Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase.

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-containing inhibitors of thymidylate synthase (TS) are described. The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region. Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM.

Comparative bioavailability of orally and vaginally administered progesterone.

Objective: To study the pharmacokinetics of progesterone (P) in healthy premenopausal female volunteers to compare the bioavailability of orally or vaginally administered hormone.

Design: Subjects were randomly allocated to receive either oral P or a vaginal pessary then crossed over to the alternate preparation 1 month later.

Setting: The study was conducted in outpatient setting.

A comparison of hormone therapy, coping skills training, and relaxation for the relief of premenstrual syndrome.

Approximately 10% of women are severely affected by premenstrual syndrome (PMS) during their reproductive years. Several biological theories of causation have been proposed and each has provoked treatment attempts through medication to little sustained effect. As many of the reported complaints are psychological, a new treatment approach was considered using cognitive-behavioral therapy.

Psychopathology among substance abusing juvenile offenders.

The prevalence of substance abuse and coexisting DSM-III psychiatric disorders was evaluated in 111 juvenile offenders. As expected, a high rate of conduct disorder (91%) was present in both substance abusing and nonsubstance abusing juvenile offenders. However, significantly higher rates of attention deficit disorder and aggressive subtype of conduct disorder were present in those offenders who abused drugs and alcohol (54%).

The role of protein kinase C in interleukin 1 and tumor necrosis factor alpha induction of fibroblasts to produce and release granulocyte-macrophage colony-stimulating activity.

The process of signal transduction by interleukin 1 (IL-1) or tumor necrosis factor alpha (TNF alpha) for the production of hematopoietic growth factors by cultured fibroblasts was studied using inhibitors for protein kinase C, cyclic nucleotide-dependent protein kinases, calmodulin-dependent protein kinases, and the Na(+)-H+ antiport system. The protein kinase C inhibitor H-7 was shown to inhibit both IL-1 beta- and TNF alpha-induced granulocyte-macrophage colony-stimulating activity (GM-CSA) production and release from cultured fibroblasts in a dose-dependent manner, with 40 microM H-7 demonstrating maximum suppression of the GM-CSA response. In addition, 100-200 nM staurosporine, a more potent inhibitor of protein kinase C, also completely suppressed GM-CSA from IL-1 beta- and TNF alpha-induced fibroblasts.

Predicting substance abuse in juvenile offenders: attention deficit disorder versus aggressivity.

The relative predictive significance of attention deficit disorder (ADD) and aggressive behavior for consequent substance abuse was examined in 114 juvenile offenders. ADD, aggressivity, and substance abuse were assessed according to DSM-III criteria. Results from logistic regression indicate that aggressivity, but not an ADD diagnosis, significantly predicts substance abuse.

Urinary 6-sulphatoxy melatonin levels within the menstrual cycle and in patients with premenstrual syndrome.

The present investigation examined the production of urinary 6-sulphatoxy melatonin (aMT.6S) during the early follicular and late luteal (premenstrual) phases in healthy, normal women and in patients with premenstrual syndrome (PMS). There was no significant difference in levels of aMT.

Lactoferrin decreases monocyte-induced fibroblast production of myeloid colony-stimulating activity by suppressing monocyte release of interleukin-1.

Lactoferrin (Lf) is a negative regulator of myelopoiesis which operates by suppressing the release from mononuclear phagocytes of GM colony-stimulating factor (GM-CSF) or monokines which can then induce the release of GM-CSA from accessory cells. In this study, endotoxin-depleted, purified iron-saturated human Lf was assessed for its effect on the production of interleukin-1 by cultured monocytes and their subsequent effect on colony-stimulating factor release from cultured fibroblasts. Monocytes were grown with or without Lf and Lf that had previously been incubated with monoclonal anti-Lf.

Feline oral neoplasia: a ten-year survey.

A retrospective histological study was conducted on 371 neoplasms of the oral cavity in cats. Oral neoplasia accounted for 10% of feline neoplasms identified during the survey period. Eighty-nine percent of the oral neoplasms were malignant.

Equine juvenile mandibular ossifying fibroma.

Benign proliferative fibro-osseous lesions of the rostral mandible in six young horses are classified as equine juvenile mandibular ossifying fibroma. Histologically there is a characteristic abrupt transition from subgingival fibroblastic stroma to a zone of proliferating osteoblasts that form irregular spicules of osteoid. The layer of proliferating osteoblasts blends with a deeper zone of bony trabeculae rimmed by osteoblasts and separated by intertrabecular spaces of moderate cellular density.

Gastric hyperplastic polyp in a horse.

An unusually large, pedunculated (20 cm long) mass arising the gastric pylorus which produced complete obstruction of the proximal duodenum and severe gastric distension was found in a 13-year old castrated male Arabian horse. The histological diagnosis was gastric hyperplastic polyp, which has not been reported previously in the horse. The clinico-pathological findings in this horse are compared with hyperplastic (inflammatory) gastric polyps of man.

Menstrual migraine: a double-blind trial of percutaneous estradiol.

The present study investigated whether administration of percutaneous estradiol for the 7 days encompassing menstruation (the paramenstruum) would be effective in alleviating menstrual migraine. The study was a double-blind cross-over placebo comparison of percutaneous estradiol in gel form. Twenty-two women who suffered from regular recurring menstrual migraine were studied during 2 assessment menstrual cycles, 4 treatment cycles (2 of estradiol gel, 2 of placebo gel), and 1 follow-up (no treatment) cycle.

Increased expression of alpha 1-adrenergic receptors in the hypothalamus of spontaneously hypertensive rats.

The specificity and molecular weights of alpha 1-adrenergic receptors in various tissues of spontaneously hypertensive (SH) rat were compared with normotensive controls (Wistar-Kyoto; WKY) with the use of [125I]HEAT and [125I]azidoprazosin, specific alpha 1-adrenergic receptor antagonists. Binding of [125I]HEAT to membranes prepared from SH rat brain hypothalamus was significantly higher, due to a 75% increase in the Bmax, than the WKY control. In contrast, the Bmax and Kd of [125I]HEAT binding to brainstem and liver membranes from SH rats were not significantly different from those of WKY controls.

The factor structure of symptom reports in premenstrual syndrome.

Premenstrual Syndrome (PMS) is characterised by negative moods, physical changes and alterations in cognitions and behaviours during the latter part of the menstrual cycle. Symptoms diminish at the onset of menstruation or during the menstrual flow and the post-menstrual (follicular) phase is usually one of calm and well-being. The factor structure of self-reports from a group of 75 treatment-seeking women was examined for simple structure.

Receptors for phorbol esters are primarily localized in neurons: comparison of neuronal and glial cultures.

Binding of [3H]PDB has been measured in the present study to determine the levels of protein kinase C in the neuronal and astrocytic glial cells in culture from rat brain. Binding of [3H]PDB to homogenates of cultured neuronal cells from the brains of normotensive and hypertensive rats was time-dependent and specific. The relative potency for competition by various phorbol esters to [3H]PDB binding was TPA greater than beta-PDD greater than POE greater than alpha-PDD greater than or equal to 4 alpha phorbol.

Menstrual cycle symptoms: comparison of a non-clinical sample with a patient group.

This study compared findings of a community group of women (n = 32), who claimed they did not require help for menstrual cycle complaints, with a patient group (n = 75) with confirmed premenstrual syndrome (PMS). Subjects completed a battery of psychological tests to identify personality characteristics, levels of depression, anxiety, stress and marital adjustment. Menstrual cycle symptoms were assessed with the Menstrual Distress Questionnaire (MDQ, Moos, 1985) during follicular (day 6-8) and premenstrual phases (day 26-28) of two adjusted cycles and with daily symptom ratings.

Esophageal phytobezoar in a horse.

A 23-year-old Thoroughbred stallion was admitted to the hospital for treatment of acute esophageal obstruction. Clinical examination and contrast radiography confirmed the presence of an esophageal obstruction. The horse was euthanatized, and examination revealed a bolus of feed material occluding the esophageal lumen 6 cm caudal to the thoracic inlet, with underlying necrosis of the esophageal mucosa.

Skeletal muscle ventricles in circulation. One to eleven weeks' experience.

Skeletal muscle ventricles were constructed from canine latissimus dorsi and connected to the thoracic aorta in six dogs. These ventricles were stimulated to contract synchronously during diastole. The skeletal muscle ventricles were capable of continuous stroke work when placed within the arterial circulation for several weeks.