Long-Term follow up after intra-Uterine transfusionS; the LOTUS study

<p>Abstract</p> <p>Background</p> <p>The Leiden University Medical Center (LUMC) is the Dutch national referral centre for pregnancies complicated by haemolytic disease of the fetus and newborn (HDFN) caused by maternal alloimmunization. Yearly, 20-25 affected fetuses with severe anaemia are transfused with intra-uterine blood transfusions (IUT). Mothers of whom their fetus has undergone IUT for HDFN are considered high responders with regard to red blood cell (RBC) antibody formation. Most study groups report high perinatal survival, resulting in a shift in attention towards short- and long-term outcome in surviving children.</p> <p>Methods/Design</p> <p>We set up a large long-term observational follow-up study (LOTUS study), in cooperation with the Sanquin Blood Supply Foundation and the LUMC departments of Obstetrics, Neonatology and ImmunoHematology & Bloodtransfusion.</p> <p>The first part of this study addresses several putative mechanisms associated with blood group alloimmunization in these mothers. The second part of this study determines the incidence of long-term neurodevelopment impairment (NDI) and associated risk factors in children treated with IUT. All women and their life offspring who have been treated with IUT for HDFN in the LUMC from 1987-2008 are invited to participate and after consent, blood or saliva samples are taken. RBC and HLA antigen profile and antibodies are determined by serologic or molecular techniques. Microchimerism populations are tested by real time polymerase chain reaction (RT PCR).</p> <p>All children are tested for their neurological, cognitive and psychosocial development using standardised tests and questionnaires. The primary outcome is neurodevelopmental impairment (NDI), a composite outcome defined as any of the following: cerebral palsy, cognitive or psychomotor development < 2 standard deviation, bilateral blindness and/or bilateral deafness.</p> <p>Discussion</p> <p>The LOTUS study includes the largest cohort of IUT patients ever studied and is the first to investigate post-IUT long-term effects in both mother and child. The results may lead to a change in transfusion policy, in particular future avoidance of certain incompatibilities. Additionally the LOTUS study will provide clinicians and parents better insights in the long-term neurodevelopmental outcome in children with HDFN treated with IUTs, and may improve the quality of antenatal counselling and long-term guidance.</p

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Zollinger-Ellison syndrome associated with neurofibromatosis type 1: a case report

BACKGROUND: Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder with characteristic features of skin and central nervous system involvement. Gastrointestinal involvement is rare, but the risk of malignancy development is considerable. Zollinger-Ellison syndrome is caused by gastrin-secreting tumors called gastrinomas. Correct diagnosis is often difficult, and curative treatment can only be achieved surgically. CASE PRESENTATION: A 41-year-old female affected by neurofibromatosis type 1 presented with a history of recurrent epigastric soreness, diarrhea, and relapsing chronic duodenal ulcer. Her serum fasting gastrin level was over 1000 pg/mL. An abdominal CT scan revealed a 3 × 2-cm, well-enhanced mass adjacent to the duodenal loop. She was not associated with multiple endocrine neoplasia type 1. Operative resection was performed and gastrinoma was diagnosed by immunohistochemical staining. The serum gastrin level decreased to 99.1 pg/mL after surgery, and symptoms and endoscopic findings completely resolved without recurrences. CONCLUSION: Gastrinoma is difficult to detect even in the general population, and hence symptoms such as recurrent idiopathic peptic ulcer and diarrhea in neurofibromatosis type 1 patients should be accounted for as possibly contributing to Zollinger-Ellison syndrome

"I'm not being rude, I'd want somebody normal" Adolescents' perception of their peers with Tourette's syndrome; an exploratory study

Background: Tourette’s syndrome (TS) is a highly stigmatised condition, and typically developing adolescents’ motives and reason for excluding individuals with TS have not been examined. Aims: The aim of the study was to understand how TS is conceptualised by adolescents and explore how individuals with TS are perceived by their typically developing peers. Method: Free text writing and focus groups were used to elicit the views of twenty-two year ten students from a secondary school in South East England. Grounded theory was used to develop an analytical framework. Result: Participants’ understanding about the condition was construed from misconceptions, unfamiliarity and unanswered questions. Adolescents who conceived TS as a disorder beyond the individual’s control perceived their peers as being deprived of agency and strength and as straying from the boundaries of normalcy. People with TS were viewed as individuals deserving pity, and in need of support. Although participants maintained they had feelings of social politeness towards those with TS, they would avoid initiating meaningful social relationships with them due to fear of “social contamination”. Intergroup anxiety would also inhibit a close degree of social contact. Participants that viewed those with TS as responsible for their condition expressed a plenary desire for social distance. However, these behavioural intentions were not limited to adolescents that elicited inferences of responsibility to people with TS, indicating that attributional models of stigmatisation may be of secondary importance in the case of TS. Implications for interventions to improve school belonging among youths with TS are discussed

Expression of CIAPIN1 in human colorectal cancer and its correlation with prognosis

<p>Abstract</p> <p>Background</p> <p>The cytokine-induced anti-apoptotic molecule (CIAPIN1) had been found to be a differentially-expressed gene involved in a variety of cancers, and it was also considered as a candidate tumour suppressor gene in gastric cancer, renal cancer and liver cancer. However, studies on the role of CIAPIN1 in colorectal cancer were still unavailable. The aim of this study was to determine the prognostic impact of CIAPIN1 in 273 colorectal cancer (CRC) samples and to investigate the CIAPIN1 expression in CRC cell lines after inducing differentiation.</p> <p>Methods</p> <p>Immunohistochemical analysis was performed to detect the expression of CIAPIN1 in CRC samples from 273 patients. The relationship between CIAPIN1 expression and patients' characteristics (gender, age, location of cancer, UICC stage, local recurrence and tumour grade factors) was evaluated. In addition, these patients were followed up for five consecutive years to investigate the relationship between CIAPIN1 expression and the prognosis of CRC. We induced the differentiation of the CRC cell lines HT29 and SW480, in order to detect the expression of CIAPIN1 in the process of CRC cells differentiation.</p> <p>Results</p> <p>Results indicated that CIAPIN1 was mainly expressed in the cytoplasm and nucleus, and that its expression level in cancer samples was significantly lower than in normal tissues. The Wilcoxon-Mann-Whitney test showed a significant difference in the differential expression of CIAPIN1 in patients with different T and UICC stages, and tumour grade (<it>P </it>= 0.0393, 0.0297 and 0.0397, respectively). The Kaplan-Meier survival analysis demonstrated that the survival time of CRC patients with high expression of CIAPIN1 was longer than those with low expression during the 5-year follow up period (<it>P </it>= 0.0002). COX regression analysis indicated that low expression of CIAPIN1, cancer stage of > pT1, distant organ metastasis (pM₁), regional lymph node metastasis (> pN₁) and local recurrence (yes) were independent, poor prognostic factors of CRC (<it>P </it>= 0.012, <it>P </it>= 0.032, <it>P <</it>0.001, <it>P <</it>0.001, <it>P <</it>0.001 respectively). Both Western blotting and RT-PCR showed that CIAPIN1 expression was increased with the degree of differentiation of HT29 and SW480 cells.</p> <p>Conclusions</p> <p>CIAPIN1 played an important role in the differentiation of CRC cells, and the differential expression of CIAPIN1 in CRC was closely related to prognosis.</p

Thiothymidine combined with UVA as a potential novel therapy for bladder cancer

BACKGROUND: Thiothymidine (S4TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S4TdR and UVA could be an effective treatmentfor bladder cancer. METHODS: Uptake and incorporation of S4TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S4TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. RESULTS: Thiothymidine (200 uM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S4TdR (10–200 uM) and UVA (1–5 kJm-2) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S4TdR into DNA (up to 20-fold at IC5) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S4TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. CONCLUSION: These data indicate that the combination of S4TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components