How Were Conflicts of Interest Handled?

Conflicts of interest were potentially great but they were minimized by the great conviction from both Doctors and Health Ministry that something had to be done to improve data on perinatal health. To decrease the number of hospitals where deliveries took place, to concentrate doctors, nurses and equipment, to define staff and to acquire equipment and to train nurses and paediatricians was the way. One the point of view of cost-effectiveness, centralization of expensive technologies, and development of expertise concentrating cases in a same centre - Surgery, VLBW, etc- and lowering mortality rates and get better outcomes were clear health gains. In 1989 after the political decision of closing small maternities the committee return to villages and cities to explain to political local power and people, the decision, which kind of care they will have in the future, why and expected gains. Level I hospitals and Health Centers stop to have deliveries; Health Centers were given a great responsibility: the follow up of the most part of the normal pregnancies by GP. There was no economic pressure because the National Health Service is free, there are no economic incentives for obstetrical or neonatal care, hospitals are financed through ICD, hospital level is defined according to both delivery and newborn care. In 1989 the rule was “No results can be obtained without the interested and responsible participation of all – institutions and people”. At that time the emphasis was on training. There are geographic influences on regionalization for example for islands and inner and far geographic areas. Also we would like to emphasize the influence of demographics on regionalization. As birth rate continues to decrease the hospitals left open 20 years ago with more than 1500 deliveries have to be closed now because the number of deliveries decreased. It was much more difficult and unacceptable to close some few maternities now than 20 years ago. All the difference was that at that time reasons were explained and now it was a Minister order. Other fearful events are the opening of private hospitals, the lowering gross national income, the economic difficulties and financial problems.

Confined Placental Mosaicism in Chorionic Vilus Sampling - Case Report

Objectives: Chorionic Vilus Sampling (CVS) has several advantages over amniocentesis: it may be performed at an earlier gestational age, the results are quicker to obtain and there’s a lower miscarriage risk – 1%. However, the higher prevalence of discrepant fetal and vilus sampling material’s karyotype findings is a disadvantage of this technique – 0.5%. This is caused, amongst other causes, by placental mosaicism which consists of two genetically different cell lines. There are three types of placental mosaicism according to the abnormal cell line location: Type I – in the cytotrophoblast; Type II – in the vilus’ stroma; Type III – in both the above locations. Material and Methods: We present a case report about a 36-year-old pregnant woman going through our Department’s 1st trimester combined screening program; a CVS was performed, which showed Confined Placental Mosaicism (CPM). Results and Conclusion: Although the pregnant woman was in the low-risk group for aneuploidy, the patient wanted the cytogenetic study to be performed in order to reduce maternal anxiety. CVS was performed at the gestational age of 12 weeks + 5 days and the karyotype was 47XY+2/46XY. For the correct interpretation of this data an amniocentesis was performed at the gestational age of 15 weeks + 6 days, which showed a 46XY karyotype. We therefore conclude that the cytogenetic analysis of the CVS was the result of a CPM. A careful follow-up including fetal echocardiogram and seriated ultrasonographic monitoring was used to safely exclude malformations and fetal growth restriction. We verified no occurences throughout pregnancy, delivery and perinatal period. CVS practice was recently implemented in our country and has many advantages over amniocentesis. Besides the fact that an earlier gestational age usually means less affective bonding to the fetus and therefore makes medical termination of pregnancy somewhat less difficult, one should consider specific situations like the one reported in which CPM may be diagnosed. This condition is associated with increased risk of fetal growth restriction, so the clinician should be aware of the need for a more careful follow-up, since perinatal complications, which should be anticipated and treated, can be expected in 16-21% of these cases.

Recurrence After Operative Management of Intrahepatic Cholangiocarcinoma

INTRODUCTION: Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. METHODS: We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. RESULTS: During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01-2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10-2.25; P = .04), and tumor size ≥5 cm (HR, 1.84; 95% CI, 1.28-2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. CONCLUSION: Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.

Differential Internalization of Amphotericin B - Conjugated Nanoparticles in Human Cells and the Expression of Heat Shock Protein 70

Although a variety of nanoparticles (NPs) functionalized with amphotericin B, an antifungal agent widely used in the clinic, have been studied in the last years their cytotoxicity profile remains elusive. Here we show that human endothelial cells take up high amounts of silica nanoparticles (SNPs) conjugated with amphotericin B (AmB) (SNP-AmB) (65.4 12.4 pg of Si per cell) through macropinocytosis while human fibroblasts internalize relatively low amounts (2.3 0.4 pg of Si per cell) because of their low capacity for macropinocytosis. We further show that concentrations of SNP-AmB and SNP up to 400 mg/mL do not substantially affect fibroblasts. In contrast, endothelial cells are sensitive to low concentrations of NPs (above 10 mg/mL), in particular to SNP-AmB. This is because of their capacity to internalize high concentration of NPs and high sensitivity of their membrane to the effects of AmB. Low-moderate concentrations of SNP-AmB (up to 100 mg/mL) induce the production of reactive oxygen species (ROS), LDH release, high expression of pro-inflammatory cytokines and chemokines (IL-8, IL-6, G-CSF, CCL4, IL-1b and CSF2) and high expression of heat shock proteins (HSPs) at gene and protein levels. High concentrations of SNP-AmB (above 100 ug/mL) disturb membrane integrity and kill rapidly human cells(60% after 5 h). This effect is higher in SNP-AmB than in SNP.

Achondroplasia and Down’s Syndrome – Case Report of a Rare Association

The association of achondroplasia and Down’s syndrome is very rare and only five cases have been reported in the literature so far. These two genetic alterations have overlapping features such as short stature, developmental delay or hypotonia that complicate management and follow up. We report the case of a girl that is unique since she was born from a mother with achondroplasia and a healthy father. Achondroplasia was dominantly inherited from the mother but at birth she had features of Down’s syndrome as well, confirmed later by kariotype. We review her evolution regarding physical health, cognitive problems and adaptive behavior during her eight years of life. To our knowledge this is the first report of the combination of both disorders in which the achondroplasia was inherited and not a “de novo” mutation. We address the problems resulting from the additional burden of having two disorders, and how they can be improved, aiming to help others in the future to deal with these cases.

The Oncological and Functional Risks of the Organ Preservation Experimental Treatment Approach

We increasingly face conservative surgery for rectal cancer and even the so called ‘wait and see’ approach, as far as 10–20% patients can reach a complete pathological response at the time of surgery. But what can we say to our patients about risks? Standard surgery with mesorectal excision gives a <2% local recurrence with a post operative death rate of 2–8% (may reach 30% at 6 months in those over 85), but low AR has some deterioration in bowel function and in low cancer a permanent stoma may be required. Also a long-term impact on urinary and sexual function is possible. Distant metastasis rate seem to be identical in the standard and conservative approach. It is difficult to evaluate conservative approach because a not clear standardization of surgery for low rectal cancer. Rullier et al tried to clarify, and they found identical results for recurrence (5–9%), disease free survival (70%) at 5y for coloanal anastomosis and intersphinteric resection. Other series have found local recurrence higher than with standard approach and functional results may be worse and, in some situations, salvage therapy is compromised or has more complications. In this context, functional outcomes are very important but most studies are incomplete in measuring bowel function in the context of conservative approach. In 2005 Temple et al made a survey of 122/184 patient after sphinter preserving surgery and found a 96.9% of incomplete evacuation, 94.4% clustering, 93.2% food affecting frequency, 91.8% gas incontinence and proposed a systematic evaluation with a specific questionnaire. In which concerns ‘Wait and see’ approach for complete clinical responders, it was first advocated by Habr Gama for tumors up to 7cm, with a low locoregional failure of 4.6%, 5y overall survival 96%, 72% for disease free survival; one fifth of patients failed in the first year; a Dutch trial had identical results but others had worse recurrence rates; in other series 25% of patients could not be salvaged even with APR; 30% have subsequent metastatic disease what seems equal for ‘wait and see’ and operated patients. In a recent review Glynne Jones considers that all the evaluated ‘wait and see’ studies are heterogeneous in staging, inclusion criteria, design and follow up after chemoradiation and that there is the suggestion that patients who progress while under observation fare worse than those resected. He proposes long-term observational studies with more uniform inclusion criteria. We are now facing a moment where we may be more aggressive in early cancer and neoadjuvant treatment to be more conservative in the subsequent treatment but we need a better stratification of patients, better evaluation of results and more clear prognostic markers.

Evaluation of CSF Neurotransmitters and Folate in 25 Patients with Rett Disorder and Effects of Treatment

Background: Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis. Patients and Methods: We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy. Results: CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels. Conclusion: Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.