Systematic review supports the role of DNA methylation in the pathophysiology of preeclampsia: a call for analytical and methodological standardization.

BACKGROUND: Studies have recently examined the role of epigenetic mechanisms in preeclampsia pathophysiology. One commonly examined epigenetic process is DNA methylation. This heritable epigenetic marker is involved in many important cellular functions. The aim of this study was to establish the association between DNA methylation and preeclampsia and to critically appraise the roles of major study characteristics that can significantly impact the association between DNA methylation and preeclampsia. MAIN BODY: A systematic review was performed by searching PubMed, Web of Science, and EMBASE for original research articles published over time, until May 31, 2019 in English. Eligible studies compared DNA methylation levels in pregnant women with vs. without preeclampsia. Ninety articles were included. Epigenome-wide studies identified hundreds of differentially methylated places/regions in preeclamptic patients. Hypomethylation was the predominant finding in studies analyzing placental tissue (14/19), while hypermethylation was detected in three studies that analyzed maternal white blood cells (3/3). In candidate gene studies, methylation alterations for a number of genes were found to be associated with preeclampsia. A greater number of differentially methylated genes was found when analyzing more severe preeclampsia (70/82), compared to studies analyzing less severe preeclampsia vs. controls (13/27). A high degree of heterogeneity existed among the studies in terms of methodological study characteristics including design (study design, definition of preeclampsia, control group, sample size, confounders), implementation (biological sample, DNA methylation method, purification of DNA extraction, and validation of methylation), analysis (analytical method, batch effect, genotyping, and gene expression), and data presentation (methylation quantification measure, measure of variability, reporting). Based on the results of this review, we provide recommendations for study design and analytical approach for further studies. CONCLUSIONS: The findings from this review support the role of DNA methylation in the pathophysiology of preeclampsia. Establishing field-wide methodological and analytical standards may increase value and reduce waste, allowing researchers to gain additional insights into the role of DNA methylation in the pathophysiology of preeclampsia.

Distal venous arterialization and reperfusion injury: focus on oxidative status.

In patients with unreconstructable arterial occlusive disease distal venous arterialization (DVA) seems to be a promising option in the treatment. The goals of this prospective study were to assess clinical efficiency and possible impact of DVA on tissue damage by estimating oxidative status of patients with critical limb ischemia treated with this procedure. The subjects were 60 randomized patients: 30 were undergoing DVA and 30 were treated with antiaggregation therapy. During the mean follow-up period (6.13 ± 4.32 months for DVA vs. 6.74 ± 0.5 months for antiaggregation therapy) survival (p < 0.01), limb salvage (p < 0.001), pain relief (p < 0.001) and wound healing (p < 0.001) rates were significantly different between the two groups of patients in favor of the DVA group. Ten minutes after declamping we observed a decreasing trend in the lactate level in the blood of the deep venous system (p < 0.001). Also, on postoperative day 7 digital systolic pressure and digital-brachial index were higher than before the operation (p < 0.001). In blood samples collected immediately before and successively at 1, 3, 5 and 10 min postoperatively, prooxidative status (thiobarbituric acid reactive substances, O(2)(-), H(2)O(2) and nitric oxide) and antioxidative enzymes (superoxide dismutase, catalase and glutathione reductase) were determined spectrophotometrically. Using the nonparametric Friedman test, we noted statistically nonsignificant differences (p > 0.05) in values of both prooxidative parameters and enzymes of the antioxidative defense system, before and successively at 1, 3, 5 and 10 min after operation. These results indicate that there was no statistically significant reperfusion injury after revascularization, which could have been expected after this surgical procedure, thus confirming its validity in these patients.

Survivin expression in patients with newly diagnosed nodal diffuse large B cell lymphoma (DLBCL).

Survivin is one of the inhibitors of apoptosis proteins (IAP) that might play an important role in the pathogenesis of diffuse large B cell lymphoma (DLBCL). The present study was designed to investigate the clinical and prognostic significance of survivin expression in nodal DLBCL. We analyzed lymph node biopsy specimens obtained from 56 patients with newly diagnosed nodal DLBCL, treated with immunochemotherapy (R-CHOP). The expression of survivin was analyzed using the standard immunohistochemical method on formalin-fixed and routinely processed paraffin-embedded lymph node specimens and evaluated semiquantitatively as a percentage of tumor cells. Survivin immunoexpression (>45 % positive tumor cells) was found in 22 (39.28 %) and observed as cytoplasmic staining in 15 patients, or mixed (cytoplasmic and nuclear) staining in 7 patients. A significant difference in survivin immunoexpression was noticed between the GCB and the non-GCB subtypes of DLBCL (p = 0.031). However, survivin immunoexpression had no significant association with IPI, "bulky" disease, extranodal localization, hemoglobin, Ki-67 immunoexpression or other clinicopathological parameters. A univariate analysis showed that survivin positivity was an unfavorable factor for therapy response and a predictor of shorter survival in patients with DLBCL (p = 0.048 and p = 0.034, respectively). Patients with survivin overexpression experienced a relapse more often than patients without expression of this apoptotic protein (27.3 vs. 11.8 %), but this difference did not reach statistical significance (p = 0.131). The results of this study showed that disregulation of survivin expression had an important role in the determination of the course of the disease in patients with nodal DLBCL treated with R-CHOP. Therefore, survivin represents a potential target for therapeutic intervention in DLBCL.

[Acute upper gastrointestinal nonvariceal bleeding--how to determine low risk patients for rebleeding and mortality after endoscopic sclerotherapy?].

INTRODUCTION: Successful endoscopic sclerotherapy is effective in securing hemostasis for bleeding lesions and remains the first line and only needed therapy for most of the patients (pts), but bleeding reoccurs in 10% to 30% pts, and 4% to 14% of the pts die after acute nonvariceal upper gastrointestinal bleeding (UGIB). The need for hospitalization and its duration for all the bleeding pts is still a controversial question. AIM: To create the simple scoring system able to determine low risk pts for rebleeding and mortality by establishing the relative importance of risk factors for rebleeding and mortality after successful endoscopic sclerotherapy of acute nonvariceal UGIB. PATIENTS AND METHODS: Prospective study included 3 15 pts who where admitted to hospital because of acute nonvariceal UGIB. All of them underwent gastroscopy with successful sclerotherapy within 12 hours after the admission. We investigated the episode of rebleeding and death during the initial hospitalization, and analyzed the following parameters: age, gender, drug intake, shock, bleeding stigmata, location of bleeding lesion and comorbidity. RESULTS: Rebleeding occurred in 53 pts (16.8%) and was determined by shock, bleeding stigmata and comorbidity. Eleven pts (3.5%) died and shock, rebleeding and comorbidity were all independent, statistically significant predictors of pts' mortality. The numerical scores for determination of pts with different risk levels for rebleeding and mortality have been developed using the significant predictors of rebleeding and death. The score values for rebleeding ranged from 3 to 9 and pts with values < or = 4 had low risk of rebleeding. We identified 59 pts (18.7% of all) with score for rebleeding < or = 4. Score values for mortality risk ranged from 3 to 8 and the values < 5 revealed negligible risk of death. In our group we found 290 pts (92.1% of all) with low mortality score values. CONCLUSION: Following the successful initial endoscopic sclerotherapy, these scores can help to identify pts with low risk of rebleeding and negligible risk of death, so they can be treated as outpatients.

Acute fatty liver of pregnancy -- an underlying condition for herpes simplex type 2 fulminant hepatitis necessitating liver transplantation.

The infrequent occurrence of herpes simplex virus (HSV) hepatitis in healthy women in comparison with the high prevalence of HSV infections suggests that, in addition to deranged immunity, an underlying condition in the liver might be necessary to develop HSV hepatitis. We report the case of a 28-year-old pregnant woman in the 28 (th) week of gestation. Following HSV type 2 infection of the uterine cervix, acute liver failure developed, necessitating urgent liver transplantation. In addition to fulminant HSV type 2 hepatitis, the explanted liver also showed the histological features of acute fatty liver of pregnancy. The presented case suggests a possible pathogenetic role of acute fatty liver of pregnancy in the development of fulminant HSV hepatitis following recurrent infection with HSV in healthy pregnant women. We believe that early histopathological diagnosis, followed by specific antiviral treatment and liver transplantation in selected patients may improve the clinical outcome of otherwise almost uniformly fatal HSV hepatitis.

Can we evaluate the pressure of perihepatic packing? Results of a study on dogs.

The pressure of perihepatic packing can cause organ perfusion disturbances. The problem is to determine the pressure applied during the operative procedure. The objective of this animal study was to assess the perihepatic packing pressure and its effect on the pressure in the inferior vena cava (IVC). In order to assess the pressure in the IVC a catheter was introduced through the femoral vein. A rearranged tourniquet for blood pressure measurement was placed on the dog liver and with various perihepatic pressures the resulting pressures in the IVC were assessed. It was established, that by applying pressure of 30 mm Hg to the liver, the pressure in the IVC did not exceed 10 cm of water. Two clinical cases are reported where the method was shown to be crucial for the management. The first one is related to haemodynamic instability after successful perihepatic packing for grade V injury. In the second case, an otherwise stable patient had significantly elevated pressure in the IVC, which crucially influenced the treatment. The introduction of a catheter into the IVC to monitor the pressure in patients with liver injuries is useful.

Hepatobiliary cystadenoma can protrude and grow into the bile ducts.

BACKGROUND/AIMS: To evaluate the phenomenon and the potential reasons for protrusion and growth of hepatobiliary cystadenoma into the extrahepatic bile ducts in our patients, accomplished by a review of the data regarding hepatobiliary cystadenomas published elsewhere. METHODOLOGY: In a retrospective open study conducted over the last eight years, five patients with hepatobiliary cystadenoma and one patient with hepatobiliary cystadenocarcinoma were operated on. All the patients were females aged between 25 to 61 years. Diagnostic procedures, laboratory, operative and histopathological findings and treatment were evaluated. RESULTS: Most of our patients were found to have hepatobiliary cystadenoma located in the left surgical liver. In three out of five patients with HBC mesenchymal stroma was histologically detected. In two of the three, protrusion and growth into the extrahepatic bile ducts was found. CONCLUSION: Considering the pathogenesis, location and the morphology of HBC, the mesenchymal stroma may present the competent potential for intraductal progression of the tumor. Radical excision should be performed for successful treatment of hepatobiliary cystadenomas, because of the potential for reoccurrence.

How to record peritoneal catheter infections.

Due to discrepant definitions of exit-site infections and/or tunnel infections (ESI/TI), as well as to the variety of infection rates, data on ESI/TI are extremely difficult to compare. Twardwski et al. have defined exit site, while Nolph et al. have proposed new monitoring and reporting of ESI/TI. The aim of our prospective study was to try combining both systems. From January 1992 to December 1995 we treated 127 patients, in whom 147 double-cuff peritoneal catheters (PCs) were inserted. Tunnel infection was defined as external-cuff infection (ECI), inter-cuff segment infection (ICSI), and/or internal-cuff infection (ICI). Sixty-four PCs (43.5%) were infected. Thirty-eight (25.8%) had acute PC infection (PCI) from 2.4% to 4.7% of the total patient-months of care per year, and 26 (17.7%) PCs were chronically infected from 2.1 to 11.1% of the time per year. Almost all cases of removed acutely and chronically infected PCs had ECI in combination with ESI. According to our experience, ECI should be classified as TI. The proposed approach to monitoring and reporting is very useful for ESI, but does not include TI. Comparison between different peritoneal dialysis units is only possible when they share a common PC classification system, and when their personnel are well experienced, highly trained, and very accurate.

Venous drainage of the dorsal sector of the liver: differences between segments I and IX. A study on corrosion casts of the human liver.

The aim of this study was to determine the venous drainage of the dorsal sector of the liver in order to define the differences between segments I and IX and their implications for sectorially and segmentally oriented hepatic surgery. The study was based on corrosion casts of 61 macroscopically healthy livers. The drainage pathways of veins at least 10 mm long and 1 mm wide were evaluated and statistically analysed. On average, 9 veins drained the two segments and three veins from both segments entered the inferior vena cava. In 95% of cases the veins from segment I drained predominantly into the inferior vena cava, whereas in segment IX this pathway was dominant in only 30% of cases. In 64% of cases a vein originating in segment IX entered the right hepatic v. The difference in the venous drainage of the two segments suggests that segment IX partly belongs to the neighbouring segments and may thus be only a paracaval region of the right liver.

Prognostic factors: classification approaches in patients with lung cancer.

With the proliferation of potential prognostic factors for lung cancer, it is becoming increasingly more difficult to integrate the information provided by these factors into a single accurate prediction of clinical outcome. Here we reviewed five classification methods for their capabilities in classification of 200 patients with lung cancer into distinct prognostic groups using survival outcome as a criteria. The source of patient data for this study is a Lung Tumour Registry from Institute for Lung Diseases, University Clinical Hospital, Belgrade. Almost all developed classification algorithms determined prognostic groups according to biochemical tumour markers LDH and alkaline phosphatase, producing most significant split, instead of commonly used staging variables. The choice of which approach to use for a given classification problem depends not only on statistical properties of method, but also on medical considerations, such as whether more differential findings are given greater weight and the applicability of a classification rule.

The diffusion of computer-based information technology into health institutions of Republic of Serbia (FR Yugoslavia).

The basic purpose of this study was to analyze the diffusion of computer-based information technology into the health care institutions of the Republic of Serbia in the year 1994, and to compare the results with a similar investigation in 1992 in order to determine the state and progress of its development. The instrument of investigation was a questionnaire with 24 questions, distributed to all the independent health institutions in Serbia (total 238). The overall response rate was 40.8%. Of the number of responding health institutions, 92.8% own computers which are in use, six PCs on average, and on average use two application softwares, obligatory one for accounting and billing. In conclusion, health care institutions in the Republic of Serbia are unsatisfactorily equipped with information technology and without the developed institutional information system, except on the level of the project. So, careful planning, selection, implementation and management with national coordination will be needed to ensure the appropriate use of technology and information systems in health care.

Health care delivery and the status of the population's health in the current crises in former Yugoslavia using EPI-design methodology.

BACKGROUND: The aim of this study was to assess accessibility to health care services and the needs of the population and demands on the health service in the areas most affected by the current crisis in the former Yugoslavia. The delivery of health care services and problems in its realization and the status of the population's health in the crisis period (from the second half of 1993 to the end of the first half of 1994) were also investigated together with the results of Government measures concerning health care priorities during the period of UN Sanctions in Yugoslavia. METHOD: By the end of the 1980s, as an alternative to traditional data collection, a new method called 'Rapid Health Assessment' appeared. The EPI design (Experienced Programme on Immunization), the most frequently applied method, was used in this study. It is a cluster sample selection, where a household is the basic unit. RESULTS: This study showed that the first effects of the crisis appeared in the field of health care delivery and then in the population's health status. The difficulties were not the same for all categories of the population, and children and urgent cases had less problems than others. The expected difficulties in vaccination coverage were not shown in this survey. The morbidity structure for children and adults changed in comparison with routine statistical data but the size of the chosen sample, as well as the short period of the crisis investigated, mean that definite conclusions cannot be drawn on this issue. This study provides recent data on health care delivery, morbidity structure, and vaccination coverage, as well as giving a more complex and precise estimate of the real situation.

[Some aspects on medical research systems at the medical school in Belgrade]. / Elementi racunarske podrske u naucnim istrazivanjima iz oblasti medicine.

The ongoing development of new technologies is rapidly expanding the number and/or quality of medical researches. In order to evaluate the situation in our country we analysed master - degree and doctoral thesis that have been done at the Belgrade Medical School in 1987., 1990. and 1994. year. These years have been chosen because of medical knowledge's known rate of exponential growth. According to the main tasks of medical research: data management system and data analyses, we classified medical researches in two major categories: prospective and retrospective. The crucial difference is whether or not the investigators collect new data for analyses. First has been discovered in 11 doctoral and 10 master theses out of 225 reviewed. Medical researchers use variety of different database management systems and statistical techniques to store, retrieve and analyse data. These were identified in respectively 23 percent and 24 percent. Beside these major research activities we were interested in usage of application programmes such as text processors or graphical packages that were found in 28 percent and 20 percent of analysed theses. In summary, technological advances in computer hardware and software have reduced the barriers to long - term storage and processing of rich biomedical data. The development of new techniques for analysing such a data also encourages the discovery and validation of new medical relationships.

[Health care delivery in the period of crises by means of EPI design methodology]. / Koriscenje zdravstvene sluzbe u uslovima krize primenom metoda brze procene.

New methods "Rapid health assessment" fulfill the request for a methodologically clear and efficient way of gaining the recent data, using relatively limited resources. The aim of the study was an assessment of health care delivery and problems in its realization and the population health status, in the period of crises (and of 1993/begining of 1994). The study showed that first effects of crises are shown in the field of health care delivery and than in the population health status. The difficulties were not the same for all, children and urgent cases had less problems than others. The morbidity structure among children and adults was changed. The morbidity structure among children and adults was changed in comparison with routine statistical data. The period of crises has been too short to draw any definitive conclusions.

[Models of the epigastric cavity, the liver vessels and bile ducts as an anatomic and surgical teaching tool]. / Modelle des oberen Bauchraumes, der Lebergefässe und der Gallengänge als anatomische und chirurgische Lehrmittel.

During the "Alps-Adria Hepatobiliary School" in Ljubljana a workshop was held at which various liver surgery techniques were performed in practice. These techniques required the introduction of original methods which enabled practical exercise on isolated liver. Plastic casts of the upper part of the abdominal cavity were made, as well as the corrosion models of the hepatic vessels and bile ducts. Isolated livers were conserved by means of freezing. The results showed that the freezing and thawing did not alter the consistency of livers, which made them useful material for surgical practice. Corrosion casts were used for studying three-dimensional structure of the vessels and bile ducts before the surgical techniques were applied. Various possibilities of further use and application of models and corrosion casts are discussed. The role of working on the models and casts for a better performance of a surgery workshop is emphasized.

Frequency of various types of peritoneal catheter infections and therapeutic outcome of treatment.

To analyze peritoneal catheter infections (PCIs), primarily the type (acute or chronic), frequency, and therapeutic outcome, we assessed 113 patients treated between January 1992 and December 1994. The average age was 56.3 +/- 15.3 years, and 38% were diabetics. One hundred and thirty peritoneal catheters (PCs) were placed surgically in the lateral abdominal wall. The peritonitis rate fell from 0.61 episodes/year to 0.33 episodes/year, but the exit-site and/or tunnel infection (ESI/TI) rate increased (from 0.48 episodes/year to 0.61 episodes/year). Seventy-nine cases of PCI were observed; 58 (73.4%) were acute ESI/TI and 21 (26.6%) were exacerbations of chronic ESI/TI. Thirty-one (53.4%) acute PCIs were cured, 17 (29.3%) became persistent, and in 10 (17.2%) cases the PC was removed. In chronic ESI/TI, of the 21 exacerbations registered, in 12 cases (57.1%) conservative treatment was effective, while in 9 cases (42.9%) the PC was removed. We conclude that ESI/TIs are the most frequent type of continuous ambulatory peritoneal dialysis (CAPD) infection and the more frequent cause of PC removal compared to peritonitis (p < 0.001). PC removal is more frequent in chronic than in acute ESI/TI (p < 0.005). The progression of infection towards the external and even the internal cuff is a poor prognostic sign. Staphylococcus aureus and Pseudomonas aeruginosa were the most common causes of infection and the most serious infective agents, causing chronic infection or catheter removal. Clinical evaluation of ESI/TI can be helped significantly by ultrasound examination, which is 100% positive in chronic ESI/TI and not more than 52.1% positive in acute ESI/TI (p < 0.005).