ABSTRACT
Aims Although psychostimulant drug abuse carries with it several potential health risks, the chronic abuse of amphetamines carries the danger of permanent brain injury. The purpose of these ...experiments is to develop animal models to understand the long‐lasting influences of methamphetamine exposure on cerebral cortex and cognitive function.
Methods The approach taken is to administer a regimen of methamphetamine known to be neurotoxic to dopamine and serotonin nerve terminals in the rat, and to investigate the influences of that dosing regimen on (i) cortical neuron integrity and function using anatomical stains and (ii) novel object recognition memory.
Results In rodents, repeated administration of methamphetamine during a single day produces long‐lasting damage to striatal dopamine and forebrain serotonin terminals as well as degeneration of somatosensory cortical neurons. The degeneration of somatosensory cortical neurons may represent only the most visible form of long‐term deleterious effects on cerebral cortex, as exposure of rats to methamphetamine can reduce the immediate early gene responses of neurons in widespread cortical areas, even long after exposure to the drug. Together with the death and long‐lasting functional impairments of cortical neurons, rats exposed to methamphetamine have impaired cognitive function. When tested for object recognition memory, methamphetamine‐treated rats show deficiencies lasting for at least 3 weeks after drug exposure.
Conclusions Using a rodent model, these findings provide an avenue to study the cortical influences of methamphetamine and their cognitive sequelae.
Abstract
Background
Few data exist on cardiac fibrosis and inflammation in youth with HIV, particularly in sub-Saharan Africa.
Purpose
Our objective was to assess the association between HIV status ...and cardiovascular magnetic resonance (CMR) measures of subclinical cardiac fibrosis, inflammation, and function.
Methods
We performed CMR on a cross-section of youth in South Africa: youth with perinatally acquired HIV (YPHIV), youth with non-perinatally acquired HIV (YNPHIV), and HIV-seronegative youth (YHIV-). Subclinical fibrosis late gadolinium enhancement (LGE) mass and fraction, extracellular volume (ECV), inflammation native T1 and T2 mapping, and cardiac function (cine, strain, and strain rate) were assessed. CD4, viral load (VL), and fasting glucose, insulin for Homeostatic Model Assessment-Insulin Resistance (HOMA) and lipids were obtained. Unadjusted and adjusted quantile regression models were used to assess the association between HIV status and CMR outcomes. In sub-group analyses of youth with HIV, we additionally adjusted for HIV factors.
Results
Of 464 youth, 287 were YPHIV, 87 YNPHIV, and 90 YHIV-. YNPHIV were older with a higher proportion self-identifying as female than YPHIV and YHIV- (median age 20 vs 18 and 17 years; 85% vs 50% and 49%, respectively). YPHIV had lower body surface area (1.6 vs 1.7 and 1.7m2) and a higher proportion with prior TB disease (70% vs. 20% vs 8%) compared to YNPHIV and YHIV-. Tobacco use, HOMA, total cholesterol, and low-density lipoproteins were similar between groups. Among youth with HIV, YPHIV had a higher proportion with CD4<200 cells/mm3 (10% vs 4%) or VL>50 copies/mL (39% vs 13%) but lower proportion on integrase inhibitors (33% vs 84%). LGE mass (0.13 vs 0.12 vs 0.07g respectively) and fraction (0.3% vs 0.3% vs. 0.2% respectively) were higher in YPHIV and YNPHIV than YHIV-; native T1 was highest in YNPHIV compared to YPHIV and YHIV- (Table). In adjusted analyses, compared to YHIV-, median LGE mass was higher in YPHIV and YNPHIV (β:0.06, p=0.01 for YPHIV, β:0.05, p=0.03 for YNPHIV) and LGE% was higher in YPHIV (β:0.14, p=0.02); native T1 and ECV did not differ between groups in adjusted analyses. Among youth with HIV, CMR outcomes did not differ significantly for persons with perinatal vs non-perinatal HIV. Findings did not vary in analyses restricted to females.
Conclusion
In one of the largest studies of CMR among youth with HIV in sub-Saharan Africa, we found that despite their young age, YPHIV and YNPHIV appear to have higher subclinical cardiac fibrosis than YHIV- and healthy adults in South Africa. Youth with HIV may benefit from early screening and long-term monitoring for cardiovascular disease.TableFigure
Aims
Current guidelines do not explicitly recommend statin use in heart failure (HF). Relatively low numbers of atherothrombotic events among HF patients, in the context of their elevated competing ...risks for non‐atherothrombotic causes of death, may have prevented previous analyses of clinical trials from detecting a benefit for statins. We pooled data from two landmark trials of HF patients not on statin therapy randomized to rosuvastatin 10 mg daily vs. placebo, CORONA and GISSI‐HF, in order to improve our power to detect statistically significant differences in atherothrombotic events. We also accounted for competing risks from other causes of death.
Methods and results
We used competing risks analyses to evaluate atherothrombotic events in the context of death from other cardiovascular and non‐cardiovascular causes. We also performed traditional Cox survival analyses of the same data with the intention that these statistical approaches would be complementary. CORONA participants (n = 5011, median follow‐up 32.8 months) were older and sicker than GISSI‐HF participants (n = 4574, median follow‐up 46.9 months) by design. Rosuvastatin decreased risk for myocardial infarction (MI) among CORONA and GISSI‐HF participants with ischaemic aetiology of HF (hazard ratio 0.81, 95% confidence interval 0.66–0.99, P < 0.05). There were no significant differences between rosuvastatin and placebo in risks for stroke or death from other causes.
Conclusion
This individual‐level reanalysis of two landmark trials demonstrates a small but statistically significant decreased risk for MI among patients with ischaemic HF randomized to rosuvastatin vs. placebo. Rosuvastatin appears to be effective in preventing MI in ischaemic HF patients not already on statins.
To report a single-institution experience and analysis of the role of supplemental external beam radiotherapy (EBRT) with brachytherapy. EBRT is often used in addition to low-dose-rate brachytherapy ...in the treatment of prostate cancer, particularly for disease with adverse features.
A cohort of 189 consecutive patients, who had undergone low-dose-rate brachytherapy at our institution and who had demographic, disease, and treatment information and a minimum of 2 years of follow-up available, constituted the study group. This cohort was divided into two major groups according to the use of supplemental EBRT. Using two successive prostate-specific antigen rises greater than 1 ng/mL as the definition of failure, biochemical failure-free survival curves were constructed for the EBRT and no-EBRT groups and compared using the log-rank test. Additionally, a multivariate analysis of all major disease and treatment factors was performed using the Cox proportional hazards model.
Despite the greater proportion of adverse disease factors in the EBRT group, the 5-year biochemical failure-free survival rate in the EBRT versus no-EBRT groups was 80% versus 59%, respectively (
P <0.01). On multivariate analysis, the only factor reaching significance in predicting biochemical control was the use of EBRT (
P = 0.043).
In our study, the addition of EBRT conferred a significant biochemical control advantage when added to low-dose-rate brachytherapy. Because our study was not designed to permit detailed subset analyses, more work is needed to determine the precise brachytherapy population that will benefit from this use of supplemental EBRT.
The protein tyrosine phosphatase (PTPase) inhibitor pervanadate (vanadyl hydroperoxide) stimulated protein tyrosine phosphorylation 29-fold more than did thrombin in intact and saponin-permeabilized ...platelets. Increased tyrosine phosphorylation preceded, or was coincident with, a fall in PtdIns(4,5)P2 levels, production of PtdIns(3,4)P2 and phosphatidic acid, mobilization of intracellular Ca2+, stimulation of protein kinase C-dependent protein phosphorylation, secretion of dense and alpha-granules, increased actin polymerization, shape change and aggregation which required fibrinogen and was mediated by increased surface expression of GPIIb-IIIa. The tyrosine kinase inhibitor RG 50864 totally prevented induction of tyrosine phosphorylation by pervanadate, as well as all other responses measured; in contrast, the inactive structural analogue, tyrphostin #1, had no effect. Dense-granule secretion induced by pervanadate required protein kinase C activity; however, aggregation and alpha-granule secretion were independent of protein kinase C. In saponin-permeabilized platelets pervanadate and thrombin stimulated phospholipase C activity by GTP-independent and GTP-dependent mechanisms respectively. We conclude that PTPases are important regulators of signal transduction in platelets.
The evaluation of estrogens (estrone, estradiol, and their sulfates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of estrone sulfate (E
1 S) ...which is 15–25 times higher than in the plasma. Breast cancer tissue contains the enzymes necessary for local synthesis of estradiol and it was demonstrated that, despite the presence of the sulfatase and its messenger in hormone-dependent and hormone-independent breast cancer cells, this enzyme operates particularly in hormone-dependent cells. Different progestins: Nomegestrol acetate, Promegestone, progesterone, as well as Danazol, can block the conversion of E
1 S to E
2 very strongly in hormone-dependent breast cancer cells. The last step in the formation of estradiol is the conversion of E
1 to this estrogen by the action of 17β-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E
2) in hormone-dependent cells, but oxidative (E
2 → E
1) in hormone-independent cells. Using intact hormone-dependent cells it was observed that Nomegestrol acetate can block the conversion of E
1 to E
2. It is concluded, firstly, that in addition to ER mutants other factors are involved in the transformation of hormone-dependent breast cancer to hormone-independent, this concerns the enzymatic activity in the formation of E
2; it is suggested that stimulatory or repressive factor(s) involved in the enzyme activity are implicated as the cancer evolves to hormone-independence; secondly, different drugs can block the conversion of E
1 S to E
2. Clinical trials of these “anti-enzyme” substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.
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