Glutamate levels in the medial prefrontal cortex of healthy pregnant women compared to non-pregnant controls.

Very little is known about maternal cerebral changes during pregnancy. Since there is an increased risk for major depression during pregnancy and postpartum, it is important to understand the structural and neurochemical changes that occur in the brain during pregnancy. Using proton magnetic resonance spectroscopy (1H-MRS) (3 T field strength), glutamate (Glu) levels were measured in the medial prefrontal cortex (MPFC) of 21 healthy gravid subjects 2-3 weeks before their due date (6.74 ± 1.39), and in 14 non-pregnant healthy controls during their follicular phase (8.53 ± 1.55). Water quantified MPFC Glu levels were decreased in pregnant women (p < 0.01). We also observed a 13.9% decrease in percentage grey matter (%GM) (p < 0.01) in our MPFC voxel. As Glu is mostly found in GM, we repeated the statistical analysis after adjustment for %GM and found that the difference in Glu levels was no longer statistically significant when adjusted for %GM (p = 0.10). This investigation is the only systematic direct investigation of brain tissue composition and Glu levels in pregnant women. The main finding of this investigation is the decreased %GM in healthy pregnant women compared to non-pregnant women. These findings of decreased %GM in pregnancy may be responsible for the frequent complaints by pregnant women of cognitive difficulties also described as pregnesia.

Chronic myelogenous leukemia with acquired t(11;14)(q13;q32) CCND1-IGH: A case report and literature review.

Approximately 5-10% of chronic myeloid leukemia (CML) patients are found to have structural or numerical additional chromosomal abnormality (ACAs) in addition to the characteristic t(9;22)(q34;q11.2) BCR/ABL1 at the time of diagnosis. The prognostic significance of such additional chromosomal abnormalities has been controversial. Translocation t(11;14)(q13;q32) CCND1-IGH is typically associated with mantle cell lymphoma or a subset of plasma cell myeloma and is exceedingly rare in myeloid neoplasm. Here we report a unique case describing a patient found at diagnosis of chronic phase CML to have both the Philadelphia chromosome as well as t(11;14)-a rare cytogenetic combination. The patient was treated with imatinib with appropriate hematologic response but persistent disease by FISH and RT-PCR. She was switched to dasatinib and eventually achieved cytogenetic remission in both translocations, but still with persistent RT-PCR evidence of BCR-ABL1 fusion. As cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6 and is required for the cells to progress through the G1 phase of the cell cycle, overexpression of cyclin D1 will likely promote cells into cell cycle. This may further augment proliferation in addition to upregulated ABL1 kinase activity in the index case. It may also contribute to the resistance to imatinib, as imatinib only targets on BCR-ABL fusion. Therefore, the addition of t(11;14)(q13;q32) may have significant implication in patient management.

Total adiponectin does not predict cardiovascular events in middle-aged men in a prospective, long-term follow-up study.

AIM: Plasma total adiponectin is a marker of insulin resistance, but its role in predicting cardiovascular events is unclear. We aimed to investigate the role of adiponectin as a predictor of cardiovascular risk in middle-aged men, and to describe the association between adiponectin and glucose metabolism. METHODS: In this population-based prospective study of middle-aged men (n=3885), total adiponectin was analyzed. All individuals had undergone an oral glucose tolerance test (OGTTs), and the mean follow-up duration was 27 years. Regression analyses were carried out for indices of glucose metabolism in relation to quintiles (Q1-Q5) of total adiponectin levels. After stratification for smoking or not, the association between total adiponectin and the first incidence of fatal or non-fatal cardiovascular disease (CVD) was analyzed, using Cox's proportional-hazards regression model. RESULTS: In a separate multiple-regression analysis and after adjusting for possible confounders, the relationship between adiponectin levels and markers of glucose metabolism were found to be significant (P<0.05). However, adiponectin did not independently predict the risk of stroke, coronary events, or a combination of these two outcomes. CONCLUSION: Levels of total plasma adiponectin are not useful for predicting long-term cardiovascular events in middle-aged men, but are strongly associated with glucose metabolism and markers of insulin resistance.

Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo.

We evaluated the capacity of estradiol (E(2)) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E(2) caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E(2) tamoxifen. E(2) also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E(2) production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.

Stress-induced activation of nitric oxide-producing neurons in the rat brain.

Nitric oxide (NO) is a gaseous neurotransmitter that may mediate a decrease in sympathetic output to the periphery. This implication predicts that NO-producing neurons in the brain are activated in animals experiencing increased levels of sympathetic activity. To test this prediction, we subjected three groups of experimental rats to differing levels of environmental stimulation for 1 hour: minimal stimulation, moderate stimulation, and restraint stress. NO-producing neurons were histochemically visualized in sections of the brain, and activation of these neurons was assessed according to the neuronal expression of the immediate early gene c-fos. Constitutive activation of NO-producing neurons was found in the hypothalamus (paraventricular and supraoptic nuclei), dorsal raphe nuclei, and spinal nucleus of the trigeminal nerve of minimally stimulated rats. When animals were subjected to a novel environment (moderate stimulation), additional NO-producing neurons were activated in the medial septum, medial amygdala, hypothalamic nuclei (lateral, periventricular, and posterior), colliculi, nucleus raphe obscurus, medial vestibular nucleus, nucleus of the tractus solitarius, and several components of the ventrolateral medulla. Restraint stress caused the activation of NO-producing neurons in all of these areas, often in increasing numbers, and the activation of additional NO-producing neurons in the diagonal band of Broca, lateral and medial preoptic areas, basomedial and basolateral amygdalar nuclei, hypothalamic nuclei (dorsomedial, retrochiasmatic supraoptic, and circularis), nucleus raphe pontus, lateral parabrachial nucleus, and pontine nuclei. Expressed as a proportion of NO-producing neurons per section, the largest percentages (>20%) of double-stained neurons were found in the basolateral amygdala (46%), hypothalamic paraventricular nucleus (35%), corpora quadrigemina (estimated at 40%), dorsal raphe (45%), nuclei raphe pontus (33%) and obscurus (63%), lateral parabrachial nucleus (22%), medial vestibular nucleus (25%), lateral division of the nucleus paragigantocellularis (26%), and lateral reticular nucleus (35%). Evidence from other studies increasingly supports the concept that NO plays a generalized role in autonomic regulation by decreasing sympathetic output. Our results show that more NO-producing neurons were activated during stress than during minimal or moderate levels of stimulation. Together, the evidence suggests that NO is a neurochemical messenger that is utilized by individual autonomic neurons as the organism responds to increased levels of sympathetic activity.