Chorioamnionitis induces enteric nervous system injury: effects of timing and inflammation in the ovine fetus.

BACKGROUND: Chorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC). Recently, we have shown that chronic chorioamnionitis is associated with significant structural enteric nervous system (ENS) abnormalities that may predispose to later NEC development. Understanding time point specific effects of an intra-amniotic (IA) infection on the ENS is important for further understanding the pathophysiological processes and for finding a window for optimal therapeutic strategies for an individual patient. The aim of this study was therefore to gain insight in the longitudinal effects of intrauterine LPS exposure (ranging from 5 h to 15 days before premature delivery) on the intestinal mucosa, submucosa, and ENS in fetal lambs by use of a well-established translational ovine chorioamnionitis model. METHODS: We used an ovine chorioamnionitis model to assess outcomes of the fetal ileal mucosa, submucosa and ENS following IA exposure to one dose of 10 mg LPS for 5, 12 or 24 h or 2, 4, 8 or 15 days. RESULTS: Four days of IA LPS exposure causes a decreased PGP9.5- and S100ß-positive surface area in the myenteric plexus along with submucosal and mucosal intestinal inflammation that coincided with systemic inflammation. These changes were preceded by a glial cell reaction with early systemic and local gut inflammation. ENS changes and inflammation recovered 15 days after the IA LPS exposure. CONCLUSIONS: The pattern of mucosal and submucosal inflammation, and ENS alterations in the fetus changed over time following IA LPS exposure. Although ENS damage seemed to recover after prolonged IA LPS exposure, additional postnatal inflammatory exposure, which a premature is likely to encounter, may further harm the ENS and influence functional outcome. In this context, 4 to 8 days of IA LPS exposure may form a period of increased ENS vulnerability and a potential window for optimal therapeutic strategies.

Thyroid function alters during neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).

This side study investigated the effect of chemotherapy on thyroid function and the extent to which it can predict pathological complete response (pCR) in patients with early breast cancer taking part in NEOZOTAC phase III trial, randomizing between neoadjuvant chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on toxicity. Serum samples of 38 patients were available for analyses. Free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were compared between baseline and before the 6th cycle and between subjects with and without pCR. The relation between toxicity and the variation in fT4 and TSH levels during chemotherapy was tested. Samples at baseline and before the 6th cycle were available for 31 and 21 patients, respectively. The mean baseline fT4 level was 16.0 pmol/L and TSH level 1.11 mU/L, and these did not differ between both arms at each time point. During six cycles of chemotherapy, fT4 levels decreased (p = 0.0001), and TSH levels increased significantly (p = 0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting, or neuropathy, than in patients with those side effects (p = 0.037, p = 0.043, and p = 0.050, respectively). Baseline TSH levels tended to be higher in patients with pCR (p = 0.035 univariate analysis and p = 0.074 multivariate analysis). Chemotherapy blunts thyroid function, which was associated with less side effects. These data urge further evaluation of the effects of thyroid function on toxicity and outcome of breast cancer therapy.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. PATIENTS AND METHODS: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. RESULTS: Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. CONCLUSIONS: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Vitamin D (25-0H D3) status and pathological response to neoadjuvant chemotherapy in stage II/III breast cancer: Data from the NEOZOTAC trial (BOOG 10-01).

BACKGROUND: Serum levels of 25-OH vitamin D3 (vitamin D) have been shown to be prognostic for disease-free survival in patients with breast cancer. We investigated the predictive value of these levels for pathological response after neoadjuvant chemotherapy in patients with breast cancer taking part in the NEOZOTAC phase-III trial. Additionally, the effect of chemotherapy on vitamin D levels was studied. MATERIALS AND METHODS: Serum vitamin D was measured at baseline and before the last cycle of chemotherapy. The relationship between these measurements and clinical outcome, as defined by pathological complete response in breast and lymph nodes (pCR) was examined. RESULTS: Baseline and end of treatment vitamin D data were available in 169 and 91 patients, respectively. Median baseline vitamin D values were 58.0 nmol/L. In patients treated with chemotherapy only, serum vitamin D levels decreased during neoadjuvant chemotherapy (median decrease of 16 nmol/L, P = 0.003). The prevalence of vitamin D levels < 50 nmol/L increased from 38.3% at baseline to 55.9% after chemotherapy. In the total population, baseline and end of therapy vitamin D levels were not related to pathological response. No associations were found between pCR and vitamin D level changes. CONCLUSION: The significant decrease in vitamin D post-neoadjuvant chemotherapy suggests that vitamin D levels should be monitored and in case of decrease of vitamin D levels, correction may be beneficial for skeletal health and possibly breast cancer outcome.

[Acute dyspnoea following transfusion of plasma-containing blood products]. / Acute kortademigheid na transfusie van plasmabevattende bloedproducten.

A 35-year-old male patient who was given chemotherapy because of chronic myeloid leukaemia became dyspnoeic after transfusion of thrombocytes; initially, no explanation could be found for this dyspnoea. He went home before all diagnostic procedures were evaluated. Chest X-ray revealed bilateral pulmonary oedema, which could be due to transfusion-related acute lung injury (TRALI), especially since there were no indications for a cardiac aetiology. The patient was sent to the nearest hospital where he was treated with diuretics and observed for 24 hours. There were no complications. The pathogenesis of TRALI has been attributed to an interaction between anti-granulocyte antibodies and granulocytes. In addition, bioactive compounds produced during the storage of blood products have been implicated. It is important to recognize TRALI as the cause of dyspnoea when cardiac or pulmonary causes are excluded. The overall prognosis is good when treatment is started in time. The management of TRALI is supportive, with mechanical ventilation when necessary. After excluding donors with proven anti-granulocyte antibodies from further donation, there is no increased risk for recurrent episodes after future transfusion of plasma-containing blood products.

Prenatal exposure to hyperoxia modifies the thromboxane prostanoid receptor-mediated response to H2O2 in the ductus arteriosus of the chicken embryo.

O2 tension plays a critical role in the control of prenatal patency and postnatal closure of the ductus arteriosus (DA). We hypothesized that exposure of chicken embryos to hyperoxia alters the morphology and function of DA. Hyperoxia was induced by incubating fertilized eggs at 60% O2 from day 15 to 19 of the 21-d incubation period. DA reactivity (assessed by wire myography), morphometry and mRNA expression of antioxidant enzymes were studied on day 19. Hyperoxic incubation neither affected embryonic growth nor induced signs of DA constriction or changed the mRNA expression of superoxide dismutase and catalase. The contractions induced by O2 (21%), KCl, 4-aminopyridine, phenylephrine, and endothelin-1 and the relaxations induced by acetylcholine (ACh), sodium nitroprusside, isoproterenol, and hydroxyfasudil were similar in DA from embryos incubated under normoxic or hyperoxic conditions. In contrast, hyperoxic incubation impaired the thromboxane prostanoid (TP) receptor-mediated contractions evoked by U46619, 15-E2t-Isoprostane and high concentrations (≥3 µM) of ACh. Exogenous hydrogen peroxide (H2O2) evoked endothelium-dependent contraction in the normoxic DA and endothelium-dependent relaxation in the hyperoxic group. The presence of the TP receptor antagonist SQ 29548 unmasked a relaxant response to H2O2 in the normoxic DA and the cyclooxygenase (COX) inhibitor indomethacin blocked H2O2-induced contraction (in the normoxic group) and relaxation (in the hyperoxic group). Altogether our functional data suggest that, in the chicken DA, exogenous H2O2 induces the release of endothelium-derived COX metabolite(s) with contractile and relaxant properties. Under normal conditions H2O2-induced contraction prevails and relaxation is unmasked after pharmacological or functional (i.e.hyperoxia) TP receptor impairment.

A case-control pilot study on cognitive functioning, symptom validity and psychological wellbeing in HIV-1-infected patients in the Netherlands.

The objective of this study was to examine and relate both cognitive functioning and psychological wellbeing in Dutch HIV-1-infected patients (n = 30) in comparison with a matched healthy control group (n = 30), taking symptom validity into account. Significant differences in performance between patients and controls were found in the domain Working memory (P = 0.036), but not in the other cognitive domains. There was a significant difference in all dimensions of the psychological wellbeing scale, measured with the SCL-90-R (P values between 0.002 and 0.023), except for agoraphobia, cognitive performance difficulty and sleep disturbances. No correlations were found between the performance on the Working memory domain and wellbeing. Future research should focus on unravelling the underlying mechanisms of neurocognitive dysfunction further using neuropsychological tests, including a symptom validity test in combination with neuroimaging techniques in larger samples.

Effects of prenatal hypoxia on pulmonary vascular reactivity in chickens prone to pulmonary hypertension.

Among chickens, meat-producing broiler strains are highly prone to develop severe pulmonary hypertension (PH) that is accompanied by endothelial dysfunction in the conduit extrapulmonary arteries. We hypothesized that exposure to chronic prenatal mild hypoxia would accelerate PH and endothelial dysfunction in smaller intrapulmonary arteries from broiler chickens. Fertilized broiler and layer (White Leghorn, WL) eggs were incubated under normoxic or hypoxic conditions. Endothelium-dependent (tested with acetylcholine, ACh ) and -independent (tested with sodium nitroprusside, SNP) relaxations of the caudomedial intrapulmonary artery were studied on fetal day 19 and at 2 weeks post-hatch. The response to acute hypoxia in vitro was also studied in the 2 wk-old vessels. Relaxations induced by ACh and SNP were similar in broiler and layer chickens and were unaffected by chronic mild hypoxia during incubation. However, during in vitro acute hypoxia the broiler arteries showed a markedly enhanced contraction. Chronic prenatal hypoxia did not affect the response of intrapulmonary arteries to acute hypoxia. We conclude that early endothelial dysfunction is not present in the small pulmonary arteries of fast-growing broilers after incubation under normoxic or hypoxic conditions. The higher susceptibility of the broiler pulmonary arteries to acute hypoxia might, at least partially, explain the higher susceptibility to PH.

Nodular fasciitis: an unexpected finding on computed tomography and positron emission tomography.

Nodular fasciitis is an uncommon lesion that is also designated as a pseudosarcomatous, self-limiting reactive process. We describe a 40-year-old woman with a nodular fasciitis that was detected by computed tomography (CT), positron emission tomography (PET) with 18F-fluorodeoxyglucose (18-FDG), and histology while she was being examined for upper abdominal pain.