Pharmacokinetics of gemcitabine and 2',2'-difluorodeoxyuridine in a patient with ascites

Gemcitabine (dFdC) is a prodrug that undergoes metabolism by cytidine deaminase to form an inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU). The pharmacokinetics of dFdC and dFdU have been studied; however, their disposition has never been evaluated in a patient with ascites. A patient with pancreatic cancer and malignant ascites was treated with dFdC 1,500 mg/m2 over 150 minutes weekly for 3 weeks, repeated every 4 weeks. Serial plasma and ascites samples were obtained on weeks 1 and 2 of cycle 2. High-pressure liquid chromatography was used to quantify dFdC and dFdU in plasma and ascites. The systemic dispositions of dFdC and dFdU were similar to those reported in patients without ascites. The concentration of dFdC in ascites approached 1 mg/ml. Ascitic fluid did not serve as a depot for dFdC, and the agent's concentration in ascites approached that at which its phosphorylation is saturated.     

Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents

In unrestrained rabbits with generalized epileptic seizures induced by systemic application of convulsant drugs, regional changes in blood-brain barrier (BBB) permeability to macromolecules were investigated using Evans Blue (EB) as indicator. BBB leakage due to seizures was present only in animals in which the mean arterial blood pressure rose about 50 mm Hg with the onset of convulsive motor activity. However, a blood pressure increase was not necessarily associated with the occurrence of BBB opening.Pentylenetetrazole-induced seizures resulted in bilateral EB leakage mainly in the hypothalamus, with exception of the mammillary bodies, and the preoptic area, and they were associated, in most cases, with an intensive staining of the cerebellum and also of the midbrain tegmentum. In contrast, seizures due to the GABA receptor blocker bicuculline brought about a penetration of the dye in the region of the pallidum, whereas the GABA synthesis inhibitor methoxypyridoxine produced BBB breakdown in the hippocampus. Methionine-sulfoximine convulsions resulted in a selective stain of the corpora mammillaria, and kainic acid induced a diffuse leakage in neocortical brain areas. As a rule, BBB breakdown was bilateral and confined to anatomically limited brain areas, suggesting that BBB integrity was not only disturbed by abrupt increases in the intraluminal pressure, but was also influenced from the brain tissue.The fluorescence microscopic observations revealed that the tracer penetrated into the neuropil through larger vessels. It had the tendency to accumulate in neurons. In case of the hippocampus, CA2 pyramidal cells revealed more intense uptake of EB than those of the adjacent fields.     

Diffusions-Tensor-Bildgebung (DTI) bei Patienten im apallischen Syndrom

Zusammenfassung Hintergrund und Ziel: Die Diagnostik des apallischen Syndroms beschränkte sich bisher auf die klinische Untersuchung und Zusatzuntersuchungen mittels EEG und evozierter Potentiale. Die Bildgebung spielte bei der Diagnosesicherung keine Rolle. Mit der Diffusions-Tensor-Bildgebung (DTI) sollte versucht werden, den Defektbereich im Hirnstamm zu visualisieren. Patienten und Methodik: Sieben Patienten im apallischen Syndrom nach Schädel-Hirn-Trauma (SHT) wurden in einem 1,5-Tesla-MRT-Gerät (INTERA, Fa. Philips) mit koronaren diffusionsgewichteten Spinechosequenzen untersucht. Es wurden sechs nicht kolineare Gradientenanregungen entlang den kortikospinalen Bahnsystemen verwendet. Die Untersuchung fand im Mittel 6 Monate nach SHT statt. Die Rekonstruktion der Faserbahnen erfolgte mit einem IDL-basierten (Interactive Data Language; Research System Inc.) Fiber-Tracking-Tool. Im Defektbereich wurden des weiteren der ADC (apparent diffusion coefficient) und die FA (fraktionelle Anisotropie) bestimmt und mit einer Kontrollgruppe von 20 gesunden Probanden verglichen. Ergebnisse: Die Faserdarstellung zeigte bei allen Patienten eine Unterbrechung der kortikospinalen Bahnsysteme auf Höhe des Mesencephalons. Die ADC-Werte im Defektbereich waren im Vergleich zur Kontrollgruppe normal bis leicht erhöht. Die FA-Werte waren um fast 40% reduziert als Ausdruck einer Schädigung auf zellulärer Ebene. Patienten mit Kontrollen nach 5 Monaten zeigten atrophische Hirnstammveränderungen in Pons und Mesencephalon als morphologisches Korrelat einer Schädigung auf zellulärer Ebene. Schlussfolgerung: Mit Hilfe der DTI ist es erstmals gelungen, die Unterbrechung kortikospinaler Bahnsysteme bei apallischen Patienten zu visualisieren. Die FA-Werte können als Marker der Schädigung auf zellulärer Ebene angesehen werden und dürften für den Verlauf und die Verlaufsbeurteilung dieser Patientengruppe von Bedeutung sein.     

Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men

Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.     

Contrasting patterns of Y chromosome and mtDNA variation in Africa: evidence for sex-biased demographic processes

To investigate associations between genetic, linguistic, and geographic variation in Africa, we type 50 Y chromosome SNPs in 1122 individuals from 40 populations representing African geographic and linguistic diversity. We compare these patterns of variation with those that emerge from a similar analysis of published mtDNA HVS1 sequences from 1918 individuals from 39 African populations. For the Y chromosome, Mantel tests reveal a strong partial correlation between genetic and linguistic distances (r=0.33, P=0.001) and no correlation between genetic and geographic distances (r=-0.08, P>0.10). In contrast, mtDNA variation is weakly correlated with both language (r=0.16, P=0.046) and geography (r=0.17, P=0.035). AMOVA indicates that the amount of paternal among-group variation is much higher when populations are grouped by linguistics (Phi(CT)=0.21) than by geography (Phi(CT)=0.06). Levels of maternal genetic among-group variation are low for both linguistics and geography (Phi(CT)=0.03 and 0.04, respectively). When Bantu speakers are removed from these analyses, the correlation with linguistic variation disappears for the Y chromosome and strengthens for mtDNA. These data suggest that patterns of differentiation and gene flow in Africa have differed for men and women in the recent evolutionary past. We infer that sex-biased rates of admixture and/or language borrowing between expanding Bantu farmers and local hunter-gatherers played an important role in influencing patterns of genetic variation during the spread of African agriculture in the last 4000 years.     

Functional MASP2 single nucleotide polymorphism plays no role in psoriasis

BACKGROUND: Psoriasis is a heritable disease and genome-wide scans have implicated several loci of susceptibility. The gene for MASP-2, a protease involved in complement activation, is located within one of these loci on chromosome 1p. OBJECTIVES: To assess whether partial or total MASP-2 deficiency is a risk factor for developing psoriasis. METHODS: We screened a cohort of patients affected by plaque psoriasis and their parents by restriction fragment length polymorphism analyses. RESULTS: We detected a single nucleotide polymorphism that leads to an amino acid exchange, which results in dissociation of MASP-2 from a carbohydrate recognition complex. CONCLUSIONS: We show that this mutant allele is not associated with psoriasis. There was no favoured transmission from parents to affected offspring. The calculated allele frequency in this psoriasis group (Scottish and English) was 0.0326, and in the unaffected group 0.0379.     

Using HIV surveillance data: recent experiences and avenues for the future

HIV surveillance systems provide information that is crucial to our understanding of epidemic dynamics among different populations in different settings. Surveillance data are also used for advocacy, to inform policies and programming, and for monitoring. Multiple data sources may be used and will expand in the future as service statistics from prevention and treatment programmes become available. Important and new priorities in HIV surveillance data use at the national and local levels can build on past experience with surveillance reports, national estimates, advocacy materials, and communications to the media. A new framework, integrated analysis of data from expanded surveillance systems and other sources, is proposed to inform improved programming. The approach allows making effective programme choices, based on the analysis of biological and behavioral data and the coverage of interventions in an integrated fashion. The comparison of surveillance data with financial data provides added insights in the adequacy of the response. These findings and experiences set a new agenda for technical and structural directions to improve data use in countries.     

Polyp size at CT colonography after electronic subtraction cleansing in an anthropomorphic colon phantom

PURPOSE: To evaluate the effect of various bowel contrast material concentrations and subtraction software on size measurements of well-defined polyp lesions in a colon phantom at CT colonography. MATERIALS AND METHODS: Repeated scanning and a precise reference standard required the use of a colon phantom in which 21 polyps were randomly distributed. Two readers who had each reviewed computed tomographic (CT) colonographic images from more than 100 cases evaluated polyp size on images obtained when the phantom was partially filled with varying concentrations of contrast material, scanned by using CT colonography, and subjected to electronic subtraction cleansing. The single largest dimension was recorded for each reader for a randomized series of polyps. These measurements were compared with a reference standard that was based on a combination of the manufacturer's polyp size specifications and the subsequent verification of these sizes by an independent consensus panel. Six weeks after initial observations, readers evaluated images of the phantom scanned without the presence of contrast material. Polyp size estimations for the two readers for each series were compared with the reference standard to obtain a mean absolute measurement error for each reader for each series. Data for each reader were compared by using a nonparametric Kruskal-Wallis analysis of variance test. A pair-wise comparison of the experimental and control series was then performed by using the Dunn post hoc test. RESULTS: Contrast material dilutions resulting in an average attenuation of less than 500 HU resulted in complete subtraction and the absence of streak artifacts. There was no statistically significant difference between the average measurement error for contrast attenuations between 300 and 500 HU when compared with that of control. Streak artifact was noticeable for the highest dilution (mean, 840 HU). No statistically significant differences were observed for series in which cleansing software was used in the absence of bowel contrast material. CONCLUSION: The combination of electronic cleansing and bowel contrast enhancement in the range of 300-500 HU results in no substantial change in readers' estimations of polyp size at CT colonography.     

Differential effects of prolonged isoflurane anesthesia on plasma,extracellular, and CSF glutamate,neuronal activity, <Superscript>125</Superscript>I-Mk801 NMDA receptor binding,and brain edema in traumatic brain-injured rats

Summary Background. Volatile anesthetics reduce neuronal excitation and cerebral metabolism but can also increase intracellular water accumulation in normal and injured brains. While attenuation of neuronal excitation and glutamate release are beneficial under pathological conditions, any increase in edema formation should be avoided. In the present study we investigated duration-dependent effects of the commonly used isoflurane/nitrous oxide (N₂O) anesthesia on EEG activity, specific NMDA receptor binding, extracellular, CSF, and plasma glutamate, and cerebral water content in brain-injured rats subjected to short (30 minutes) or prolonged (4 hours) anesthesia.Methods. Before controlled cortical impact injury (CCI), during prolonged (4–8 hours) or short anesthesia (7.5–8 hours after CCI), and before brain removal, changes in neuronal activity were determined by quantitative EEG analysis and glutamate was measured in arterial plasma. Brains were processed to determine acute and persisting changes in cerebral water content and ¹²⁵I-Mk801 NMDA receptor binding at 8 and 32 hours after CCI, i.e., immediately or 24 hours after short or prolonged anesthesia. During prolonged anesthesia glutamate was measured via microdialysis within the cortical contusion. CSF was sampled before brain removal.Findings. Prolonged isoflurane (1.8 vol%) anesthesia significantly increased EEG activity, plasma, cortical extracellular, and CSF glutamate, cortical and hippocampal ¹²⁵I-Mk801 NMDA receptor binding, and cerebral water content in brain-injured rats. These changes were partially reversible within 24 hours after prolonged anesthesia. At 24 hours, CSF glutamate was significantly reduced following long isoflurane anesthesia compared to rats previously subjected to short anesthesia despite an earlier significant increase.Conclusions. The partially reversible increases in EEG activity, ¹²⁵I-Mk801 NMDA receptor binding, cerebral water content, plasma and CSF glutamate appear important for physiological, pathophysiological, and pharmacological studies requiring prolonged anesthesia with isoflurane. Increases in extracellular cortical and plasma glutamate could contribute to acute aggravation of underlying tissue damage.