Dynamic cerebellar herniation in Chiari patients during the cardiac cycle evaluated by dynamic magnetic resonance imaging.

PURPOSE: Cerebellar herniation in Chiari patients can be dynamic, following the cerebrospinal fluid pulsatility during the cardiac cycle. We present a voxel intensity distribution method (VIDM) to automatically extract the pulsatility-dependent herniation in time-resolved MRI (CINE MRI) and compare it to the simple linear measurements. The degree of herniation is furthermore compared on CINE and static sequences, and the cerebellar movement is correlated to the presence of hydrocephalus and syringomyelia. METHODS: The cerebellar movement in 27 Chiari patients is analyzed with VIDM and the results were compared to linear measurements on an image viewer (visual inspection, VI) using a paired t test. Second, an ANOVA test is applied to compare the degree of herniation on static 3D MRI and CINE. Finally, the Pearson's correlation coefficient is calculated for the correlation between cerebellar movement and the presence of hydrocephalus and syringomyelia. RESULTS: VIDM showed significant movement in 85% of our patients. Assuming that movement < 1 mm cannot be detected reliably on an image viewer, VI identified movement in 29.6% of the patients (p = 0.002). The herniation was greater on static sequences than on CINE in most cases, but this was not statistically significant. The cerebellar movement was not correlated with hydrocephalus or syringomyelia (Pearson's coefficient < 0.3). CONCLUSIONS: VIDM is a sensitive method to detect tissue movement on CINE MRI and could be used for Chiari patients, but also for the evaluation of cyst membranes, ventriculostomies, etc. The cerebellar movement appears not to correlate with hydrocephalus and syringomyelia in Chiari patients.

Implementation of genetic evaluation and mating designs for the endangered local pig breed 'Bunte Bentheimer'.

A pedigree including 1538 individuals of the endangered pig breed 'Bunte Bentheimer' and 3008 records of the fertility traits 'number of piglets born alive' (NBA) and 'number of piglets weaned' (NW) were used to i) characterize the population structure, ii) to estimate genetic (co)variance components and estimated breeding values (EBVs) and iii) to use EBVs for the application of the concept of optimal genetic contributions. The average coefficient of inbreeding increased from F = 0.103 to F = 0.121 within the two recent cohorts. Average rate of inbreeding amounted to 1.66%, which resulted in an effective population size of Ne  = 30 animals in the recent cohort. Average generation interval was 3.07 years considering the whole pedigree, and in total, only 612 sows and boars generated offspring. Estimated heritabilities for both traits NBA and NW were 0.12, and the estimated genetic correlation between both traits was 0.96. The variance component due to the service sire was higher than in commercial pig breeds, presumably due to the widespread use of natural service boars. The EBVs for NBA from 333 selection candidates (63 boars and 270 sows) were used to determine optimal genetic contributions. Based on selected animals and their optimal genetic contributions, specific mating designs were evaluated to minimize inbreeding in the next generation. Best results were achieved when using a simulated annealing algorithm and allowing artificial insemination.

Controlling inbreeding and maximizing genetic gain using semi-definite programming with pedigree-based and genomic relationships.

Because of the relatively high levels of genetic relationships among potential bull sires and bull dams, innovative selection tools should consider both genetic gain and genetic relationships in a long-term perspective. Optimum genetic contribution theory using official estimated breeding values for a moderately heritable trait (production index, Index-PROD), and a lowly heritable functional trait (index for somatic cell score, Index-SCS) was applied to find optimal allocations of bull dams and bull sires. In contrast to previous practical applications using optimizations based on Lagrange multipliers, we focused on semi-definite programming (SDP). The SDP methodology was combined with either pedigree (a(ij)) or genomic relationships (f(ij)) among selection candidates. Selection candidates were 484 genotyped bulls, and 499 preselected genotyped bull dams completing a central test on station. In different scenarios separately for PROD and SCS, constraints on the average pedigree relationships among future progeny were varied from a(ij)=0.08 to a(ij)=0.20 in increments of 0.01. Corresponding constraints for single nucleotide polymorphism-based kinship coefficients were derived from regression analysis. Applying the coefficient of 0.52 with an intercept of 0.14 estimated for the regression pedigree relationship on genomic relationship, the corresponding range to alter genomic relationships varied from f(ij) = 0.18 to f(ij) = 0.24. Despite differences for some bulls in genomic and pedigree relationships, the same trends were observed for constraints on pedigree and corresponding genomic relationships regarding results in genetic gain and achieved coefficients of relationships. Generally, allowing higher values for relationships resulted in an increase of genetic gain for Index-PROD and Index-SCS and in a reduction in the number of selected sires. Interestingly, more sires were selected for all scenarios when restricting genomic relationships compared with restricting pedigree relationships. For example, at constraint of f(ij)=0.185 and selection on Index-PROD, the number of selected sires was 35. In contrast, only 21 sires were selected at the comparable constraint on additive genetic relationship of a(ij)=0.09. A further reduction in relationships is possible when using SDP output (i.e., suggested genetic contributions of selected parents) and applying a simulated annealing algorithm to define specific mating plans. However, the advantage of this strategy is limited to a short-term perspective and probably not successful in the period of genomic selection allowing a substantial reduction of generation intervals.

Exploration of relationships between production and fertility traits in dairy cattle via association studies of SNPs within candidate genes derived by expression profiling.

The objective of this work was to integrate findings from functional genomics studies with genome-wide association studies for fertility and production traits in dairy cattle. Association analyses of production and fertility traits with SNPs located within or close to 170 candidate genes derived from two gene expression studies and from the literature were performed. Data from 2294 Holstein bulls genotyped for 39557 SNPs were used. A total of 111 SNPs were located on chromosomal segments covered by a candidate gene. Allele substitution effects for each SNP were estimated using a mixed model with a fixed effect of marker and a random polygenic effect. Assumed covariance was derived either from marker or from pedigree information. Results from the analysis with the kinship matrix built from marker genotypes were more conservative than from the analysis with the pedigree-derived relationship matrix. From sixteen SNPs with significant effects on both classes of traits, ten provided evidence of an antagonistic relationship between productivity and fertility. However, we found four SNPs with favourable effects on fertility and on yield traits, one SNP with favourable effects on fertility and percentage traits, and one SNP with antagonistic effects on two fertility traits. While most quantitative genetic studies have proven genetic antagonisms between yield and functional traits, improvements in both production and functionality may be possible when focusing on a few relevant SNPs. Investigations combining input from quantitative genetics and functional genomics with association analysis may be applied for the identification of such SNPs.

Epistatic kinship a new measure of genetic diversity for short-term phylogenetic structures--theoretical investigations.

The epistatic kinship describes the probability that chromosomal segments of length x in Morgan are identical by descent. It is an extension from the single locus consideration of the kinship coefficient to chromosomal segments. The parameter reflects the number of meioses separating individuals or populations. Hence it is suggested as a measure to quantify the genetic distance of subpopulations that have been separated only few generations ago. Algorithms for the epistatic kinship and the extension of the rules to set up the rectangular relationship matrix are presented. The properties of the epistatic kinship based on pedigree information were investigated theoretically. Pedigree data are often missing for small livestock populations. Therefore, an approach to estimate epistatic kinship based on molecular marker data are suggested. For the epistatic kinship based on marker information haplotypes are relevant. An easy and fast method that derives haplotypes and the respective frequencies without pedigree information was derived based on sampled full-sib pairs. Different parameters of the sampling scheme were tested in a simulation study. The power of the method decreases with increasing segment length and with increasing number of segments genotyped. Further, it is shown that the efficiency of the approach is influenced by the number of animals genotyped and the polymorphism of the markers. It is discussed that the suggested method has a considerable potential to allow a phylogenetic differentiation between close populations, where small sample size can be balanced by the number, the length, and the degree of polymorphism of the chromosome segments considered.

Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas.

BACKGROUND/AIMS: Patients with advanced unresectable hepatobiliary carcinomas have a dismal prognosis. The efficacy of systemic chemotherapy in these patients is negligible and often, in particular in patients with hepatocellular carcinomas, the toxicity of chemotherapy outweighs the potential palliative effect of antineoplastic agents. Gemcitabine is a new anticancer agent with a mild toxicity profile, which has demonstrated antineoplastic activity in many solid tumors. Therefore we investigated the effect of gemcitabine in patients with advanced nonresectable hepatocellular and cholangiocellular carcinomas in a phase II study. METHODOLOGY: Twenty-three patients with cholangiocellular carcinoma and 20 patients with hepatocellular carcinoma were enrolled into the study. Eighteen of the 20 patients with hepatocellular carcinomas had liver cirrhosis. Gemcitabine was administered once weekly over 30 min for 3 consecutive weeks out of every 4 weeks. Patients with cholangiocellular carcinomas received gemcitabine also in the forth week of the first cycle with no rest to the following cycle. Disease status was assessed every 4 weeks. RESULTS: Overall the regimen was well tolerated. The median number of gemcitabine administration was 15 (range, 3-37) in the group of patients with cholangiocellular carcinomas and 7.6 (range, 3-21) in the group of patients with hepatocellular carcinomas. In the group of patients with hepatocellular carcinomas thrombocytopenia was the most frequent side effect (30% grade 3/4). Among the patients with cholangiocellular carcinomas nausea and neutropenia were the most commonly observed side effects. The overall response rate of hepatocellular carcinomas was only 5% and chemotherapy generally did not improve the tumor symptoms of the patients in this group. In contrast, in the group of cholangiocellular carcinomas, seven patients achieved a partial response (overall response rate 30%). Eleven patients with cholangiocellular carcinomas revealed tumor symptoms before the onset of gemcitabine treatment. Seven of these patients developed a treatment related clinical benefit as defined as a relief of tumor symptoms or gain of weight. CONCLUSIONS: Our results indicate that the treatment of cholangiocarcinomas with gemcitabine is effective and should be further evaluated in phase III studies. In contrast, palliative chemotherapy with gemcitabine cannot be recommended in patients with hepatocellular carcinoma and liver cirrhosis.

Survey of yeast mastitis in dairy herds of small-type farms in the Lublin region, Poland.

The purpose of this study was to isolate fungi from the quarter milk of cow udders in 9 dairy farms. The samples were collected between May 1996 and April 2000 in the Lublin region. Six hundred and four milk samples collected from the quarters of 172 cows with clinical and subclinical mastitis were examined. Milk samples were plated as soon as possible on blood agar (BA), Mac Conkey agar, aesculin-tallium acetate-crystal violet blood agar, and Sabouraud agar with chloramphenicol and gentamicin. Fifty eight (9.6%) of the samples were positive for fungi. All of the fungal isolates were yeasts of the genera Candida, Rhodotorula and Trichosporon. We also isolated Streptococcus agalactiae (4.9%), Str. spp.(6.4%), Staphylococcus aureus (10.4%), coagulase-negative staphylococci-CNS (36.6%), Escherichia coli (3.5%), other microorganisms (2.6%) and no growth (25.8%).

IkappaBalpha gene therapy in tumor necrosis factor-alpha- and chemotherapy-mediated apoptosis of hepatocellular carcinomas.

The transcription factor nuclear factor kappaB (NFkappaB) is an essential antagonist of apoptosis during liver regeneration and embryonal development of hepatocytes. Several reports have indicated that NFkappaB may also inhibit the programmed cell death induced by cytokines, ionizing radiation, or cytotoxic drugs in some cancer cell lines. Because hepatocellular carcinomas (HCCs) are one of the most resistant tumors to systemic chemotherapy, we investigated the activation of NFkappaB and the consequence of its inhibition by an IkappaBalpha-super repressor during tumor necrosis factor alpha (TNFalpha)- and chemotherapy-induced apoptosis in HCC cell lines. We demonstrate that both TNFalpha and adriamycin activate NFkappaB in hepatoma cells. Activation of NFkappaB could be blocked through an adenoviral vector expressing the IkappaBalpha super repressor, regardless of the activating agent. Inhibition of NFkappaB enhanced the apoptosis induced by TNFalpha, whereas IkappaBalpha had an anti-apoptotic effect on chemotherapy-induced programmed cell death. A strong inhibition of chemotherapy- and TNFalpha-induced apoptosis by dominant-negative Fas-associated death domain indicated an essential contribution of death receptor-mediated apoptosis. To elucidate the different role of NFkappaB in chemotherapy-induced apoptosis, we investigated the expression of Fas (CD95) and Fas ligand (CD95 ligand), which have been described as important mediators of chemotherapy-induced cell death and as target genes of NFkappaB. However, our investigations demonstrated that in hepatoma cells, the chemotherapy-induced up-regulation of Fas (CD95) and Fas ligand (CD95 ligand) is not transcriptionally mediated through NFkappaB. Thus, other molecular mechanisms must account for the anti-apoptotic effect of IkappaBalpha in adriamycin-induced death of hepatoma cells. In summary, our investigations indicate that the activation of NFkappaB in response to cytotoxic drugs, in contrast to TNFalpha, exerts a pro-apoptotic stimulus rather than an anti-apoptotic function, which has implications for therapy of HCCs.

Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area.

AIMS/BACKGROUND: This study was undertaken in order to assess the main features of hepatocellular carcinoma in Germany, a country with low incidences of this tumor. METHODS: Two hundred and eighty consecutive patients with hepatocellular carcinomas admitted to the Medical School Hannover between 1993-1997 were retrospectively studied. RESULTS: Reliable data for the assessment of the etiology and the tumor stage of HCC were available for 268 patients. The female/male ratio was 1/4. In 51.9% of the patients, HCC was associated with hepatitis virus B or C (HBV, HCV) infection: 35.1% with HBV, 26.9%) with HCV and 10% coinfection with HBV/HCV This result emphasizes the major impact of HBV and HCV infection in liver cancer in Germany. Of all patients with HCC 74.6%) had liver cirrhosis. The predominant majority of the HCC (87%) were restricted to the liver: in only 5.9% could regional lymph node metastases as well as 8.5%) metastases in other organs be clinically diagnosed by chest X-ray, computed tomography scan or sonography. Data to asses the Okuda tumor stage were available for 166 patients: 47% were classified as stage I, 47% as stage II and only 6% as stage III. Serum AFP were determined in 195 patients. In 66% of the patients, the AFP value was elevated, but only in 30% did the AFP level reach the value of 500 microg/l, which is considered to be significant for HCC diagnosis in patients with liver cirrhosis. The proportion of liver cirrhosis was higher in HCV (97.8%) versus HBV (80.6%) associated HCC, which was the only significant (p<0.05) difference in the characteristics of HCC according to the etiology. CONCLUSION: Our study shows that liver cirrhosis is the prime risk factor for hepatocarcinogenesis in Germany. However, the very high proportion of hepatitis virus related HCC, in particular the high proportion of HBV infections, contradicts the common view that alcohol is by far the most important etiological factor for hepatocarcinogenesis in low hepatitis virus endemic areas such as Germany.

NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis.

NFkappaB is an essential survival factor in several physiological conditions such as embryonal liver development and liver regeneration. However, NFkappaB is also a main mediator of the cellular response to a variety of extracellular stress stimuli, and it has been shown that some viral-induced host cell apoptosis appears to be dependent on NFkappaB activation. The activation of NFkappaB upon viral infection may be a rapid way of initiating an innate immune response against the viral particles. We have assessed the role of NFkB during the early phase of adenoviral hepatitis in a nude mouse model using an adenoviral vector expressing a mutant form of IkappaBalpha. Administration of a LacZ-expressing adenoviral vector induces NFkB DNA and correlates with the up-regulation of Fas (CD95) mRNA, but not FasL (CD95L) mRNA, during the early phase of adenoviral hepatitis. The rapid increase in NFkappaB DNA binding after adenoviral infection of the liver could be very effectively inhibited by IkappaBalpha. Compared with the LacZ control virus, the IkappaBalpha-expressing adenoviral vector inhibits the increase of Fas (CD95) mRNA expression, in particular in the very early phase of the hepatitis. Reporter gene experiments in hepatoma cell lines with a Fas promoter-luciferase construct indicated that the repression of Fas (CD95) mRNA by IkappaBalpha was transcriptionally mediated. The functional relevance of the NFkappaB-dependent increase in Fas (CD95) transcription was assessed by caspase 3 assays and terminal dUTP nick-end labeling tests. Compared with the control, IkappaBalpha adenoviral infection resulted in reduced caspase 3 activity during the early phase of viral hepatitis and in a prevention of liver cell apoptosis 24 h after adenoviral administration. Therefore our study demonstrates a new pro-apoptotic function of NFkappaB in Fas (CD95)-mediated apoptosis of hepatocytes. Interestingly, NFkappaB mediates liver cell apoptosis upon viral infection even in a phase where tumor necrosis factor-alpha is already induced, as shown by the time curves of tumor necrosis factor-alpha serum levels. Therefore, the pro- or anti-apoptotic role of NFkappaB appears to be more determined by the nature of the death stimulus than by the origin of the tissue.

Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases.

Because previous findings have been inconsistent, we explored the association of serum concentrations of uric acid with all-cause and cardiovascular disease mortality and myocardial infarction prospectively. We used data from 1,044 men who are members of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) Augsburg cohort. The men, 45-64 years of age in 1984-1985, were followed through 1992. There were 90 deaths, 44 of which were related to cardiovascular disease; 60 men developed incident nonfatal or fatal myocardial infarction. We estimated hazard rate ratios from Cox proportional hazard models. Uric acid levels > or =373 micromol/liter (fourth quartile) vs < or =319 micromol/liter (first and second quartile) independently predicted all-cause mortality [hazard rate ratio = 2.8; 95% confidence interval (CI) = 1.6-5.0] after adjustment for alcohol, total cholesterol/high-density lipoprotein cholesterol ratio, hypertension, use of diuretic drugs, smoking, body mass index, and education. The adjusted risk of cardiovascular disease mortality was 2.2 (95% CI = 1.0-4.8), and that of myocardial infarction was 1.7 (95% CI = 0.8-3.3). Although residual confounding cannot be excluded, our results are among the few, in men, demonstrating a strong positive association of elevated serum uric acid with all-cause mortality. Future investigations may be able to evaluate whether uric acid contributes independently to the development of cardiovascular disease or is simply a component of the atherogenic metabolic condition known as the insulin resistance syndrome.

[Differential mortality by sex in the Baltic Basin]. / Diferencni umrtnost podle pohlavi v Pobalti.

PIP: "The article describes [the] demographic situation from the point of view of mortality and its differences by sex in Estonia, Lithuania, Latvia, Finland and Sweden. These countries were chosen...as the representatives of two mortality models, which occur in contemporary Europe: ¿western' and ¿eastern' models. Countries of [Eastern] Europe reach higher values of mortality probabilities in all age groups with corresponding attained lower medium life span at birth." The author also considers life expectancy at older ages, male excess mortality, and causes of death. (EXCERPT)^ieng

Isolation and characterization of methanophenazine and function of phenazines in membrane-bound electron transport of Methanosarcina mazei Gö1.

A hydrophobic, redox-active component with a molecular mass of 538 Da was isolated from lyophilized membranes of Methanosarcina mazei Gö1 by extraction with isooctane. After purification on a high-performance liquid chromatography column, the chemical structure was analyzed by mass spectroscopy and nuclear magnetic resonance studies. The component was called methanophenazine and represents a 2-hydroxyphenazine derivative which is connected via an ether bridge to a polyisoprenoid side chain. Since methanophenazine was almost insoluble in aqueous buffers, water-soluble phenazine derivatives were tested for their ability to interact with membrane-bound enzymes involved in electron transport and energy conservation. The purified F42OH2 dehydrogenase from M. mazei Gö1 showed highest activity with 2-hydroxyphenazine and 2-bromophenazine as electron acceptors when F420H2 was added. Phenazine-1-carboxylic acid and phenazine proved to be less effective. The Km values for 2-hydroxyphenazine and phenazine were 35 and 250 microM, respectively. 2-Hydroxyphenazine was also reduced by molecular hydrogen catalyzed by an F420-nonreactive hydrogenase which is present in washed membrane preparations. Furthermore, the membrane-bound heterodisulfide reductase was able to use reduced 2-hydroxyphenazine as an electron donor for the reduction of CoB-S-S-CoM. Considering all these results, it is reasonable to assume that methanophenazine plays an important role in vivo in membrane-bound electron transport of M. mazei Gö1.

Electronic information retrieval in nursing.

Electronic information networks are explored in terms of the political and economic impact of such concepts as the National Information Infrastructure. The relevancy of electronic information retrieval to nursing is discussed as it applies to current health-care information management. Electronic information sources applicable to nursing are described along with examples of how they may be utilized. Network functions, such as bulletin boards, Freenets and literature searches, are explained and the implications for evolution of health-care delivery are summarized.

Immune responsiveness in orthopedic surgery patients after transfusion of autologous or allogeneic blood.

BACKGROUND: The proposed immunosuppressive effect of blood transfusion is not yet understood, and the clinical relevance is a controversial topic of discussion. STUDY DESIGN AND METHODS: The effect of blood transfusions on the capacity of the host's immunocompetent cells to react to mitogenic stimulation was evaluated. Patients undergoing hip replacement surgery received either allogeneic (n = 13) or autologous (n = 14) buffy coat-depleted red cells or plasma. Patients' blood samples taken before and on Days 1 and 5 after surgery were stimulated in a whole-blood assay. The release of interleukin 2, soluble interleukin 2 receptor, interleukin 6, tumor necrosis factor alpha, interferon alpha 2, and interferon gamma was assessed by enzyme-linked immunosorbent assay. In addition, the white cell counts and frequencies of the lymphocyte subsets CD4+, CD8+, and natural killer cells were analyzed. RESULTS: For both groups, decreased levels of interleukin 2 and interferon-gamma were detected postoperatively, whereas the values for soluble interleukin 2 receptor and tumor necrosis factor alpha showed no significant change. Interferon alpha 2 was decreased on Day 1, but returned to normal by Day 5. Interleukin 6 increased during the time of observation. There were no significant differences between the two groups in cytokine production and lymphocyte-subset analysis that could be attributed to the transfusion of allogeneic blood. CONCLUSION: The transfusion of buffy coat-depleted red cells showed no immediate suppressive effect on the immune function of the host's peripheral blood cells.

How old is the genetic code? Statistical geometry of tRNA provides an answer.

The age of the molecular organization of life as expressed in the genetic code can be estimated from experimental data. Comparative sequence analysis of transfer RNA by the method of statistical geometry in sequence space suggests that about one-third of the present transfer RNA sequence divergence was present at the urkingdom level about the time when archaebacteria separated from eubacteria. It is concluded that the genetic code is not older than, but almost as old as our planet. While this result may not be unexpected, it was not clear until now that interpretable data exist that permit inferences about such early stages of life as the establishment of the genetic code.