BACKGROUNDOver 90% of patients with systemic sclerosis suffer from gastroesophageal reflux. Esophageal motility disturbances are associated with a reduced life quality and may force interstitial lung ...disease progression. We wanted to determine whether we can improve gastroesophageal reflux in these patients by esophageal stem-cell injection. METHODSWe performed a pilot study including eights patients with systemic sclerosis and symptomatic gastroesophageal reflux. Sampling of adipose tissue was performed by an experienced plastic surgeon under local anesthesia. The collected fat was injected into the submucosa of the distal esophagus, each time 1 ml in all four quadrants starting 2, 4 and 6 cm proximal to the Z line (ending up to a total volume of 12 ml). Before the intervention, 3, 6 and finally 12 months after the procedure, patients answered the Gastroesophageal Reflux Disease Health-Related Quality of Life Questionnaire (GERD HRQL) and a high-resolution manometry was performed to quantify changes in motility function. RESULTSAll patients showed an improvement in the GERD HRQL score after the stem-cell injection and a lower dosage of proton-pump inhibitors. The manometric findings showed no change throughout the time. A serious adverse event occurred, as one patient developed multiple cerebellar embolic infarcts. CONCLUSIONBecause of the favorable effect in all patients, a safe route for esophageal fat injection needs to be developed.
Scope
Allergies to lipid transfer proteins involve severe adverse reactions; thus, effective and sustainable therapies are desired. Previous attempts disrupting disulfide bonds failed to maintain ...immunogenicity; thus, the aim is to design novel hypoallergenic Pru p 3 variants and evaluate the applicability for treatment of peach allergy.
Methods and results
Pru p 3 proline variant (PV) designed using in silico mutagenesis, cysteine variant (CV), and wild‐type Pru p 3 (WT) are purified from Escherichia coli. Variants display homogenous and stable protein conformations with an altered secondary structure in circular dichroism. PV shows enhanced long‐term storage capacities compared to CV similar to the highly stable WT. Using sera of 33 peach allergic patients, IgE‐binding activity is reduced by 97% (PV) and 71% (CV) compared to WT. Both molecules show strong hypoallergenicity in Pru p 3 ImmunoCAP cross‐inhibition and histamine release assays. Immunogenicity of PV is demonstrated with a phosphate‐based adjuvant formulation in a mouse model.
Conclusions
An in silico approach is used to generate a PV without targeting disulfide bonds, T cell epitopes, or previously reported IgE epitopes of Pru p 3. PV is strongly hypoallergenic while structurally stable and immunogenic, thus representing a promising candidate for peach allergen immunotherapy.
Engineering of the lipid transfer protein Pru p 3 from peach results in the generation of stable protein fold variants. These molecules demonstrate very low allergenic potency opposed to the wild‐type allergen. Proline variant presents enhanced integrity and elicits an immune response in a mouse model, thus representing a candidate molecule for allergen immunotherapy of peach allergic patients.
Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of ...cases t-MNs develop in the context of hereditary cancer predisposition syndromes.
The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array.
A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively.
It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.
Background The major allergens of trees belonging to the Fagales order are collectively known as the Bet v 1 family. Members of the Fagales order have distinct geographic distribution, and it is ...expected that depending on the exposure pattern of the individual, inclusion of other Bet v 1 family members might increase the efficacy of the treatment. Objective We aimed to generate molecules that are suitable for specific immunotherapy not only against birch pollen allergy but also against allergies caused by other cross-reactive tree pollens. Methods Fourteen genes of the Bet v 1 family were randomly recombined in vitro by means of DNA shuffling. This library of chimeric proteins was screened for molecules displaying low capacity to induce release of inflammatory mediators but with T-cell immunogenicity higher than that of the parental allergens. Results Two chimeric proteins were selected from the library of shuffled clones displaying low allergenicity and high immunogenicity, as determined in in vitro assays using human and animal cells and antibodies, as well as in vivo in animal models of allergy. Conclusion Our results show that it is possible to randomly recombine in vitro T- and B-cell epitopes of a family of related allergens and to select chimeric proteins that perfectly match the criteria presently thought to be relevant for improving allergen-specific immunotherapy. Clinical implications The hypoallergenic chimeras described here recombine epitopes of the major Fagales pollen allergens and thus can efficiently substitute a mixture of extracts used for treating patients with tree pollen–induced spring pollinosis worldwide.
Abstract Objective To evaluate the prognostic potential of serum C-terminal provasopressin (CT-proAVP or Copeptin) and midregional pro-A-type natriuretic peptide (MR-proANP) to predict neurological ...outcome following resuscitation from cardiac arrest. Methods In this prospective observational study, we employed novel ultra sensitive immunoassay technology to examine serial serum samples from 134 cardiac arrest patients. Patients were either allocated to mild therapeutic hypothermia using an endovascular device or normothermia. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first 7 days in an intensive care unit, and serum Copeptin and MR-proANP were measured. Cerebral function assessments were made using cerebral performance categorization (CPC) at discharge from hospital. Copeptin and MR-proANP data were analyzed using dichotomized CPC scores (1–2 versus 3–5). Results Sixty-nine patients (51%) had a poor outcome (CPC 3–5) at hospital discharge. MR-proANP and Copeptin peaked on day 1 (i.e. 0–24 h) with the medians being 249.3 pmol/L and 77.2 pmol/L, respectively. In the first 48 h maximum levels of MR-proANP and Copeptin showed an AUC in the ROC of 0.743 (95% CI: 0.658–0.828) and 0.677 (95% CI: 0.583–0.771). Binary logistic regression revealed MR-proANP and Copeptin within 48 h after ROSC being significantly associated with functional outcome ( p < 0.05). Copeptin within 48 h was also associated with outcome in the hypothermia group ( p < 0.05). Conclusion Systemic levels of MR-proANP and Copeptin peak early in cardiac arrest patients in the 48 h post-resuscitation period. MR-proANP and Copeptin were highly predictive for poor outcome in comatose resuscitated patients.
Zusammenfassung
Die Anti-NMDA(N-Methyl-D-Aspartat)-Rezeptor-Enzephalitis ist eine seltene autoimmunologisch bedingte Erkrankung mit verschiedenen neuropsychiatrischen Symptomen, die durch den ...Nachweis von NMDA-Rezeptor-Antikörpern im Liquor diagnostiziert wird. Die gängigen Behandlungsprotokolle beinhalten ein Stufenschema der Immuntherapien; allerdings beruhen die therapeutischen Entscheidungen derzeit auf einem Grad-IV-Evidenzniveau. Wir berichten hier über zwei junge, unterschiedlich betroffene Patientinnen und beschreiben die Therapiestrategien inklusive der Kombination verschiedener Immuntherapien einschließlich Ocrelizumab und Überlegungen bezüglich Fertilitätserhalt.
Angesichts des rasanten wirtschaftlichen und wissenschaftlichen Aufstrebens Chinas offenbart sich an deutschen Hochschulen ein deutlicher Mangel an China-Kompetenzen auf allen Ebenen. Wie sind ...chinesische Kooperationspartner*innen einzuschätzen? Wie sollten Studierende ausgebildet werden, damit sie in Zukunft informiert und (selbst-)bewusst zusammenarbeiten können? Wie kann erreicht werden, dass chinesische Studierende ihre Zeit in Deutschland als akademisch und persönlich bereichernd empfinden? Best-Practice-Beispiele aus elf deutschen Hochschulen geben Anregungen, die sich auch übergreifend auf verschiedene Bildungseinrichtungen und Partnerländer übertragen lassen. (DIPF/Verlag)
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