Influence of Δ9 and cannabidiol on photically evoked after-discharge potentials

Two cannabinoids, ⁹ and cannabidiol, and several reference drugs were compared relative to their effects in a recently developed anticonvulsant test system, the after-discharge potentials of the visually evoked response; the potentials were recorded electrophysiologically from electrodes permanently mounted over the visual cortices of conscious rats. In anticonvulsant doses, trimethadione and ethosuximide produced an extensive depression of after-discharge activity, whereas diphenylhydantoin and cannabidiol exerted no such effect. In contrast, anticonvulsant doses of ⁹ and subconvulsant doses of pentylenetetrazol markedly increased after-discharge activity, which may represent a manifestation of their central nervous system excitatory properties. The data from the present study support our previously published observations from several other anticonvulsant tests that indicate the anticonvulsant characteristics of cannabidiol resemble those of diphenylhydantoin rather than those of trimethadione and that the central excitatory properties of ⁹ distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.     

Temporal relation between temperature change and FDG uptake in brown adipose tissue

Objectives It has been reported that the prevalence of ¹⁸F fluorodeoxyglucose (FDG) uptake in brown adipose tissue (BAT) is related to outdoor temperature, i.e., more frequent during the colder periods of the year. The purpose of this study was to assess the temporal relationship between BAT FDG uptake and temperature. We correlated the prevalence of BAT with average temperatures (divided into five temperature ranges) of seven different durations. Methods One thousand four hundred ninety-five consecutive FDG Positron emission tomography (PET) studies in 1,159 patients (566 male and 593 female, mean age = 60.4 years) were retrospectively reviewed. FDG uptake with distinct patterns compatible with BAT was identified by a consensus of two readers. The local daily average temperature from January 2000 to November 2003 (beginning 60 days before the date of first PET scan) were obtained, and 2-, 3-, 7-, 14-, 30-, and 60-day average temperatures before the date of a PET study were calculated. The prevalence of BAT FDG uptake was correlated with these various average temperatures. Results The daily, 2-day, 3-day, and 7-day average temperature had an inverse relation with the prevalence of BAT, i.e., the lower the temperature, the higher prevalence of BAT. When the temperature was averaged over 14 days or longer, this inverse relationship between the temperature and the prevalence of BAT was no longer preserved. Conclusions Our data suggest that increased FDG uptake in BAT occurs more often as an acute response to cold weather (1–7 days) rather than to prolonged periods of average cold weather.     

The trans/cis photoisomerization in hydrogen bonded complexes with stability controlled by substituent effects: 3-(6-aminopyridin-3-yl)acrylate case study

The association of aminopyridine-based acrylic acid and its salt was studied by NMR titration experiments. The AA (acceptor, acceptor) hydrogen-bonding pattern present in the salt forms a complex readily with a DD (donor, donor) hydrogen-bonding pattern of the substituted ureas even in polar and competitive environment. The double carbon–carbon bond in the acrylic acid derivative is subjected to photoisomerization. This is dependent on the association with substituted urea derivatives. The substituent in ureas influences the trans/cis isomerization kinetics and position of the photostationary state. Two mechanisms that influence the photoisomerization were proposed. To the best of our knowledge, the trans/cis photoisomerization influenced by the substituent in such a hydrogen-bonding pattern has not observed previously. It was shown that interaction with urea derivatives causes lowering of the trans-to-cis photoreaction rates.

The association of aminopyridine-based acrylic acid and its salt was studied by NMR titration experiments.     

Pelvic osteoid osteoma in a skeletally mature female

Osteoid osteoma is the most common bone-producing tumor that typically presents with "throbbing night pain" and that improves dramatically with use of low-dose salicylates. Few cases of pelvic osteoid osteoma have been reported, and most have involved patients younger than age 30. Surgical excision classically has been the treatment of choice, but, recently, less invasive modalities, including radiofrequency ablation, have begun to supplant surgical management of osteoid osteoma, resulting in a decrease in the need for definitive surgical diagnosis and treatment. We present a rare case of osteoid osteoma in the pelvis of a woman older than age 30.     

Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma

PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.     

Distribution of high affinity choline transporter immunoreactivity in the primate central nervous system

A mouse monoclonal antibody (clone 62-2E8) raised against a human recombinant high-affinity choline transporter (CHT)-glutathione-S-transferase fusion protein was used to determine the distribution of immunoreactive profiles containing this protein in the monkey central nervous system (CNS). Within the monkey telencephalon, CHT-immunoreactive perikarya were found in the striatum, nucleus accumbens, medial septum, vertical and horizontal limb nuclei of the diagonal band, nucleus basalis complex, and the bed nucleus of the stria terminalis. Dense fiber staining was observed within the islands of Calleja, olfactory tubercle, hippocampal complex, amygdala; moderate to light fiber staining was seen in iso- and limbic cortices. CHT-containing fibers were also present in sensory and limbic thalamic nuclei, preoptic and hypothalamic areas, and the floccular lobe of the cerebellum. In the brainstem, CHT-immunoreactive profiles were observed in the pedunculopontine and dorsolateral tegmental nuclei, the Edinger-Westphal, oculomotor, trochlear, trigeminal, abducens, facial, ambiguus, dorsal vagal motor, and hypoglossal nuclei. In the spinal cord, CHT-immunoreactive ventral horn motoneurons were seen in close apposition to intensely immunoreactive C-terminals at the level of the cervical spinal cord. CHT immunostaining revealed a similar distribution of labeled profiles in the aged human brain and spinal cord. Dual fluorescent confocal microscopy revealed that the majority of CHT immunoreactive neurons contained the specific cholinergic marker, choline acetyltransferase, at all levels of the monkey CNS. The present observations indicate that the present CHT antibody labels cholinergic structures within the primate CNS and provides an additional marker for the investigation of cholinergic neuronal function in aging and disease.     

Prenatal cocaine administration increases glutathione and alpha-tocopherol oxidation in fetal rat brain

Recent findings suggest that prenatal cocaine exposure results in significant attenuation of uterine and placental blood flow. The extent of blood flow reduction to fetuses positively correlates with reductions in glial-derived neurotrophic factor (GDNF) and dopamine (DA). However, whether such changes in uterine blood flow are sufficient to induce oxidative stress have yet to be determined. In the following experiments, the impact of prenatal cocaine exposure on fetal brain levels of the endogenous antioxidant glutathione (GSH and its oxidized form GSSG) or the exogenous antioxidant alpha-tocopherol (alpha-T and its oxidized quinone form) was investigated. It was hypothesized that cocaine exposure would result in greater oxidation of both GSH and alpha-T. Results indicated that a single injection of cocaine to a drug-naive pregnant dam results in significant (-16.38%) reductions in the levels of GSH. GSSG can be either raised or reduced as a result of fetal uterine position: fetuses at the ovarian extremes show significant increases in GSSG in response to cocaine (+64.73%), whereas cervically situated fetuses show decreased GSSG (-47.91%). Additionally, cocaine significantly decreased the levels of alpha-T (-15.9%) and increased the levels of its oxidative product alpha-Tquinone (alpha-Tq, +34.05%). Levels of alpha-T were not affected by fetal uterine position. These data collectively suggest that cocaine exposure increases the utilization of both endogenous and exogenous anti-oxidants in the fetal rat brain. Along with previous studies, these data support the hypothesis that cocaine-induced vasoconstriction results in oxidative stress in the gestating fetus.