Selective alterations in the patterns of newly synthesized proteins by acetaminophen and its dimethylated analogues in primary cultures of mouse hepatocytes.

Alterations in protein synthesis following exposure to and recovery from hepatotoxic doses of acetaminophen (APAP) and its analogues, 3,5-dimethyl acetaminophen (3,5-DMA) and 2,6-dimethyl acetaminophen (2,6-DMA), were investigated in primary cultures of mouse hepatocytes. The rates of protein synthesis decreased within 4 hr after administration of 10 mM APAP and occurred after significant depletion of intracellular glutathione and covalent binding of APAP to proteins, but preceded the leakage of lactate dehydrogenase into the media. The inhibition of protein synthesis was reversible only if APAP exposure did not exceed 8 hr. Electrophoretic analysis of 35S-labeled proteins by one-dimensional SDS-PAGE revealed two consistent alterations in the patterns of newly synthesized proteins. First was a progressive diminution in the de novo synthesis of a protein migrating at approximately 58 kDa (p58). This was observed with APAP (10 mM) and 3,5-DMA (5 mM) but not with 2,6-DMA (10 mM). If exposure to APAP exceeded 8 hr, the biosynthesis of this protein was not only further decreased but was also no longer detectable during the recovery period. The second major alteration was an increase in the relative rate of biosynthesis of a 32-kDa protein (p32) following exposure and recovery from APAP and 3,5-DMA but not 2,6-DMA. Exposure to heme or arsenite induced the synthesis of a protein of similar molecular weight but did not result in the inhibition of p58 biosynthesis. The fact that the reactive metabolites of both APAP and 3,5-DMA, but not 2,6-DMA, possess oxidative properties suggests that the alterations in the synthesis of p32 and p58 may be related to an oxidative component induced by these compounds.     

Nonimmune hydrops caused by massive fetomaternal hemorrhage and treated by intravascular transfusion.

Fetal hydrops at 26 weeks' gestation was diagnosed following a massive fetomaternal hemorrhage. Fetal intravascular transfusion was performed, and the hydrops completely resolved within 72 hours. The fetus required one more transfusion at 27 weeks' gestation. A subsequent percutaneous umbilical blood sampling at 30 weeks' gestation demonstrated a normal fetal hematocrit. A vaginal delivery at term resulted in a normal newborn. Massive fetomaternal hemorrhage is a well-known cause of nonimmune hydrops and may occur spontaneously in an otherwise normal pregnancy. Confirmation by percutaneous umbilical blood sampling and treatment by intravascular transfusion is recommended when massive fetomaternal hemorrhage causes hydrops in preterm gestations.     

Fertilization and early embrology: Monozygotic twinning in the human is associated with the zona pellucida architecture

Six cases of identical twin pregnancies which occurred in 2163cycles of in-vitro fertilization during a 3 year period arereported. Monozygosity was confirmed when the number of fetusesexceeded the number of embryos replaced (n = 4) or when twoconcepti were observed in a single amniotic sac (n = 2). Eachof the reported pregnancies resulted from replacement of embryoseither with naturally thin zonae pellucida or embryos whosezonae had been breached during micromanipulation for assistedfertilization (subzonal sperminsertion) or assisted hatching.That such cases exclusively gave rise to monozygosity suggestsa link between the physical state of the zona pellucida, hatching,and generation of identical twins.     

BIBLIOTHERAPY

Bibliotherapy is the use of literature to help heal. It can be an effective intervention for nurse-midwives to use with clients. Presented is a discussion of how to do bibliotherapy and an annotated bibliography of resources.     

C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties.

We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.     

Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder.

BACKGROUND: Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS: Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS: Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS: The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.     

q-Space diffusion of myelin-deficient spinal cords.

The apparent water diffusion anisotropy in white matter (WM) of excised spinal cords of myelin-deficient (md) rats and their age-matched controls was studied by high-b-value q-space diffusion MRS and MRI at different diffusion times. Non-monoexponential signal decay was observed at long diffusion times. The mean displacements in the md spinal cords were found to be higher than those of the controls. The apparent anisotropy (AA) of the fast-diffusing component was found to decrease more dramatically with the increase in diffusion time for the md spinal cords as compared with controls, whereas the AA of the slow-diffusing component in the controls was found to increase with the increase in diffusion time while that of the md cords decreased with the increase in diffusion time. When diffusion MRI was performed, similar diffusion anisotropy was extracted for the md and control spinal cords at diffusion times of 22 and 50 ms. Only at a diffusion time of about 200 ms was a significant difference obtained in the AA of the two groups. This originates from the much smaller increase in the mean displacement perpendicular to the fiber direction in the control group vs. the md group when the diffusion time was increased.     

Verbal Working Memory and Atherosclerosis in Patients with Cardiovascular Disease: An fMRI study

BACKGROUND AND PURPOSE: Intimal-medial thickening (IMT) of the carotid wall is an accepted peripheral marker of atherosclerosis. It is associated with increased risk for myocardial infarction and stroke, and lower attention-executive-psychomotor functioning. The purpose of this study was to examine the relationship between IMT and brain activity during a verbal working memory (VWM) task in patients with cardiovascular disease (CVD). METHODS: Thirteen CVD patients underwent functional magnetic resonance imaging (fMRI) during a 2-Back VWM task, and B-mode ultrasound of the carotid arteries. IMT was calculated using an automated algorithm based on a validated edge-detection technique. The relationship between IMT and 2-Back-related brain activity was modeled using partial correlations controlling for age and small vessel disease as measured by white matter signal hyperintensities on MRI (WMH). RESULTS: Higher IMT was associated with lower 2-Back-related signal intensity and in the right middle frontal gyrus, independent of age and WMH. CONCLUSIONS: IMT may be one mechanism contributing to brain dysfunction in CVD. The blood oxygenation level-dependent (BOLD) contrast appears to be highly sensitive to peripheral vascular health as measured by IMT. Future studies should examine the sensitivity and specificity of the BOLD response for predicting cognitive decline in CVD.     

Impact of early lifetime trauma in later life: depression among Holocaust survivors 60 years after the liberation of Auschwitz.

RATIONALE: Holocaust survivors, who experienced trauma 60 years ago, provide an opportunity to explore the impact of early lifetime trauma in later life and, in particular, the interplay of depression and posttraumatic stress disorder (PTSD). In this study, the authors contrast depressed Holocaust survivors (HD), nondepressed Holocaust survivors (HND), and older depressed persons (CD). METHODS: The sample consisted of 36 consecutive Holocaust survivors (mean age: 79 years) treated in a primary care practice, among whom 20 (56%) were diagnosed as having a major depressive disorder and 16 as nondepressed; 18 depressed non-Holocaust Jewish primary care patients served as controls (mean age: 84 years). The authors examined nine clinical and social variables. The Kruskal-Wallis, Mann-Whitney U, and chi(2) tests were used to contrast the groups. The authors used a conservative significance level of .01. RESULTS: In contrast to the CD group, the HD group was significantly older, more likely to report PTSD and guilt symptoms, to have higher Beck Anxiety Inventory (BAI) and Brief Psychiatric Rating Scale (BPRS) scores, and to have more impaired social functioning. In contrast to the HND group, the HD group was significantly more likely to report PTSD and guilt feelings, to have higher Hamilton Depression Scale (HAM-D), BAI, and BPRS scores, and to have more impaired social functioning. In contrast to the CD group, the HND group was significantly more likely to have PTSD symptoms and to have lower HAM-D and BPRS scores. CONCLUSIONS: The prevalence of depression and PTSD symptoms were very high among survivors. Depressed survivors had significantly worse psychologic and social functioning than depressed controls. Depressed survivors had more PTSD symptoms than nondepressed survivors, although it is unclear as to the causal direction of the relationship between depression and PTSD.