CD11c.DTR mice develop a fatal fulminant myocarditis after local or systemic treatment with diphtheria toxin

To assess the role of alveolar macrophages (AMs) during a pulmonary Aspergillus fumigatus infection AMs were depleted by intratracheal application of diphtheria toxin (DTX) to transgenic CD11c.DTR mice prior to fungal infection. Unexpectedly, all CD11c.DTR mice treated with DTX died within 4–5 days, whether being infected with A. fumigatus or not. Despite measurable impact of DTX on lung functional parameters, these constrictions could not explain the high mortality rate. Instead, DTX‐treated CD11c.DTR animals developed fulminant myocarditis (FM) characterized by massive leukocyte infiltration and myocardial cell destruction, including central parts of the heart's stimulus transmission system. In fact, standard limb lead ECG recordings of diseased but not healthy mice showed a “Brugada”‐like pattern with an abnormally high ST segment pointing to enhanced susceptibility for potential lethal arrhythmias. While CD11c.DTR mice are extensively used for the characterization of CD11c⁺ cells, including dendritic cells, several studies have already mentioned adverse side effects following DTX treatment. Our results demonstrate that this limitation is based on severe myocarditis but not on the expected lung constrictions, and has to be taken into consideration if this animal model is used. Based on these properties, however, the CD11c.DTR mouse might serve as useful animal model for FM.     

Dendritic cell generation and CD4+CD25HIGHFOXP3+ regulatory T cells in human head and neck carcinoma during Radio-chemotherapy

Background

Regulatory T cells (Treg) and dendritic cells (DC) play an important role in tumor immunity and immune escape. However, their interplay and the effects of anti-cancer therapy on the human immune system are largely unknown.

Methods

For DC generation, CD14⁺ monocytes were enriched by immunomagnetic selection from peripheral blood of advanced head and neck squamous cell carcinoma (HNSCC) patients and differentiated into immature DC using GM-SCF and IL-4. DC maturation was induced by addition of TNFα. The frequency of CD4⁺CD25^highF0XP3⁺ Treg in HNSCC patients was analyzed before and after radio-chemotherapy (RCT) by four-color flow cytometry.

Results

In HNSCC patients, the frequency of Treg (0.33 ± 0.06%) was significantly (p = 0.001) increased compared to healthy controls (0.11 ± 0.02%), whereas RCT had variable effects on the Treg frequency inducing its increase in some patients and decrease in others. After six days in culture, monocytes of all patients had differentiated into immature DC. However, DC maturation indicated by CD83 up-regulation (70.7 ± 5.5%) was successful only in a subgroup of patients and correlated well with lower frequencies of peripheral blood Treg in those patients.

Conclusion

The frequency of regulatory T cells is elevated in HNSCC patients and may be modulated by RCT. Monocyte-derived DC in HNSCC patients show a maturation deficiency ex vivo. Those preliminary data may have an impact on multimodality clinical trials integrating cellular immune modulation in patients with advanced HNSCC.     

Prevalence of sexually transmitted infections in pregnant urban Aboriginal and Torres Strait Islander women in northern Australia

OBJECTIVE: To assess the prevalence of sexually transmitted infections (STI) in a cohort of pregnant urban Indigenous women and association of STI with preterm birth, low birthweight birth and perinatal mortality. DESIGN: Prospective intervention program in a cohort of women attending Townsville Aboriginal and Islander Health Services (TAIHS) for shared antenatal care between 1 January 2000 and 31 December 2003 incorporating routine screening for chlamydia, gonorrhoea, trichomoniasis, hepatitis B and syphilis. SETTING: Townsville is a provincial urban centre with a regional Indigenous population of over 16 000. PARTICIPANTS: Four hundred and fifty-six pregnant women who were screened for bacterial STI and other viral infections. MAIN OUTCOME MEASURES: Prevalence of STI, associated risk factors and perinatal outcomes. RESULTS: Of the 456 women, 403 (88.4%) were screened for chlamydia, gonorrhoea and trichomonas and 432 (94.7%) were screened for syphilis. A total of 92 cases of STI (20.2%, 95% CI 16.5-23.9) were detected, with 21 concurrent infection(s). The overall prevalence of chlamydia was 14.4%, gonorrhoea 6.1%, trichomoniasis 7.2% and infectious syphilis 2.5%. Predictors for STI were young age, harmful/hazardous alcohol use and unwanted pregnancy. Low birthweight and perinatal death were significantly associated with the presence of STI and infectious syphilis during pregnancy. CONCLUSION: The prevalence of STI among pregnant women in this urban Indigenous community is high, suggesting that screening for STI should be included in all antenatal care protocols for Indigenous women in Australia. Strategies to reach the whole Indigenous community of child-bearing age, especially those aged less than 25 years, are needed to improve perinatal outcome.     

Training effective interpreters for diabetes care and education: a new challenge

PURPOSE: This article describes a pilot project to improve knowledge, attitudes, and skills of ad hoc interpreters working with Native American diabetes patients with limited English proficiency. METHODS: Case-based studies reflecting clinical situations were developed. Key concepts and terms from the cases were translated into the Navajo language and carefully back translated using the newly standardized Navajo diabetes terminology. Twenty-two health care workers from 2 Indian Health Service facilities were recruited for a pilot study to compare the performance of interpreters trained in a formal workshop using the case studies with that of interpreters who independently reviewed a video made from the training. RESULTS: Workshop participants noted significant improvements in their knowledge and comfort level in interpretation of diabetes concepts but not about unrelated topics; the independent study group perceived less improvement. CONCLUSION: Formal training for interpreters working with diabetes patients should be considered by diabetes educators working in settings where medical interpreters are needed. Diabetes educators should encourage back translation of key diabetes concepts to understand exactly what is being said to patients. Those working with multiple interpreters should make sure there are opportunities for interpreters to discuss translations of key concepts with each other and the educators so that translations are accurate and consistent among interpreters. Independent study did not appear to be an effective way to improve the ability of interpreters to translate current diabetes concepts accurately.     

Bladder cancer. I. Molecular and genetic basis of carcinogenesis.

The transformation of a normal into a malignant cell is a multistep mechanism, which involves various alterations on the molecular and genetic level. These molecular alterations occur spontaneously or are induced by carcinogens (e.g. naphthylamine--a component of cigarette smoke and one of the most important carcinogens leading to bladder tumor carcinogenesis). This report summarizes some of the most important molecular and genetic alterations in bladder cancer. As in most other malignancies the generation of bladder cancer is caused by the accumulation of various molecular changes. The expression of oncogenes (ras, erbB-2 and EGF receptor), tumor-suppressor genes (Rb, p53), cell-cycle genes (p15, p16) and DNA-repair genes is altered mostly by mutation or chromosomal aberration. Loss of heterozygosity of chromosome 9p and 9q has been shown to be a crucial event in the transition of normal urothelium to papillary transitional cell carcinoma while p53 is primarily involved in the development of carcinoma in situ.     

Parallel deletion and duplication at 7q11.23 in a silent carrier for two reciprocal syndromic disorders

Partial deletions at chromosome 7q11.23 are causative for the autosomal-dominant Williams–Beuren syndrome (WBS), whereas the partial duplication of this region leads to the 7q11.23 duplication syndrome. Both syndromes are highly penetrant and occur with a frequency of 1:7500–10,000 (WBS) and 1:13,000–20,000 (7q11.23 duplication syndrome). They are associated with multiple organ defects, intellectual disability, and typical facial dysmorphisms showing broad phenotypic variability. The 7q11.23 region is susceptible to chromosomal rearrangements due to flanking segmental duplications and regions of long repetitive DNA segments. Here, we report on a family with two children affected by WBS and clinically unaffected parents. Interestingly, metaphase fluorescence in situ hybridization (FISH) revealed a deletion on 7q11.23 in the father. Intensive genetic testing, using interphase FISH, whole genome sequencing and optical genome mapping led to the confirmation of a 1.5 Mb deletion at one 7q11.23 allele and the identification of a reciprocal 1.8 Mb duplication at the other allele. This finding is highly important regarding genetic counseling in this family. The father is a silent carrier for two syndromic disorders, thus his risk to transmit a disease-causing allele is 100%. To the best of our knowledge we, here, report on the first case in which the phenotype of a microdeletion/microduplication syndrome was compensated by its reciprocal counterpart.