Comparing survival and mortality in patients with late-onset and young-onset vascular dementia.

OBJECTIVES: Vascular dementia (VD) is one of the more common types of dementia. Much is known about VD in older adults in terms of survival and associated risk factors, but comparatively less is known about VD in a younger population. This study aimed to investigate survival in people with young-onset VD (YO-VD) compared to those with late-onset VD (LO-VD) and to investigate predictors of mortality. DESIGN: Retrospective file review from 1992 to 2014. SETTING: The inpatient unit of a tertiary neuropsychiatry service in Victoria, Australia. PARTICIPANTS: Inpatients with a diagnosis of VD. MEASUREMENTS AND METHODS: Mortality information was obtained from the Australian Institute of Health and Welfare. Clinical variables included age of onset, sex, vascular risk factors, structural neuroimaging, and Hachinksi scores. Statistical analyses used were Kaplan-Meier curves for median survival and Cox regression for predictors of mortality. RESULTS: Eighty-four participants were included with few clinical differences between the LO-VD and YO-VD groups. Sixty-eight (81%) had died. Median survival was 9.9 years (95% confidence interval 7.9, 11.7), with those with LO-VD having significantly shorter survival compared to those with YO-VD (6.1 years and 12.8 years, respectively) and proportionally more with LO-VD had died (94.6%) compared to those with YO-VD (67.5%), χ2(1) = 9.16, p = 0.002. The only significant predictor of mortality was increasing age (p = 0.001). CONCLUSION: While there were few clinical differences, and older age was the only factor associated with survival, further research into the effects of managing cardiovascular risk factors and their impact on survival are recommended.

Homoeolog expression bias and expression level dominance in allopolyploid cotton.

Allopolyploidy is an evolutionary and mechanistically intriguing process, in that it entails the reconciliation of two or more sets of diverged genomes and regulatory interactions. In this study, we explored gene expression patterns in interspecific hybrid F(1), and synthetic and natural allopolyploid cotton using RNA-Seq reads from leaf transcriptomes. We determined how the extent and direction of expression level dominance (total level of expression for both homoeologs) and homoeolog expression bias (relative contribution of homoeologs to the transcriptome) changed from hybridization through evolution at the polyploid level and following cotton domestication. Genome-wide expression level dominance was biased toward the A-genome in the diploid hybrid and natural allopolyploids, whereas the direction was reversed in the synthetic allopolyploid. This biased expression level dominance was mainly caused by up- or downregulation of the homoeolog from the 'non-dominant' parent. Extensive alterations in homoeolog expression bias and expression level dominance accompany the initial merger of two diverged diploid genomes, suggesting a combination of regulatory (cis or trans) and epigenetic interactions that may arise and propagate through the transcriptome network. The extent of homoeolog expression bias and expression level dominance increases over time, from genome merger through evolution at the polyploid level. Higher rates of transgressive and novel gene expression patterns as well as homoeolog silencing were observed in natural allopolyploids than in F(1) hybrid and synthetic allopolyploid cottons. These observations suggest that natural selection reconciles the regulatory mismatches caused by initial genomic merger, while new gene expression conditions are generated for evaluation by selection.

Lymphosarcoma in a sea otter (Enhydra lutris).

Lymphoblastic lymphosarcoma involving the mesenteric lymph node and thymus was discovered in a 4 yr old male sea otter (Enhydra lutris). Diagnosis was based on gross and light microscopic studies. The cause of this neoplasm was not determined. This is the first case of lymphosarcoma reported in sea otters.

Castration rapidly decreases hypothalamic gamma-aminobutyric acidergic neuronal activity in both male and female rats.

The postcastration LH response is greater and somewhat more rapid in male than female rats. We have previously demonstrated that hypothalamic gamma-aminobutyric acid (GABA)ergic neuronal activity decreases following gonadectomy in male rats. To investigate whether these same hypothalamic GABA neurons decrease their activity postcastration in female rats, and whether more rapid and or greater postcastration decreases occur in male rats, we determined the timing and magnitude of the postcastration decreases in GABA turnover which are associated with the sexually dimorphic postcastration LH response. Adult male and 4-day cycling female rats were castrated between 0800 and 1000 h (females ovariectomized on diestrus day 1). Serum LH levels increased significantly by 12 h postcastration in both males and females with the magnitude of the increases being 6.2-fold in males and 2.8-fold in females. GABA turnover was determined in 16 microdissected brain structures by the GABA transaminase inhibition method at 0 h (sham-operated controls), 6 h, 12 h and 1, 2, 4 and 6 days postcastration. In male rats, in the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis [DBB(ovlt)], the rate of GABA turnover decreased significantly already by 6 h postcastration compared with the 0 h controls, and remained suppressed through 6 days. This rapid down regulation of DBB(ovlt) GABAergic neurons also occurred in female rats, however, the duration of the decrease was not as prolonged as in male rats. Similar changes occurred in the tuberoinfundibular GABAergic (TIGA) neurons projecting to the median eminence in both males and females. Down regulation of these GABAergic neurons precedes or is coincident with increased postcastration LH secretion in both sexes, and the duration of the decreases is consistent with the less robust postcastration LH response in female rats. In addition, the rate of GABA turnover decreased after castration in the interstitial (bed) nucleus of the stria terminalis, ventral aspect (INSTv), the medial preoptic nucleus, dorsomedial aspect (MPNdm) and the ventromedial nucleus, ventrolateral aspect (VMNvl) in male rats, and in the INSTv and VMNvl of female rats, while there was no effect of castration in other hypothalamic regions or control structures. The result in the female VMNvl is consistent with reports that GABA facilitates lordosis behavior in this hypothalamic structure. These findings are consistent with the hypothesis that discrete hypothalamic populations of sex steroid-sensitive GABAergic neurons mediate the postcastration LH responses in both male and female rats, and may underlie other sexually dimorphic adult phenotypes such as sex behavior.

Sex differences in GABA turnover and glutamic acid decarboxylase (GAD(65) and GAD(67)) mRNA in the rat hypothalamus.

GABAergic neurons are estimated to make up more than half of the neuronal population of the hypothalamus and they likely account for some of the structural and functional sexual dimorphisms observed in the mammalian brain. We previously reported sex differences in the rate of GABA turnover in discrete hypothalamic structures of adult rats. In the present study, we extended our search for sex differences in GABA turnover to additional structures, and further determined whether these differences were associated with differences in GAD(65) and or GAD(67) mRNA levels. Utilizing the GABA transaminase inhibition method, we determined GABA turnover in 14 microdissected brain regions. The rate of GABA turnover was about 2-fold greater in male than in diestrous day one (D(1)) female rats in the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis [DBB(ovlt)], anteroventral periventricular nucleus (AVPv), median eminence (ME), and dorsomedial portion of the ventromedial nucleus (VMNdm). A sex difference also was noted in the DBB(ovlt) for GAD(65) mRNA determined by microlysate RNase protection assay. Here, GAD(65) levels were almost 2-fold greater in male rats, which suggests that differences in the activity of this GAD enzyme isoform contributes to the difference in turnover in this area. Additionally, in the dorsomedial nucleus (DMN), the GAD(65) mRNA level was significantly higher in female rats, and in the medial amygdaloid nucleus (Am), GAD(67) mRNA was higher in male rats. These data reveal striking sexual dimorphisms in the rate of GABA turnover and in GAD mRNA levels in specific populations of hypothalamic GABAergic neurons. The functional relationships between these GABAergic neurons and sexually dimorphic phenotypes associated with these structures, such as gonadotropin secretion, reproductive behaviors, seizure threshold and others, warrant further investigation.

Reconstituted basement membrane reduces proliferation and increases prolactin expression of GH3 cells.

This study investigated the effects of reconstituted basement membrane Matrigel on the proliferation and prolactin expression of GH3 cells in culture for 6 days. When cells were cultured on Matrigel, the initial attachment was increased but the cell number was not changed with time whereas rapid increase in cell number was observed in cultures on plastic. Bromodeoxyuridine (BrdU)-labeling showed that BrdU incorporation ratio of GH3 cells cultured on Matrigel was about one half of that observed with cells cultured on plastic (9.7+/-0.7% vs. 18.7+/-1.2%). Immunocytochemistry revealed that the ratio of the prolactin-immunoreactive GH3 cells was about 3.6 times (58.4+/-2.9% on Matrigel vs. 16.2+/-1.4% on plastic), which was compatible with the results of Western blot analysis. In situ hybridization demonstrated that prolactin mRNA-positive cells were identified more frequently when cells were cultured on Matrigel compared to cultures on plastic. These findings indicate that Matrigel is a proper culture substrate for the long-term culture of GH3 pituitary cells due to the inhibition of overgrowth and promotion of prolactin expression.

Tumor necrosis factor-alpha mediates endotoxin induced suppression of gonadotropin-releasing hormone pulse generator activity in the rat.

Bacterial endotoxin lipopolysaccharide (LPS) is known to suppress gonadotropin secretion and this effect is assumed to be mediated by cytokines. In the present study, we examined whether LPS affected hypothalamic electrical activity associated with LH pulses, and whether tumor necrosis factor-alpha (TNF-alpha), a major cytokine induced by LPS, was involved in this process. Ovariectomized rats were fitted with chronically implanted electrode arrays in the mediobasal hypothalamus, and multiunit activity (MUA) was recorded under conscious, unrestrained conditions. Blood samples were withdrawn every 6 min through an indwelling atrial catheter or determining serum LH concentrations. Intravenous (i.v.) injection of LPS (1 microgram) suppressed characteristic increases (volleys) in MUA associated with LH pulses throughout the experimental period up to 5 h. This suppressive effect of LPS on MUA volleys was significantly attenuated by simultaneous intracerebroventricular (icv) injection of the antibody (50 ng) to TNF-alpha through an indwelling cannula in the lateral ventricle. These changes in MUA were faithfully reflected in the LH secretory pattern. Further, either i.v. (0.4-2 micrograms) or i.c.v. (20-250 ng) injection of TNF-alpha suppressed the frequency of MUA volleys and associated LH pulses in a dose-dependent manner. These results suggest that LPS leads to the suppression of gonadotropin-releasing hormone pulse generator activity through a mechanism involving TNF-alpha.