Cannabidiol and Δ8-Tetrahydrocannabinol: Cannabinoids of Rising Interest and Concern.

Although much is known about Δ9-tetrahydrocannabinol and its inactive open ring isomer, cannabidiol, far less is known about the effects, metabolism, and pharmacodynamics of Δ9-tetrahydrocannabinol's double-bond isomer, Δ8-tetrahydrocannabinol. With the passage of the so-called United States "Farm Bill," which was made law in order to allow legal hemp cultivation in the United States, more needs to be known about the effects of Δ8-tetrahydrocannabinol, a double-bond isomer of Δ9-tetrahydrocannabinol, and cannabidiol (CBD), which is an open-ring isomer of Δ8-tetrahydrocannabinol. It is the aim of the review to summarize current knowledge of Δ8-tetrahydrocannabinol and CBD, including the pharmacodynamics and pharmacokinetics of CBD. Also, plant genetics, the effect of cannabinoids on the current topic of viral entry into mammalian cells, and the current practice of vaping, dabbing, and dripping are covered.

Opportunities in magnetic materials.

Recent discoveries of new magnetic materials may greatly improve the performance of devices containing such materials and may lead to entirely new applications. For example, boron-based temary compounds for permanent magnets make new compact motor designs practical; amorphous transformer materials show greatly reduced losses at high frequencies; and thin magnetic alloy films offer increased data storage densities. The major technical issues associated with the new magnetic materials are identified.

Suppression of the temperature-sensitive phenotype of a mutant of reovirus type 3.

A revertant of a reovirus group A temperature-sensitive mutant was crossed with wild type. More than 50 percent of the progeny were temperature sensitive. In all of the temperature-sensitive progeny examined by recombination tests, the temperature-sensitive lesion was in group A. The results indicate that the revertant was phenotypically suppressed.

Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.

The relation between viremia and clinical outcome in individuals infected with human immunodeficiency virus-type 1 (HIV-1) has important implications for therapeutic research and clinical care. HIV-1 RNA in plasma was quantified with a branched-DNA signal amplification assay as a measure of viral load in a cohort of 180 seropositive men studied for more than 10 years. The risk of acquired immunodeficiency syndrome (AIDS) and death in study subjects, including those with normal numbers of CD4+ T cells, was directly related to plasma viral load at study entry. Plasma viral load was a better predictor of progression to AIDS and death than was the number of CD4+ T cells.

Human neuroelectric patterns predict performance accuracy.

In seven right-handed adults, the brain electrical patterns before accurate performance differed from the patterns before inaccurate performance. Activity overlying the left frontal cortex and the motor and parietal cortices contralateral to the performing hand preceded accurate left- or right-hand performance. Additional strong activity overlying midline motor and premotor cortices preceded left-hand performance. These measurements suggest that brief, spatially distributed neural activity patterns, or "preparatory sets," in distinct cognitive, somesthetic-motor, and integrative motor areas of the human brain may be essential precursors of accurate visuomotor performance.

Instability and poor recovery of cannabinoids in urine, oral fluid, and hair.

Cannabinoids including, but not limited to Δ9-tetrahydrocannabinol, 11-hydroxytetrahydrocannabinol, and (-)-11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid are known to toxicologists and synthetic chemists as difficult compounds because they are subject to numerous degradative pathways. It is the purpose of this short review article to discuss common pathways that result in the disappearance of cannabinoids - such as conjugate formation, adsorption to surfaces, chemical reactions, microbial action, thermal decomposition, chemical bonding, photosensitivity, sample handling, analytical methodology, and micelle trapping - and to point out possible ways to avoid such degradation.

Developmental pattern of a serum binding protein for multiplication stimulating activity in the rat.

The concentration of multiplication stimulating activity (MSA), an insulinlike growth factor (IGF), is high in fetal rat serum. We now report that MSA is exclusively associated wth an albumin-size binding protein in fetal rat serum; the growth hormone-dependent, gamma globulin-size binding protein, which predominates in the older animal, is absent from fetal rat serum. When (125)I-MSA was incubated with fetal rat serum and then gel filtered on Sephadex G-200, specific radioactivity eluted in the void volume (peak I) and the albumin region (peak III); by contrast, specific radioactivity eluted mainly in the gamma globulin region (peak II) in adult rat serum. Pools of the Sephadex G-200 fractions were chromatographed on Sephadex G-50, in 1 M acetic acid, to separate the binding protein from IGF activity. Analysis of IGF activity by chick embryo fibroblast bioassay, competitive protein binding assay, and MSA by radioimmunoassay revealed that all the IGF activity and MSA in fetal rat serum resided in peak III. Measurement of MSA binding capacity of the stripped binding protein by Scatchard analysis demonstrated that the majority of binding capacity also was found in peak III in fetal rat serum; most of MSA binding capacity was in peak II in adult rat serum. In fetal rat sera, in addition to the peak III binding protein, which is the major carrier of endogenous MSA, there is a component in peak I capable of specifically binding (125)I-MSA. This component elutes as a single species from a Sepharose-6B column. As MSA associated with peak III gradually declined in early neonatal life, peak II-associated IGF activity measured by chick embryo fibroblast bioassay showed a rise of activity with a peak at 5 d of neonatal life, a nadir at 20 d, with an increase again to attain adult levels. These studies demonstrate that the MSA binding protein in the fetus is different from the growth hormone-dependent binding protein in adult life.

Drugs in hair. Part I. Metabolisms of major drug classes.

Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered.

Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression.

Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1alpha (IL-1alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1alpha by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1alpha. The short-term expression of IL-1alpha persists in the malignant T cells for a few days (approximately 3-6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1alpha in a short-term manner, manifested reduced tumorigenicity: approximately 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1alpha, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1alpha in activated tumor cells may allow its improved application in the treatment of malignancies.

Generation and analysis of zebrafish melanoma models.

The rapid emergence of the zebrafish as a cancer model has been aided by advances in genetic, chemical, and imaging technologies. Melanoma in particular highlights both the power and challenges associated with cancer modeling in zebrafish. This chapter focuses on the lessons that have emerged from the melanoma models as paradigmatic of what will apply to nearly all cancer models in the zebrafish system. We specifically focus on methodologies related to germline and mosaic transgenic melanoma generation, and how these can be used to deeply interrogate additional cooperating oncogenes or tumor suppressors. These transgenic tumors can in turn be used to generate zebrafish-specific, stable melanoma cell lines which can be fluorescently labeled, modified by cDNA/CRISPR techniques, and used for detailed in vivo imaging of cancer progression in real time. These zebrafish melanoma models are beginning to elucidate both cell intrinsic and microenvironmental factors in melanoma that have broader implications for human disease. We envision that nearly all of the techniques described here can be applied to other zebrafish cancer models, and likely expanded beyond what we describe here.

Further characterization of growth hormone-dependent somatomedin-binding proteins in rat serum and demonstration of somatomedin-binding proteins produced by rat liver cells in culture.

The somatomedin-like peptide multiplication-stimulating activity (MSA) binds specifically to rat serum. The pattern of MSA binding is GH dependent. Specific binding of [125I]iodo-MSA in normal rat serum is primarily in the gamma-globulin region (peak II) on Sephadex G-200, while MSA binding in hypophysectomized (hypox) rat serum is near the albumin region (peak III). This study further characterizes the peak II and peak III somatomedin-binding proteins produced by rat liver cells in culture. [125I]Iodo-MSA binding to normal rat serum is abolished by trypsin pretreatment of rat serum, suggesting that MSA binds to protein components of serum. The only detectable somatomedin activity (measured by [3H]thymidine incorporation into chick embryo fibroblast DNA) in fractions of normal rat serum chromatographed on Sephadex G-200 coincides with peak II binding of [125I]iodo-MSA. In hypox rat serum, the majority of detectable somatomedin activity is in the peak III region. There is complete displacement of the human somatomedins [125I]iodoinsulin-like growth factor I and II and [125I]iodosomatomedin A from the rat serum-binding sites by unlabeled MSA, suggesting that the human somatomedins bind to the same sites as MSA. Treatment of normal rat serum with 1 M acetic acid dissociates somatomedin activity from its binding proteins and converts somatomedin-binding proteins from peak II to peak III. Scatchard analysis of competitive binding data using [125I]iodo-MSA yields a binding affinity that is not appreciably different for either normal or hypox rat sera. The binding capacity of normal or acid-treated normal rat serum for MSA is significantly greater than that for comparably treated hypox rat sera. Although the site of synthesis of somatomedin-binding proteins in vivo is unknown, specific somatomedin-binding proteins are synthesized by two rat liver cell lines in culture. These rat liver cell somatomedin-binding proteins have the same molecular size and the same binding affinity for MSA as the peak III somatomedin-binding protein(s) in rat serum.

Differential contribution of endothelial function to vascular reactivity in conduit and resistance arteries from deoxycorticosterone-salt hypertensive rats.

The purpose of these studies was to compare changes in conduit and resistance artery function in deoxycorticosterone-salt hypertensive rats. We hypothesized that if there was a common mechanism producing changes in vascular function in hypertension, then there would be similar alterations in reactivity of conduit and resistance arteries. Helically cut strips of common carotid artery were prepared for measurement of isometric force generation, and segments of small mesenteric arteries were pressurized for video dimension analysis. Sensitivity of arteries to phenylephrine and acetylcholine was determined. Carotid arteries from deoxycorticosterone-salt hypertensive rats were more sensitive to phenylephrine than arteries from control rats, whereas mesenteric resistance arteries from hypertensive rats were less sensitive to phenylephrine. In carotid arteries, endothelial denudation or incubation with N psi-nitro-L-arginine increased phenylephrine sensitivity in control rats to the level seen in deoxycorticosterone-salt rats. These manipulations had no effect on phenylephrine sensitivity in arteries from deoxycorticosterone-salt rats. In mesenteric resistance arteries, endothelium denudation normalized the depressed phenylephrine sensitivity in arteries from hypertensive rats but had no effect on arteries from normotensive rats. This depressed phenylephrine sensitivity in deoxycorticosterone-salt mesenteric arteries was not reversed by incubation with Npsi-nitro-L-arginine. Acetylcholine-induced relaxation was depressed in carotid arteries from deoxycorticosterone-salt hypertensive rats, and Npsi-nitro-L-arginine blocked these relaxations. In contrast, acetylcholine relaxation in the mesenteric arteries from normotensive and hypertensive rats did not differ. N psi-nitro-L-arginine slightly but significantly attenuated acetylcholine dilation only in mesenteric resistance arteries from the hypertensive rats. We conclude that qualitatively different changes in vasoconstrictor sensitivity to phenylephrine occur in carotid arteries and mesenteric resistance arteries of deoxycorticosterone-salt hypertensive rats. The increased phenylephrine sensitivity in carotid arteries in this model of hypertension is due to the loss of endothelium-derived nitric oxide production. In contrast, the decreased phenylephrine sensitivity in mesenteric resistance arteries from deoxy-corticosterone-salt rats is due to a non-nitric oxide-mediated influence of the endothelium that is absent in arteries from normotensive rats.

Cytokine-induced tumor immunogenicity: endogenous interleukin-1 alpha expressed by fibrosarcoma cells confers reduced tumorigenicity.

A direct correlation between the constitutive expression of IL-1 alpha and reduced tumorigenicity of fibrosarcomas was observed. This was established in fibrosarcoma cell lines which produce IL-1 alpha 'spontaneously', possibly as an aberration of oncogene-mediated transformation or upon IL-1 alpha gene transfer. In fibroblasts intracellular or membrane-associated IL-1 alpha is expressed, whereas the secreted form of the cytokine (IL-1 beta) is absent. Studies on the mechanisms of tumor regression of the IL-1 alpha-positive fibroblastoid cell lines indicated that IL-1 alpha potentiates the development of tumor cell-specific CTLs, which are of importance for tumor eradication. Thus, IL-1 alpha induces enhanced helper T cell activity which provides auxiliary signals for the growth/development of CTLs. Non-adaptive effector cells, activated locally by IL-1 alpha-expressing fibrosarcoma cells, also contribute to the eradication of IL-1 alpha-expressing fibrosarcomas. Local IL-1 alpha expression potentiated antigen presentation, by the malignant fibroblasts as well as by tissue-resident antigen-presenting cells, thus further potentiating anti-tumor immune responses. Mice, in which IL-1 alpha-producing tumors were regressed, developed an immune memory and rejected a challenge with an IL-1 non-producing violent tumor cell line. Endogenous IL-1 alpha activates a cytokine cascade (i.e., IL-6, CSF), produced by the malignant cells and possibly also by stromal cells. However, IL-1 alpha expression is essential for fibrosarcoma eradication, while other cytokines possibly amplify and sustain its action.(ABSTRACT TRUNCATED AT 250 WORDS)

Water vacuum suction curettage (WVSC): one year's experience.

PIP: At Tripler Army Medical Center in Honolulu abortion patients underwent suction curettage using either an electric pump unit (21, group A) or a simple water vacuum pump (WVSC) (28, group B). In both groups the use of the flexible 6 mm uterine curette and method of curettage were the same. For groups A and B the average blood losses were 40 ml and 39 ml. Average tissue volumes removed were 26 ml and 39 ml (greater yield reflects more patients at gestation of 9-10 weeks). From September 1971 to August 1972 400 patients of gestation of 10 weeks or less were curettaged using WVSC. Most of the operations were performed by first-year residents. Complications requiring readmission were not skewed towards largest gestations but distributed throughout the groups suggesting importance of individual technique in equipment use. The complications included retained products of conception (6), endometritis (2), endometritis with retained products of conception (3), and hermorrhage (1). Advantages of the WVSC unit are 1) quiet sound of running water rather than harsh sound of electric pump, 2) requirement of only a standard waterhead making method available to impoverished areas where electricity may be precious, 3) failsafe, unidirectional suction, 4) easy storage, transport, and assemblage, and 5) lack of need for safety pop-off valve because of intrinsic lag time from close of system to development of maximum suction. With its simplicity, safety, and flexibility WVSC is best suited for outpatients.^ieng

5-fluorouracil modulates the toxicity of high dose methotrexate.

Pretreatment with 5-fluorouracil (FU) attenuated the toxicity of high dose methotrexate (MTX) in in vitro and in vivo models. Because dose intensification of the MTX reversed the fluoropyrimidine antagonism of MTX activity in these models, administering FU before the MTX offered the potential advantage of MTX dose intensity and low toxicity without the confounding effects of leucovorin rescue. The current study was conducted to determine the maximum dose of MTX tolerated after a priming dose of FU without leucovorin rescue, and to determine the toxicities of this combination. Subjects (n = 42) received a constant dose of FU followed in 2 hours by MTX; treatment was repeated every 3 weeks. Subjects initially received five doses of leucovorin (10 mg/m2 every 6 hours); this was reduced to two doses, then to zero doses (no rescue) if less than grade 2 toxicity occurred in prior treatments. Cohorts of subjects received escalating doses of MTX in a Fibonacci fashion. At the 1250 mg/m2 dose level, almost all previously untreated subjects tolerated the elimination of leucovorin rescue, without the occurrence of severe toxicity; this was 6 to 8 times the MTX dose that generally requires leucovorin rescue to avoid severe and lethal toxicity. The 24- and 48-hour MTX levels were at a level that usually requires leucovorin rescue. Previously treated subjects were less tolerant; 400 mg/m2 of MTX was the approximate maximum tolerated dose. Prior FU exposure appeared to protect tissues normally susceptible to MTX toxicity, and allowed safe administration of high dose MTX without leucovorin rescue.