Heroin-Induces Differential Protein Expression by Normal Human Astrocytes (NHA)

Heroin use is postulated to act as a cofactor in the neuropathogenesis of human immunodeficiency virus (HIV-1) infection. Astrocytes, integral components of the CNS, are reported to be susceptible to HIV-1 infection. Upon activation, astrocytes release a number of immunoregulatory products or modulate the expression of a number of proteins that foster the immunopathogenesis of HIV-1 infection. However, the role of heroin on HIV-1 infectivity and the expression of the proteome of normal human astrocytes (NHA) have not been elucidated. We hypothesize that heroin modulates the expression of a number of proteins by NHA that foster the neuoropathogenesis of HIV-1 infection. We utilized LTR amplification and the p24 antigen assay to quantitate the effect of heroin on HIV-1 infectivity while difference gel electrophoresis (DIGE) combined with protein identification through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the effects of heroin on the proteomic profile of NHA. Results demonstrate that heroin potentiates HIV-1 replication in NHA. Furthermore, heroin significantly increased protein expression levels for protein kinase C (PKC), reticulocalbin 1 precursor, reticulocalbin 1, tyrosine 3-monooxgenase/tryptophan 5-monooxgenase activation protein, chloride intracellular channel 1, cathepsin D preproprotein, galectin 1 and myosin light chain alkali. Heroin also significantly decreased protein expression for proliferating cell nuclear antigen, proteasome beta 6 subunit, tropomyosin 3, laminin receptor 1, tubulin alpha 6, vimentin, EF hand domain family member D2, Tumor protein D54 (hD54), ATP synthase, H+ transporting, mitochondrial F1 complex and ribosomal protein S14. Identification of unique, heroin-induced proteins may help to develop novel markers for diagnostic, preventative and therapeutic targeting in heroin using subjects.     

Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression.

Cyclosporin A (CyA) toxicity is a common occurrence in pediatric organ transplant patients. We hypothesized that reduced mdr1a expression in newborn and developing mice would affect CyA accumulation within organs and/or toxicity. For functional studies, CyA was administered (5 mg kg(-1) i.p.) to 1-, 12-, and 19-day, and adult male and female mdr1a+/+ and mdr1a-/- mice. Peak blood CyA was lower in 1-, 12-, and 19-day-old (1000 ng ml(-1)) versus adult (1500 ng ml(-1)) mice but was similar in mdr1a+/+ and mdr1a-/- mice. Kidney mdr1a expression (measured by quantitative polymerase chain reaction) increased 2.5-fold in 19-day-old male and female mice and increased another 4-fold in adult females compared with adult males. Liver mdr1a expression increased 6-fold by day 12 compared with neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8- to 9-fold) and liver/blood (12- to 15-fold) CyA levels were highest on days 12 and 19 and were not dependent on maturational changes in mdr1a mRNA levels. Adults had higher brain expression of mdr1a mRNA (3-fold), a corresponding 5-fold increase in immunodetectable P-glycoprotein, and 80% lower brain accumulation of CyA compared with 1-day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adult mice. A similar pattern was observed for the brain accumulation of the mdr1a substrate 3H-digoxin. We conclude that the risk for central nervous system drug toxicity could be higher in neonates or young children as a consequence of underdeveloped P-glycoprotein.     

Cognitive symptoms and correlates of physical disability in individuals with multiple sclerosis.

There are inconsistencies in the literature regarding the prevalence of cognitive impairment among individuals with multiple sclerosis (MS). The purpose of this study was to examine perceived cognitive impairment in secondary progressive and relapsing-remitting multiple sclerosis (MS) and to examine the relationship between level of disability, age, and number of years with MS and self-reported cognitive symptoms. The sample consisted of 447 individuals (96 participants with secondary progressive MS and 351 participants with MS) who responded to mailed data collection instruments. The Performance Scales, a self-report measure of disability in eight domains of function, and a sociodemographic data sheet were analyzedfor this study. Of individuals with secondary progressive MS, 83% reported cognitive symptoms, while 82% of individuals with relapsing-remitting MS reported cognitive symptoms. Individuals with secondary progressive MS were reportedly experiencing a significantly greater level of total disability. A statistically significant, strong, positive relationship was found between cognitive symptoms and fatigue for those with secondary progressive MS and those with relapsing-remitting MS. Statistically significant, moderate, positive relationships were also found between cognitive symptoms in those with secondary progressive MS and those with relapsing-remitting MS, and sensory symptoms, vision, hand function, bladder/bowel symptoms, and spasticity. A statistically significant, weak, positive relationship was found between cognitive symptoms and mobility in individuals with relapsing-remitting MS. There was no relationship between cognitive symptoms and mobility in those with secondary progressive MS. Cognitive symptoms were not significantly related to age in those with secondary progressive MS or those with relapsing-remitting MS. In addition, cognitive symptoms were not significantly related to the number of years with MS in individuals with secondary progressive MS or those with relapsing-remitting MS. The perception of cognitive deficits in individuals with MS was found in this study to be even more prevalent than previously reported. Because cognitive deficits occur at all stages of MS, early identification and treatment is essential. Healthcare providers must aggressively screen for cognitive impairment and rehabilitate individuals with MS who exhibit symptoms.     

Cord insulin and C-peptide--distribution in an unselected population.

OBJECTIVE: To assess the distribution of cord blood insulin in an unselected population, and examine its relation to birthweight centiles. SETTING: District General Hospital in Nottinghamshire. SUBJECTS: 209 unselected singleton births. MEAN OUTCOME MEASURE: Cord blood insulin; cord blood C-peptide; birthweight centiles. RESULTS: Hyperinsulinaemic babies (greater than 97th centile for cord insulin) were found at all birthweight centiles. 15% of high birthweight babies were hyperinsulinaemic. For low birthweight babies, the distribution of cord insulin/C-peptide was skewed indicating a high number of low values. Hypoinsulinaemic babies were present up to the 50th centile for birthweight. CONCLUSIONS: Abnormalities of fetal insulinisation may be found in babies of all birthweights.     

Control of the preovulatory luteinizing hormone surge by gonadotropin-releasing hormone antagonists Prospects for clinical application.

The preovulatory LH surge of the primate menstrual cycle represents a number of positive influences, a major component of which is a direct action of estradiol on the anterior pituitary lobe. Whether the LH surge also requires a corresponding burst of GnRH release from the hypothalamus has been debated. After many years of investigation, there is now conclusive evidence that a midcycle GnRH surge does occur in the primate. This is supported by studies in women with normal ovulatory cycles that demonstrate that blockade of the GnRH receptor by potent GnRH antagonists administered within 1-2 days of the expected midcycle can delay the LH surge. The ability to prevent the positive feedback effects of estradiol by GnRH antagonists is being employed for the controlled induction of follicular development and ovulation in the treatment of infertility and in in vitro fertilization programs.     

Evaluation of hypothesis testing for comparing two populations using NONMEM analysis

In a simulation study of inference on population pharmacokinetic parameters, two methods of performing tests of hypotheses comparing two populations using NONMEM were evaluated. These two methods are the test based upon 95% confidence intervals and the likelihood ratio test. Data were simulated according to a monoexponential model and, in that context, power curves for each test were generated for (i)the ratio of mean clearance and (ii)the ratio of the population standard deviations of clearance. To generate the power curves, a range of these parameters was employed; other pharmacokinetic parameters were selected to reflect the variability typically present in a Phase II clinical trial. For tests comparing the means, the confidence interval tests had approximately the same power as the likelihood ratio tests and were consistently more faithful to the nominal level of significance. For comparison of the standard deviations, and when the volume of information available was relatively small, however, the likelihood ratio test was more able to detect differences between the two groups. These results were then compared to results on parameter estimation in order to gain insight into the question of power. As an example, the nonnormality of estimates of the ratio of standard deviations plays an important role in explaining the low power for the confidence interval tests. We conclude that, except for the situation of modeling standard deviations with only sparse information, NONMEM produces tests of significance that are effective at detecting clinically significant differences between two populations.Partial support from the Upjohn Company, NIH-BRSG SO RR 07066, and the Burroughs Wellcome Foundation.     

Malignant oncocytoma of the maxillary sinus— An ultrastructural study

A unique case of a malignant oncocytoma of the maxillary sinus is reviewed in detail. The ultrastructural findings are presented. The histologic and ultrastructural criteria that characterize onco-cytes and the clinicopathologic features of benign and malignant oncocytomas are discussed. This case represents the eleventh reported case that would truly qualify as a malignant oncocytoma of the paranasal sinuses.