Sexual dysfunction in advanced HIV disease.
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AIDS-Related Complex↗
Biomedical subjects
D Goldstein
Publications and source records attributed to D Goldstein.
Modification of the cortical impact model to produce axonal injury in the rat cerebral cortex.
Diffuse axonal injury (DAI) is a form of brain injury that is characterized by morphologic changes to axons throughout the brain and brainstem. Previous biomechanical studies have shown that primary axonal dysfunction, ranging from minor electrophysiologic disturbances to immediate axotomy, can be related to the rate and level of axonal deformation. Some existing rodent head injury models display varying degrees of axonal injury in the forebrain and brainstem, but the extent of axonal damage in the forebrain has been limited to the contused hemisphere. This study examined whether opening the dura mater over the contralateral hemisphere could direct mechanical deformation across the sagittal midline and produce levels of strain sufficient to cause a more widespread, bilateral forebrain axonal injury following cortical impact. Intracranial deformation patterns produced by this modified cortical impact technique were examined using surrogate skull-brain models. Modeling results revealed that the presence of a contralateral craniotomy significantly reduced surrogate tissue herniation through the foramen magnum, allowed surrogate tissue movement across the sagittal midline, and resulted in an appreciable increase in the shear strain in the contralateral cortex during the impact. To evaluate the injury pattern produced using this novel technique, rat brains were subjected to rigid indentor impact injury of their left somatosensory motor cortex (1.5 mm indentation, 4.5-4.9 m/sec velocity, and 22 msec dwell time) and examined after a 2-7 day survival period. Neurofilament immunohistochemistry revealed numerous axonal retraction balls in the subcortical white matter and overlying deep cortical layers in the right hemisphere beneath the contralateral craniotomy. Retraction balls were not seen at these positions in normals, sham controls, or animals that received cortical impact without contralateral craniotomy and dural opening. The results from these physical modeling and animal experiments indicate that opening of the contralateral dura mater permits translation of sufficient mechanical deformation across the midline to produce a more widespread pattern of axonal injury in the forebrain, a pattern that is distinct from those produced by existing fluid percussion and cortical impact techniques.
Animals↗
Rapid heterologous desensitization of muscarinic and thrombin receptor-mediated phospholipase D activation.
Activation of the M3 muscarinic receptor in 1321N1 human astrocytoma cells leads to increased phospholipase D (PLD)-catalyzed hydrolysis of phosphatidylcholine, which is maximal within 1 min of exposure to agonist. Studies examining the kinetics of phosphatidylethanol formation indicate that there is no further PLD activation beyond this time. Thrombin, a mitogen for quiescent 1321N1 cells, also activates PLD only transiently. The PLD response does not recover for up to 1 hr and cells that have been exposed to carbachol or thrombin do not respond to subsequent challenge with the heterologous agonist. In contrast to the desensitization observed with agonists, phorbol-12-myristate-13-acetate induces a sustained stimulation of PLD. In addition, cells pretreated with carbachol or thrombin show a normal response to phorbol-12-myristate-13-acetate, suggesting that the enzymatic activity of PLD is not compromised. Guanosine-5'-O-(3-thio)triphosphate activation of PLD in cell-free homogenates is also unaffected by prior treatment of the cells with agonist. Agonist-stimulated PLD activation in 1321N1 cells is mediated by protein kinase C (PKC). Thrombin and carbachol cause comparable changes in redistribution of both PKC-alpha and PKC-epsilon. The increase in membrane-associated PKC-alpha is transient and is reinitiated by addition of the heterologous agonist, whereas PKC-epsilon remains membrane associated for at least 60 min and is not further increased by addition of the heterologous agonist. We suggest that desensitization of PLD activation results from the down-regulation of an as yet undefined mediator required for agonist receptor coupling to PLD and that PKC-epsilon might participate in this down-regulation.
Astrocytoma↗
A requirement for Ras protein function in thrombin-stimulated mitogenesis in astrocytoma cells.
Thrombin stimulation of 1321N1 astrocytoma cells results in polyphosphoinositide hydrolysis, Ca2+ mobilization, AP-1-mediated transcriptional activation, and DNA replication. Thrombin stimulation also activates Ras as assessed by an increase in the proportion of Ras in a GTP bound state. We examined the functional requirement for endogenous Ras protein in mediating thrombin-induced responses. Microinjection of a dominant interfering mutant of H-Ras into 1321N1 cells inhibited DNA synthesis in response to thrombin as did microinjection of an inhibitory antibody to Ras. Stimulation of AP-1-mediated transcriptional activity was also reduced by the expression of interfering Ras mutants. However, neither the stimulation of polyphosphoinositide hydrolysis nor the mobilization of intracellular Ca2+ was dependent on endogenous Ras function. These observations indicate that thrombin stimulation of mitogenesis requires Ras protein function. Our data suggest that the G-protein-coupled thrombin receptor stimulates pathways, which in part are convergent with those stimulated by tyrosine kinase growth factor receptors.
Astrocytoma↗
Human recombinant interferon-beta SER and tamoxifen: growth suppressive effects for the human breast carcinoma MCF-7 grown in the athymic mouse.
Tamoxifen is the endocrine treatment of choice for breast cancer. However, resistance to therapy and patient relapse inevitably occurs. In future treatment schedules, interferons could be administered with tamoxifen, in an attempt to prevent disease recurrence. Human recombinant interferon-beta SER (rIFN-beta SER) inhibited the growth in vitro of the estrogen receptor (ER) positive breast cancer cell line MCF-7 and the ER negative breast cancer cell line MDA-MB-231. This inhibitory effect was achieved at doses of 50 U/ml and above. The growth of MCF-7 tumors in estradiol-stimulated athymic mice was greatly inhibited by high dose rIFN-beta SER treatment (10(6)U/day). In spite of the impressive antitumor effects upon MCF-7 tumors, rIFN-beta SER had no effect upon ER levels within the tumors at either the RNA or protein level, as measured by Northern blotting and ER-EIA respectively. High dose rIFN-beta SER (10(6)U/day) did result in some inhibition in the growth in vivo of the tamoxifen-stimulated MCF-7 variant MCF-7 TAM, although not to the same extent as was observed with the estradiol-stimulated MCF-7 tumors. rIFN-beta SER was also administered to animals bearing MCF-7 tumors and treated with estradiol and tamoxifen. In the animals undergoing high dose therapy (10(6)U/day), tumor growth was completely suppressed. Furthermore, tumor growth continued to be suppressed in those animals in which the rIFN-beta SER therapy was halted and the tamoxifen capsule removed. No tumors were observed in spite of the environment of estradiol stimulation. Thus, the combination of interferon and tamoxifen was totally growth suppressive for MCF-7 xenografts in nude mice.
Animals↗
Effects of cytokines on the pituitary-adrenal axis in cancer patients.
Cytokines, which include interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF), are immunoregulatory proteins produced by lymphocytes and inflammatory cells. Several cytokines, most noteworthy IFNs and ILs, stimulate glucocorticoid secretion. In this study, the effects of variable doses and repetitive administration of IFNs and TNF on secretion of pituitary hormones and cortisol were measured. Patients were given for a period of 15 days on alternating days injections of IFN-beta (IFN-beta ser), 90 or 450 x 10(6) IU, IFN-gamma, 0.1-100 x 10(6) IU, or TNF 125-275 micrograms/m2. Sixty to 120 min after IFN-beta ser injection median levels of cortisol, adrenocorticotropin (ACTH), prolactin (PRL), and growth hormone (GH) rose two-fold. Urinary free cortisol excretion increased significantly during the day following IFN-beta ser administration. IFN-gamma > or = 30 x 10(6) IU caused a comparable rise in plasma cortisol. TNF induced two- to four-fold increases in ACTH and cortisol. The fact that increased cortisol secretion was associated with a rise in the level of ACTH as well as PRL and GH suggests that the cytokines increased cortisol by stimulating the anterior pituitary. The hormonal response induced by cytokines was unrelated to their pyrogenic effect, undiminished with repetitive treatment, and not dose-dependent above a threshold level. These observations reinforce the concept of a physiologic link between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis.
Adrenocorticotropic Hormone↗
Investigations of inhibition and interference in younger and older adults.
Previous work (Hasher, Stoltzfus, Zacks, & Rypma, 1991) suggested the existence of adult age-related differences in the ability to suppress or inhibit irrelevant information. This investigation explored age differences in the time course of suppression. Experiments 1 and 2 showed that younger adults demonstrate the same level of suppression at 300 as they do at 1,700 ms after a selection response. Older adults consistently show no suppression. Experiments 2 and 3 also examined the relationship between suppression and the degree to which distractors interfere with concurrent selection. The absence of a reliable relationship--both within and across age groups--together with other findings in the literature, raise questions about the function of suppression as a mechanism of concurrent selection. Another function, one that aids in the establishment of a coherent thought stream, is proposed.
Adolescent↗
Administration of zidovudine during primary HIV-1 infection may be associated with a less vigorous immune response.
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CD8 Antigens↗
Induction of reversible growth retardation and growth hormone deficiency by blockade of norepinephrine synthesis in the rat.
Norepinephrine is a major regulator of the release of growth hormone. Diethyldithiocarbamate, a dopamine-beta-hydroxylase inhibitor, reduces norepinephrine synthesis and acutely inhibits growth hormone (GH) secretion. To investigate the long-term effects of dopamine-beta-hydroxylase blockade on growth, we administered diethyldithiocarbamate (0, 40, 100 or 400 mg/kg sc b.i.d.) to 21-day-old female rats for 10 days. Food intake, body weight, and tail length were measured twice a week. Plasma GH levels and hypothalamic dopamine and norepinephrine content were measured; messenger ribonucleic acids (mRNAs) for GH-releasing hormone and somatostatin were determined by quantitative in situ hybridization. Diethyldithiocarbamate administration decreased GH levels (p < 0.05) and retarded growth in a dose-dependent manner (p < 0.05), without altering food intake. Co-administration of GH partially reversed the growth retardation in diethyldithiocarbamate-treated animals (p < 0.05). Diethyldithiocarbamate treatment also increased the hypothalamic dopamine/norepinephrine ratio (1.13 vs 0.41 control, p < 0.05). Local levels of GH-releasing hormone and somatostatin mRNA were not altered by treatment. After discontinuation of diethyldithiocarbamate, growth rates returned to normal or transiently even to supranormal values. Norepinephrine synthesis blockade with diethyldithiocarbamate provides a model for reversible growth retardation, in which GH levels are decreased in the absence of decreased GH-releasing hormone mRNA. These results support a role for norepinephrine in the regulation of normal growth.
Animals↗
Cognitive risk factors and neuropsychological performance in HIV infection.
Almost all investigations examining the effects of early HIV infection on neuropsychological functioning in homosexual males have excluded subjects with cognitive risk factors such as recreational drug use and head injury. While insuring that results reflect the influence of the virus on cognition, this selection bias limits the ability to generalize findings. Comprehensive neuropsychological evaluations were compared between two groups of homosexual males with a variety of cognitive risk factors. Subjects were 132 HIV seropositive males (108 CDC class II & III and 24 CDC class IVA & IVC2) and 65 HIV seronegative controls. Recreational drug use in the six months prior to exam was found to interact with HIV infection and was associated with selective areas of cognitive decline and a significantly worse overall neuropsychological performance. Although significantly lower functioning in the domains of Verbal Memory and Attention and Speed of Information processing was noted for subjects with CDC class IVA and IVC2 compared to seropositives with CDC class II & III, overall neuropsychological performance was similar in these two groups. At this early stage of HIV infection, we did not find indication of association between neuropsychological performance and decreased immunological status. A history of head injury and recent recreational drug use emerged as primary cognitive risk factors associated with decreased neuropsychological performance. As 50% of our HIV seropositive subjects reported active recreational drug use, this cognitive risk factor in particular may contribute to the appearance of HIV-related cognitive deficits during early stages of HIV infection.
Cognition Disorders↗
Chiropractic adjustment to the cervical spine and the Arnold-Chiari malformation.
OBJECTIVE: To present two cases in which patients with Type I Arnold-Chiari malformation (ACM) were treated with adjustments to the cervical spine for conditions unrelated to the anomaly. CLINICAL FEATURES: The ACM is an anomaly of central nervous system development in which structures from the posterior fossa descend below the level of the foramen magnum. INTERVENTION AND OUTCOME: The patients reported were adjusted multiple times to the cervical spine. No ill effects or complications were noted related to the ACM. CONCLUSIONS: Asymptomatic Type I ACM is not necessarily a contraindication to skilled adjustments to the cervical spine.
Adult↗
Current status of clinical trials in HIV disease in Australia.
Clinical trials in Australia in diseases related to human immunodeficiency virus (HIV) have steadily expanded from the earliest national study of zidovudine to a range of trials either actively recruiting or being activated that cover a wide spectrum of primary viral, opportunistic infection and opportunistic malignant diseases. From its earliest establishment as the National Health and Medical Research Council special unit to its current role as the clinical trials unit of the National Centre in HIV, this central group has organized a coordinated approach to the conduct of clinical trials that has been a hallmark of Australia's response to the treatment of HIV-related disease. The original local trials were in the form of collaboration in multicenter trials, initiated by the pharmaceutical industry, with the participation of only a few major treatment centers. This has now evolved to a network of more than 20 hospital and ambulatory care centers and a group of enthusiastic and committed general practitioners who have contributed data to a number of major studies. These include the national zidovudine study that generated data on the use of surrogate markers such as CD4 and p24 antigen as predictors of survival, studies of the combination of acyclovir and zidovudine that have indicated a new direction in combination antiretroviral therapy, placebo-controlled studies of zidovudine in asymptomatic individuals that may alter the timing of introduction of therapy, and the MRC/INSERM study of didanosine in advanced disease that will give the clearest indication of its activity yet to be reported.(ABSTRACT TRUNCATED AT 250 WORDS)
Antiviral Agents↗
A phase II study of crisnatol mesylate in patients with ovarian carcinoma.
Fourteen patients with advanced ovarian cancer received a 72 hour infusion of a new DNA intercalator, crisnatol mesylate, administered intravenously. There was no evidence of antitumor efficacy. A syndrome of nausea and vomiting associated with vertigo, dizziness and ataxia was observed in nearly all patients. Two of the patients developed severe CNS toxicity manifested in one by a grand-mal seizure and in the other by peripheral neuropathy. Further explorations into the potential efficacy of crisnatol mesylate administered intraperitoneally are underway.
Aged↗
The psychological, social, and sexual consequences of gestational trophoblastic disease.
Seventy-six women diagnosed with gestational trophoblastic disease (GTD) from 1985 to 1989 completed questionnaires evaluating their status on mood disturbance, marital satisfaction, sexual functioning, psychosocial response to illness, and report of the most stressful event occurring within the past year. Multivariate analyses of variance (MANOVA) were conducted on dependent measures to examine differences between diagnostic groups (partial mole, complete mole, persistent disease), time from diagnosis (less than 1 year, 1-2 years, or 3-5 years from diagnosis), and follow-up status (active disease or remission). MANOVAs revealed no significant differences in the dependent measures based on time from diagnosis, type of medical treatment received, or type of molar disease. The metastatic disease group displayed significantly greater mood disturbance (F(1, 66) = 17.63, P less than 0.0001) and reported suffering clinically significant levels of distress and significantly greater levels of distress in response to the illness (F(33, 39) = 2.32, P less than 0.006). Women with active disease also reported significantly greater levels of distress in response to the illness (F(33, 39) = 2.76, P less than 0.001). Across disease types, GTD patients experience clinically significant levels of anxiety, anger, fatigue, confusion, and sexual problems and are significantly impacted by pregnancy concerns for protracted periods of time.
Adaptation, Psychological↗
Absence of biological effects of orally administered interferon-beta ser.
To assess biological effectiveness of interferon (IFN) administered orally, we measured serum IFN and several proteins and metabolites induced by IFN after oral administration of 2.5 mg or 7.5 mg of recombinant IFN-beta ser to 6 healthy volunteers. These IFN-induced metabolites, beta 2-microglobulin, and neopterin in serum, and 2',5'-oligoadenylate (2-5A) synthetase in peripheral blood mononuclear cells, are more sensitive to the presence of IFN than bioassay of IFN in serum. Up to 48 h after oral IFN was administered, serum IFN, beta 2-microglobulin, neopterin, or 2-5A synthetase were not generally increased compared to pretreatment levels, indicating that oral IFN had no significant biological effects.
Adenine Nucleotides↗
Psychosocial adjustment among intellectually gifted adolescents: the role of cognitive-developmental and experiential factors.
Levels of psychological adjustment were examined among 51 high achieving, intellectually gifted adolescents with a mean age of 14.1 years. These students were compared with older adolescents matched with them on cognitive maturity (n = 30), and with two groups matched with them on chronological age (CA). One of the CA-matched groups contained children not identified as gifted (n = 47), while the other consisted of athletically talented youngsters (n = 39). All participants belonged to upper middle class families. On multiple indices of adjustment, intellectually gifted adolescents were comparable to older adolescents with similar cognitive skills, but differed from both groups of age mates. Differences between the gifted and non-gifted CA-matched groups were stronger than were those between the gifted group and the athletes of the same age. The findings were interpreted in terms of cognitive-developmental and experiential influences on psychological adjustment. The study also revealed gender effects which appeared to be linked with conflicts faced by gifted females between issues of achievement and those of social acceptance.
Achievement↗
Intraperitoneal administration of interferon-gamma to carcinoma patients enhances expression of tumor-associated glycoprotein-72 and carcinoembryonic antigen on malignant ascites cells.
PURPOSE: The study was designed to determine whether in vivo interferon gamma (IFN-gamma) administration could enhance tumor antigen expression on the surface of human tumor cells. MATERIALS AND METHODS: Eight patients (six with ovarian and two with gastrointestinal tumors) with a diagnosis of adenocarcinoma with secondary malignant ascites were given weekly escalating doses of IFN-gamma (ie, 0.1 to 100 MU) intraperitoneally (IP) each week for 8 weeks. Tumor cells were isolated from the patients' ascites samples, which were collected three times per week: before and 24 and 48 hours post-IFN-gamma administration. The level of expression of tumor-associated glycoprotein-72 (TAG-72) and carcinoembryonic antigen (CEA) was measured using flow cytometry and immunocytochemistry. RESULTS: IFN-gamma administered IP dramatically increased TAG-72 (as measured by binding of anti-TAG-72 monoclonal antibodies [MoAbs] B72.3 and CC 49) and CEA (measured by MoAb COL-1) expression on the surface of the carcinoma cells. The ascites-derived tumor cells from seven of the eight patients constitutively expressed TAG-72, and the level of TAG-72 expression was increased by IFN-gamma in all seven patients, as evidenced by the enhanced binding of anti-TAG-72 MoAbs to the tumor-cell surface. In some cases, IFN-gamma treatment increased the percentage of MoAb B72.3-reactive tumor cells from 10% to greater than 90%, and those changes were further corroborated by similar increases in the MoAb staining intensity observed with immunoperoxidase analysis. In addition, ascites-derived tumor cells from two patients with gastrointestinal carcinoma also expressed enhanced CEA levels after IFN-gamma. The increased TAG-72 and CEA expression were observed at low IFN-gamma doses (ie, 0.1 to 1.0 MU), which were well tolerated by all patients. CONCLUSIONS: The ability of IFN-gamma given IP to increase TAG-72 and CEA expression on tumor cells in vivo provides additional argument for the use of the cytokine as an adjuvant to enhance MoAb binding to human carcinoma-cell populations.
Antigens, Neoplasm↗