverted, the strength of the macrodipole is reduced and the negative heat of formation is increased. HOMO-LUMO gaps were correlated with the inverse of the dipole moment per monomer unit, thus indicating that the macrodipole might act as a perturbation to the supramolecular assemblies., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Using (13)C double quantum solid-state NMR spectroscopy, we were able to observe nuclei of a supramolecular BTA based additive on the nanoscale in a matrix of i-PP at a concentration of only 0.09 wt%. These nuclei exhibit the analogous structural features as the crystalline phase of the neat additive.

One of the simplest and most-versatile motifs in supramolecular chemistry is based on 1,3,5-benzenetricarboxamides. Variation of the core structure and subtle changes in the structures of the lateral substituents govern the self-assembly and determine the phase behavior. Herein, we provide a comprehensive comparison between the phase behavior and mesophase structure of a series of 1,3,5-benzene- and 1,3,5-cyclohexanetricarboxamides that contain linear and branched alkyl substituents. Depending on the substituent, different crystalline, plastic crystalline, and liquid crystalline phases were formed. The relatively rare columnar nematic (N(C)) phase was only observed in cyclohexane-based trisamides that contained linear alkyl substituents. Of fundamental interest in liquid crystalline supramolecular systems is the transition from the mesomorphic state into the isotropic state and, in particular, the question of how the order decreases. Temperature-dependent IR spectroscopy and XRD measurements revealed that columnar H-bonded aggregates were still present in the isotropic phase. At the clearing transition, mainly the lateral order was lost, whilst shorter columnar aggregates still remained. A thorough understanding of the phase behavior and the mesophase structure is relevant for selecting processing conditions that use supramolecular structures in devices or as fibrillar nanomaterials., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background/aims: From quantitative trait locus mapping in inbred mice, we identified the Nr1h4 gene encoding the nuclear bile salt receptor FXR as a candidate gene for the cholesterol gallstone susceptibility locus Lith7. Here, we investigated further an association of the gene encoding FXR and gallstone susceptibility in mice and humans., Methods: The Nr1h4 gene was sequenced in inbred mouse strains with susceptible and resistant Lith7 alleles. Quantitative RT-PCR was employed to determine mRNA expression levels. Gallstone carriers and control subjects of three different populations comprising 1004 individuals were genotyped for polymorphisms of the orthologous human gene detected by sequencing., Results: Expression and sequence analyses in inbred mice were consistent with Nr1h4 underlying Lith7. In the human populations, we identified three frequent haplotypes that accounted for > 95% of all haplotypes observed. In a Mexican population, the most common haplotype NR1H4_1 was associated with gallstone prevalence. In contrast, NR1H4_1 displayed no association with gallstone prevalence in a German population, whereas in a Chilean population we observed a trend towards a protective effect of NR1H4_1., Conclusions: Our study in an inbred mouse model and in three ethnically distinct populations indicates complex interactions of NR1H4 alleles and other risk factors for the development of cholelithiasis.

1H, 2H, and 11B NMR spectroscopy has been used to study the mechanism of the Fries rearrangement of aryl formates promoted by boron trichloride by monitoring both the substrate and the Lewis acid. DFT calculations were employed to investigate the energetics of several reaction paths and to calculate NMR chemical shifts of key intermediates and products. After the formation of a 1:1 substrate-Lewis acid adduct, the rearrangement proceeds in two steps, beginning with the cleavage of the ester bond and the release of formyl chloride in situ, which, in turn, acts as a formylating agent, introducing an aldehydic functionality into the aromatic ring. The high regioselectivity (only the ortho product is obtained) is also accounted for by the proposed intermolecular, Lewis acid-assisted mechanism.

Background: Familial pancreatic cancer (FPC) describes a group of families where the inheritance of pancreatic cancer is consistent with an autosomal-dominant mode of inheritance. The 4q32-34 region has been previously identified as a potential locus for FPC in a large American family., Methods: The region was allelotyped in 231 individuals from 77 European families using nine microsatellite markers, and haplotyping was possible in 191 individuals from 41 families. Families were selected based on at least two affected first-degree relatives with no other cancer syndromes., Results: Linkage to most of the locus was excluded based on LOD scores less than -2.0. Eight families were excluded from linkage to 4q32-34 based on haplotypes not segregating with the disease compared with a predicted six to seven families. Two groups of families were identified, which seem to share common alleles within the minimal disease-associated region of 4q32-34, one group with an apparently earlier age of cancer death than the other pancreatic cancer families. Four genes were identified with potential tumor suppressor roles within the locus in regions that could not be excluded based on the LOD score. These were HMGB2, PPID, MORF4, and SPOCK3. DNA sequence analysis of exons of these genes in affected individuals and in pancreatic cancer cell lines did not reveal any mutations., Conclusion: This locus is unlikely to harbor a FPC gene in the majority of our European families.

Background and Aims: The Union Internationale Contre le Cancer and American Joint Committee on Cancer classification propose that pN(0)-classified colorectal lymphadenectomy specimens will ordinarily include 12 or more tumor-negative lymph nodes. We performed a clinical trial to investigate whether a short-term preoperative radiotherapy (5x5 Gy) leads to a reduction of the number of lymph nodes in rectal cancer specimens after total and partial mesorectal excision (TME and PME, respectively)., Materials and Methods: Within a 5-year period, 28 (15%) of 148 rectal cancer patients underwent hypofractionated preoperative radiotherapy in this monocenter study, whereas 120 patients (85%) underwent TME/PME surgery alone. The main criterion was the number of lymph nodes in TME/PME specimens. We used a stratified one-sided Wilcoxon-Mann-Whitney test to test for a significant difference in the number of lymph nodes, stratifying for tumor location and postoperative tumor stage. Patients who were suspected of having any alterations in the number of pelvic lymph nodes were excluded from the study., Results: Fewer lymph nodes were detected in the TME/PME specimens of patients who received hypofractionated preoperative radiotherapy compared to patients who underwent TME/PME surgery alone (12 detectable lymph nodes vs 15; p=0.0005). Tumor location (p=0.095) and tumor stage (p=0.093) did not significantly influence the number of lymph nodes in this study., Conclusions: We conclude that a 5x5 Gy short-term preoperative radiotherapy leads to a reduction in the number of lymph nodes in TME/PME specimens. Because neoadjuvant therapy in rectal cancer for T(2) and T(3) tumors has advanced a new therapeutic standard procedure, in the future, less lymph nodes will be detected in TME/PME specimens. This might influence the required number of lymph nodes in current staging systems for rectal cancer in the future.

Background: Previous studies of anticipation in familial pancreatic cancer have been small and subject to ascertainment bias. Our aim was to determine evidence for anticipation in a large number of European families., Patients and Methods: A total of 1223 individuals at risk from 106 families (264 affected individuals) were investigated. Generation G3 was defined as the latest generation that included any individual aged over 39 years; preceding generations were then defined as G2 and G1., Results: With 80 affected child-parent pairs, the children died a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from pancreatic cancer was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively. These indications of anticipation could be the result of bias. Truncation of Kaplan-Meier analysis to a 60 year period to correct for follow up time bias and a matched test statistic indicated significant anticipation (p=0.002 and p<0.001). To minimise bias further, an iterative analysis to predict cancer numbers was developed. No single risk category could be applied that accurately predicted cancer cases in every generation. Using three risk categories (low with no pancreatic cancer in earlier generations, high with a single earlier generation, and very high where two preceding generations were affected), incidence was estimated without significant error. Anticipation was independent of smoking., Conclusion: This study provides the first strong evidence for anticipation in familial pancreatic cancer and must be considered in genetic counselling and the commencement of secondary screening for pancreatic cancer.

Familial pancreatic cancer (FPC) is a rare tumour syndrome and its underlying major gene defect is still unknown. Recently, CHEK2 has been identified as multi-organ cancer susceptibility gene associated with a predisposition to breast, prostate and colon cancer. Since these cancers also are associated with some FPC families, we have analysed 35 index patients of German FPC families for CHEK2 mutations. The CHEK2 * 1100delC mutation was found in 1 (3%) of 35 FPC families. Given the low expected mutation rate of up to 1.4% for CHEK2 * 1100delC in the European population our data are suggestive for possible contribution of CHEK2 mutations to a small subset of FPC.

The RNASEL (encoding ribonuclease L) gene Glu265X mutation has been implicated in familial prostate cancer, and an association between the RNASEL Arg462Gln variant and sporadic and familial prostate cancer, has also been suggested. Because prostate cancer occurs in some familial pancreatic cancer families, we evaluated the role of the RNASEL gene variants Glu265X and Arg462Gln in the etiology of pancreatic cancer. Exon 2 of the RNASEL gene was directly sequenced in the germline of 36 familial and 75 sporadic pancreatic cancer patients and in 108 controls. The Glu265X mutation was identified in one (2.8%) familial and one (1.3%) sporadic pancreatic cancer case, but not in any of the controls. Arg462Gln variants were identified in 61 (56%) controls and in 55 (73%) sporadic pancreatic cancer cases with 8 (7%) and 12 (16%) homozygotes, respectively (p = 0.009). For homozygous carriers the increased risk for pancreatic cancer was 3.5 (odds ratio [OR] = 3.53, 95% confidence interval [CI] = 1.11-11.46, p = 0.03). The population attributable fraction (PAF) was 38.7% (95% CI = 0.08-0.80). In familial pancreatic cancer no association between Arg462Gln genotypes and pancreatic cancer risk was evident. In sporadic pancreatic cancer there were no significant differences between Arg462Gln genotypes regarding clinical characteristics. In familial pancreatic cancer, however, patients with Arg462Gln variants had more aggressive tumors with more high grade cancers (OR = 15.40, p = 0.009) and more distant metastases (OR = 7.00, p = 0.04) than patients with the wild-type genotype. Our results suggest that RNASEL variants Glu265X and Arg462Gln may contribute to the tumorigenesis of sporadic and familial pancreatic cancer, which has to be proven in large scale studies., (Copyright 2005 Wiley-Liss, Inc)

Based on several case-control studies, it has been estimated that familial aggregation and genetic susceptibility play a role in up to 10% of patients with pancreatic cancer, although conclusive epidemiologic data are still lacking. Therefore, we evaluated the prevalence of familial pancreatic cancer and differences to its sporadic form in a prospective multicenter trial. A total of 479 consecutive patients with newly diagnosed, histologically confirmed adenocarcinoma of the pancreas were prospectively evaluated regarding medical and family history, treatment and pathology of the tumour. A family history for pancreatic cancer was confirmed whenever possible by reviewing the tumour specimens and medical reports. Statistical analysis was performed by calculating odds ratios, regression analysis with a logit-model and the Kaplan-Meier method. Twenty-three of 479 (prevalence 4.8%, 95% CI 3.1-7.1) patients reported at least 1 first-degree relative with pancreatic cancer. The familial aggregation could be confirmed by histology in 5 of 23 patients (1.1%, 95% CI 0.3-2.4), by medical records in 9 of 23 patients (1.9%, 95% CI 0.9-3.5) and by standardized interviews of first-degree relatives in 17 of 23 patients (3.5%, 95% CI 2.1-5.6), respectively. There were no statistical significant differences between familial and sporadic pancreatic cancer cases regarding sex ratio, age of onset, presence of diabetes mellitus and pancreatitis, tumour histology and stage, prognosis after palliative or curative treatment as well as associated tumours in index patients and families, respectively. The prevalence of familial pancreatic cancer in Germany is at most 3.5% (range 1.1-3.5%) depending on the mode of confirmation of the pancreatic carcinoma in relatives. This prevalence is lower than so far postulated in the literature. There were no significant clinical differences between the familial and sporadic form of pancreatic cancer., (Copyright 2004 Wiley-Liss, Inc.)

There are no uniformly accepted criteria for the management of epistaxis. The usefulness of ice application in the treatment of epistaxis as a first aid method is not generally accepted, but is widespread. In order to evaluate the effect of cold application on the blood vessels of the nasal mucosa, their blood flow and blood content were investigated on 56 healthy volunteers before and after exposure to cold in the neck area. Nasal mucosal microcirculatory blood flow was measured directly by non-invasive laser Doppler flowmetry in Kiesselbach's area. Changes in the nasal mucosal blood content were estimated using a conventional computer-aided rhinomanometer by measuring alterations in nasal airflow. After ice application in the neck area, no statistically significant effects on the blood vessels of the nasal mucosa were seen. These results do not support the usefulness of this manoeuvre in the treatment of epistaxis.

Background: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer., Methods: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2., Results: Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer., Conclusions: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.

Objective: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16 and p14 in familial pancreatic cancer (FPC)., Summary Background Data: The genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16 tumor suppressor gene can predispose to pancreatic cancer. The presence of p14 germline mutations has yet not been determined in this setting., Methods: Eighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16 and p14 by direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree., Results: None of 18 FPC families without malignant melanoma revealed p16 mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16 germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14 germline mutations., Conclusions: CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.

Background: The observation of a familial accumulation of ductal pancreatic adenocarcinoma (PC) and the increased risk for PC in certain hereditary tumor syndromes point to a genetic predisposition for PC. In order to evaluate the characteristics of familial PC, a German national case collection for familial pancreas cancer (FaPaCa) was established., Patients and Methods: In FaPaCa, families of patients with PC are being collected, who have at least 1 first-degree relative with PC or with malignant melanoma. Histopathologic verification of tumor diagnoses, acquisition of clinical data, and full genetic counselling are prerequisites for the enrollment of PC families in FaPaCa., Results: So far, 21 families fulfilled the criteria for partaking in FaPaCa. In 11 families, PC represented the sole tumor entity. Additional tumors included malignant melanoma in 5, breast cancer in 3, and prostatic, colon or lung cancer in 2 families. Compared to the preceding generation, a younger age at diagnosis of PC was observed in the offspring of PC patients (offspring median 53 years vs. parents median 75.5 years)., Conclusion: The association of PC and breast cancer, and of PC and malignant melanoma suggests predisposing mutations in the BRCA2 or CDKN2A genes in about one third of the FaPaCa families. Mutational analyses in both candidate genes may help to identify individuals who are at an increased risk for developing PC. A shift towards a younger age at diagnosis in our PC families may indicate genetic anticipation and/or changes of patterns of exogenous risk factors., (Copyright 2002 S. Karger GmbH, Freiburg)

Ductal pancreatic cancer is a public health problem on the increase. The lethality and incidence of this disease are almost identical. A number of these cancers cluster in families. By definition, pancreatic cancer appearing in at least two first degree relatives is named familial pancreatic cancer (FPC). The "National Case Collection Familial Pancreatic Cancer" (FaPaCa) was founded at the Philipps University of Marburg, Germany, in July 1999 within the scope of the project "Clinical and genetic examinations of familial exocrine pancreatic cancer including the foundation of a national case collection" (http://www.med.uni-marburg.de/fapaca). The aims of this project are 1 to evaluate the share of FPC of all pancreatic cancers by performing a multi-centered study, 2 to identify epidemiological risk factors that predispose to pancreatic cancer in these families, 3 to identify families with a likely genetic predisposition to pancreatic cancer, 4 to offer a screening program for high risk individuals in these families, which is to be evaluated in an observational study, and finally to identify presumed genetic defects that predispose to pancreatic cancer in FPC families. This manuscript presents the scientific concept behind the FaPaCa project and reports on its attendant screening program for FPC families.

We use optimized group sequential study designs to analyze data from two genome scans (German and CSGA) for asthma susceptibility loci with affected sib pairs from Genetic Analysis Workshop (GAW) 12. Results are compared with those from a fixed sample design and the sequential probability ratio test (SPRT). The SPRT does not reach significance at any position. Using the fixed sample design, evidence for linkage is found on chromosomes 6 and 9 in the German and on chromosome 1 in the CSGA scan. The group sequential designs identify the same regions on chromosomes 1 and 6 with a reduced sample size.

Background/aims: The prevalence of familial pancreatic cancer (FPC) and the characteristics of FPC have not yet been well investigated in the German population. Therefore, a German case collection for FPC was established in July 1999 to collect and evaluate data on FPC families., Methods: The prevalence of pancreatic cancer (PC) as well as other tumours and diseases was studied in families with at least 2 first-degree relatives with histologically confirmed PC, and in families of patients with PC and a first-degree relative with malignant melanoma. All participating family members were genetically counselled and evaluated by a standardised questionnaire., Results: In an 18-month period, 73 independent kindreds with potential FPC contacted the national case collection. So far, 20 kindreds have fulfilled the criteria for FPC and have undergone complete workups. Most families revealed an autosomal dominant pattern of inheritance. Twelve families revealed an isolated accumulation of PC. Importantly, in 8 of 20 (35%) families, additional tumour types such as melanoma, breast and prostate cancer occurred., Conclusion: The observed phenotypic heterogeneity indicates an association with predisposing tumour suppressor genes p16 and BRCA2 in up to 30% of FPC families. Mutation analysis of these candidate genes might lead to the identification of the predisposing gene defect in a proportion of FPC families.

The object of this study was to devise a unified method for comparing different thermal techniques for the estimation of blood perfusion rates and to perform a comparison for several common techniques. The approach used was to develop analytical models for the temperature response for all combinations of five power deposition geometries (spherical, one- and two-dimensional cylindrical, and one- and two-dimensional Gaussian) and three transient heating techniques (temperature pulse-decay, temperature step function, and constant-power heat-up) plus one steady-state heating technique. The transient models were used to determine the range of times (the time window) when a significant portion of the transient temperature response was due to blood perfusion. This time window was defined to begin when the difference between the conduction-only and the conduction-plus-blood flow transient temperature (or power) responses exceeded a specified value, and to end when the conduction-plus-blood flow transient temperature (or power) reached a specified fraction of its steady-state value. The results are summarized in dimensionless plots showing the size of the time windows for each of the transient perfusion estimation techniques. Several conclusions were drawn, in particular: (a) low perfusions are difficult to estimate because of the dominance of conduction, (b) large heated regions are better suited for estimation of low perfusions, (c) noninvasive heating techniques are superior because they have the potential to minimize conduction effects, and (d) none of the transient techniques appears to be clearly superior to the others.