Deceleratory growth by a rat glial tumor line in culture.

Tumors in vivo usually exhibit deceleratory rather than exponential growth kinetics. Deceleration results from a negative feedback inhibition of growth the effectiveness of which increases progressively with tumor size. A major obstacle to understanding the fine mechanisms of deceleratory growth has been the lack of a tissue culture system proven to exhibit these kinetics. Rat C6 glioma cells in culture enter a prolonged phase of deceleratory growth about 72 hr after subculture. As with tumor growth in vivo, the kinetics of the C6 deceleratory phase can be described with high accuracy by Gompertz, logistic, inverse cube root, and power functions. The least-squares correlation coefficients for the linearized forms of the rate equations for these functions were typically in the range of 0.75 to 0.90. During the deceleratory phase, the equilibrium growth rate of C6 cells is a monotonically decreasing function of population density at all observable densities, whether sub- or supraconfluent. Any change in density produces a compensatory change of opposite direction in the growth rate. To account for these relationships, a density-equilibrium hypothesis of C6 growth regulation is presented. The fine mechanisms responsible for this regulation do not involve medium or substratum depletion, production of conditioned medium factors, or the extracellular matrix. The development of growth deceleration appears to correlate with the extent of contact interactions between cells and their neighbors, indicating that deceleratory growth regulation is probably mediated by contact interactions. However, these interactions are fundamentally different from those postulated by the traditional contact inhibition theory. Confluency is irrelevant to the contact modulation which produces C6 growth deceleration. Any degree of contact, even at very sparse subconfluent densities, appears capable of exerting some degree of growth inhibition.

The inhibition of thymidine kinase in glial tumor cells by an amino sugar, D-glucosamine.

Thymidine kinase activity in rat C6 glioma cells is inhibited by 50 to 70% after 4 hr incubation with 20 mM D-glucosamine. The inhibition is uncompetitive with respect to thymidine, reducing both the apparent Km and Vmax of the enzyme. The inhibition does not appear to be caused by the reversible combination of the enzyme with a cytoplasmic inhibitor, including D-glucosamine and its metabolites. The addition of D-glucosamine or its metabolites to cell-free thymidine kinase produced an inhibition which differed quantitatively and qualitatively from that which resulted from treatment of intact cells with D-glucosamine. The presence of a reversible cytoplasmic inhibitor of the enzyme was also excluded by mixing experiments. D-Glucosamine inhibited the incorporation of labeled uridine and amino acids into acid-precipitable material. The magnitude of inhibition of thymidine kinase activity and amino acid incorporation by D-glucosamine was comparable to that produced by cycloheximide, suggesting that the inhibition might arise from interference with enzyme synthesis. However, whereas the kinetics of recovery of amino acid incorporation from inhibition was rapid, thymidine kinase activity was depressed for at least 6 hr after drug washout. The results presented are best explained by assuming either that two forms of thymidine kinase are present in rat C6 cells and are differently affected by D-glucosamine or that D-glucosamine acts by two separate mechanisms to inhibit a single form of the enzyme.

The inhibition of thymidine metabolism in tumor cells treated with D-glucosamine.

The amino sugar, D-glucosamine, inhibits the preformed route of thymidine metabolism in rat C6 glioma cells. This inhibition results from a concatenation of several distinct effects, including the inhibition of thymidine uptake, the reduction of thymidine phosphorylation, and an increased leakage of thymidine to the extracellular space. Each of these effects, while ostensibly small in magnitude, is significant and contributes to the observed inhibition of acid-precipitable thymidine incorporation by D-glucosamine. These effects of D-glucosamine, together with its known ability to reduce uridine nucleotide pools, may contribute to its toxicity toward certain experimental animal tumors.

Perceived stigma as a predictor of treatment discontinuation in young and older outpatients with depression.

OBJECTIVE: The authors' goal was to examine the extent to which perceived stigma affected treatment discontinuation in young and older adults with major depression. METHOD: A two-stage sampling design identified 92 new admissions of outpatients with major depression. Perceived stigma was assessed at admission. Discontinuation of treatment was recorded at 3-month follow-up. RESULTS: Although younger patients reported perceiving more stigma than older patients, stigma predicted treatment discontinuation only among the older patients. CONCLUSIONS: Patients' perceptions of stigma at the start of treatment influence their subsequent treatment behavior. Stigma is an appropriate target for intervention aimed at improving treatment adherence and outcomes.

Whole organisms and purified cell walls compared as immunosorbents for the detection of IgE antibodies to Staphylococcus aureus.

We have developed an immunoradiometric assay for IgE antibodies to Staphylococcus aureus (Staph IgE-Ab) which uses purified cell walls (PCW) from the Wood 46 strain of S. aureus as an immunosorbent. We compared Wood 46 PCW and whole organisms (WO) as immunosorbents for Staph IgE-Ab by performing tests on sera from patients with atopic dermatitis (AD) or the hyperimmunoglobulin E syndrome (hyper IgE syndrome). Sera with Staph IgE-Ab demonstrated dose-dependent binding to PCW and WO, but the ratio of specific to non-specific binding was much greater with PCW. Mean non-specific binding to WO was greater than to PCW, 5% versus 2%; and non-specific binding to WO varied directly with the serum concentration of IgE. Results of tests on patients' sera indicated that PCW are required in screening assays for Staph IgE-Ab to avoid false positive results caused by high levels of non-specific binding to WO.

Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules.

Dolastatin 15, a seven-subunit depsipeptide derived from Dolabella auricularia, is a potent antimitotic agent structurally related to the antitubulin agent dolastatin 10, a five-subunit peptide obtained from the same organism. We have compared dolastatin 15 with dolastatin 10 for its effects on cells grown in culture and on biochemical properties of tubulin. The IC50 values for cell growth were obtained for dolastatin 15 with L1210 murine leukemia cells, human Burkitt lymphoma cells, and Chinese hamster ovary (CHO) cells (3, 3, and 5 nM with the three cell lines, respectively). For dolastatin 10, IC50 values of 0.4 and 0.5 nM were obtained with the L1210 and CHO cells, respectively. At toxic concentrations dolastatin 15 caused the leukemia and lymphoma cells to arrest in mitosis. In the CHO cells both dolastatin 15 and dolastatin 10 caused moderate loss of microtubules at the IC50 values and complete disappearance of microtubules at concentrations 10-fold higher. Despite its potency and the loss of microtubules in treated cells, the interaction of dolastatin 15 with tubulin in vitro was weak. Its IC50 value for inhibition of glutamate-induced polymerization of tubulin was 23 microM, as compared to values of 1.2 microM for dolastatin 10 and 1.5 microM for vinblastine. Dolastatin 10 noncompetitively inhibits the binding of vincristine to tubulin, inhibits nucleotide exchange, stabilizes the colchicine binding activity of tubulin, and inhibits tubulin-dependent GTP hydrolysis (Bai et al., Biochem Pharmacol 39: 1941-1949, 1990; Bai et al. J Biol Chem 265: 17141-17149, 1990). Only the latter reaction was inhibited by dolastatin 15. Nevertheless, its structural similarity to dolastatin 10 indicates that dolastatin 15 may bind weakly in the "vinca domain" of tubulin (a region of the protein we postulate to be physically close to but not identical with the specific binding site of vinca alkaloids and maytansinoids), presumably in the same site as dolastatin 10 (the "peptide site").

Gynecologic carcinoma associated with dermatomyositis-polymyositis.

Dermatomyositis-polymyositis was associated with gynecologic carcinoma in ten patients treated at the Mayo Clinic between 1952 and 1982. Only two patients did not manifest the typical skin changes of acute dermatomyositis. In all ten cases, the onset of dermatomyositis-polymyositis preceded evidence of carcinoma. The intervals between initial symptoms of dermatomyositis-polymyositis and subsequent diagnosis of carcinoma ranged from three months to six years. Usually, the carcinoma became evident within two years. The carcinomas were ovarian in five cases, cervical in three, endometrial in one, and vaginal in one. Ages of the ten patients ranged from 40 to 66 years (mean, 53 years). In most cases, symptoms of dermatomyositis-polymyositis regressed markedly after diagnosis and treatment of the underlying carcinoma. In selected patients for whom more detailed follow-up information was available, the manifestations of dermatomyositis-polymyositis progressed and regressed in synchrony with tumor spread and effective treatment, respectively.

Seborrheic keratoses of penis.

A case is reported of a forty-nine-year-old black man in whom numerous skin-colored papules and verrucoid plaques had developed on his penis over the course of fifteen years. He did not seek medical attention, and some of the lesions had become quite large. The initial clinical impression was condyloma acuminatum, and prior to therapeutic intervention histologic evaluation revealed findings diagnostic of seborrheic keratosis. Seborrheic keratoses should be considered in the differential diagnosis of penile lesions especially because of clinical similarities to condylomata acuminata.

Lindane neurotoxic reaction in nonbullous congenital ichthyosiform erythroderma.

A 3-year-old boy with nonbullous congenital ichthyosiform erythroderma with a four-month history of scabies was treated with a single dose of lindane cream. In a 48-hour period, he developed nausea and vomiting and also suffered from an epileptiform convulsion and muscular spasms. Seventy-two hours after application of the cream, his blood lindane level was 54 ng/mL. Caution should be exercised when using lindane in patients with compromised epidermal barrier function.

Management of psoriasis vulgaris with a hydrocolloid occlusive dressing.

Because clinical improvement of psoriasis vulgaris was recently observed after the prolonged application of tape, 26 patients with symmetric plaque-type psoriasis were enrolled in a prospective bilateral comparison study evaluating the clinical efficacy of the adhesive hydrocolloid occlusive dressing (HCD). The majority of localized plaques of psoriasis achieved improvement (41%, 14/34) or resolution (47%, 16/34) with the prolonged application of HCD; also, HCD was therapeutically superior to twice-daily applications of fluocinolone acetonide cream, and was comparably effective as erythemogenic ultraviolet B treatment. Although the therapeutic mechanism is not completely understood, occlusive dressings have great potential in the management of limited psoriasis vulgaris.

Management of leg ulcers with hydrocolloid occlusive dressing.

Twenty-two patients with 31 leg ulcers of various causes received local wound management consisting of the application of an adhesive hydrocolloid (HC) occlusive dressing (DuoDerm). Group 1 comprised 15 patients (11 outpatients) with 19 ulcers. Approximately two thirds (12/19) of the ulcers healed when treated solely with the HC dressing; mean treatment time was 57 days. Group 2 comprised seven hospitalized patients with at least two leg ulcers of similar size and distribution. The 20 ulcers in the seven patients were treated with either mild topical antimicrobial wet dressings (Sweitzer's 1:32 solution) or HC dressings, with each patient serving as his own "control." All 20 ulcers healed; the average time to healing was 44 days with HC dressing and 42 days with wet dressing management. Most of the patients reported convenience in management and substantial relief of pain with the use of HC dressings.

IgE antibodies to Staphylococcus aureus. Prevalence in patients with atopic dermatitis.

We determined the prevalence of IgE antibodies to Staphylococcus aureus by optimized immunoradiometric assay methods in serum specimens from 69 patients with atopic dermatitis. All patients had positive aerobic cultures for S aureus from skin. Significant binding attributable to IgE antibodies was noted in three of 25 patients with atopic dermatitis and superimposed impetiginization or pustules, but antibodies were not detected in the remaining 44 patients whose lesions were colonized with S aureus. By comparison, IgE antibodies to S aureus were uniformly present in high titer in serum samples from patients with the hyperimmunoglobulin E syndrome. We conclude that most patients with atopic dermatitis do not have detectable levels of IgE antibodies to S aureus.

Punctuate porokeratotic keratoderma.

Two unrelated patients had numerous palmoplantar "music box spine" keratotic plugs and pits of 11 and 13 years' duration. Histologic examination revealed a compact column of parakeratosis resembling that of a cornoid lamella of porokeratotic conditions. Ultrastructurally in clinically affected skin, the stratum corneum contained numerous variable-sized pyknotic nuclei, and cells in the stratum granulosum contained fewer keratohyalin granules. The ultrastructural findings differed from those of porokeratosis of Mibelli and disseminated superficial actinic porokeratosis. The proper nosologic designation should be punctuate porokeratotic keratoderma.

Adult Kawasaki syndrome.

Kawasaki syndrome (KS) is an idiopathic, acute, febrile, exanthemous illness that primarily affects infants and children. We describe a 20-year-old black woman who fulfilled the clinical criteria for the diagnosis of KS and excluded other possible causes. In addition, we reviewed data on 21 patients with adult KS reported in the English literature and accepted ten cases as representing this syndrome. The epidemiologic, clinical, laboratory, and pathologic features of the 11 cases representing adult KS are discussed. Although the initial reports of adult KS in the United States may have actually represented toxic shock syndrome, the occurrence of KS in adults should be acknowledged.

Catecholamine levels in the injured spinal cord of monkeys.

The authors report a study of catecholamine levels in the spinal cords of monkeys following a 300 gm-cm blow to the midthoracic spinal cord. There was a progressive decrease in norepinephrine (NE) activity as a first-order process with a half-life of 6.4 hours. The NE activity in injured tissue never exceeded control levels, which remained unchanged both above and below the injured segment. Dopamine activity remained unchanged in the injured tissue as well as in control segments above and below the area of trauma for the first hour.

Blood flow in normal and injured monkey spinal cord.

The authors used indicator fractionation techniques to determine blood flow in normal and bluntly traumatized spinal cords of Macaca rhesus monkeys. Normal flow rates were determined for several levels of spinal cord as well as differential values for white and gray matter from representative areas. Flow rates in traumatized tissue, obtained at several different time intervals up to 4 hours after injury, demonstrated marked differences in regional perfusion of the white matter and gray matter after trauma. Gray matter perfusion was nearly obliterated while white matter blood flow persisted and in fact was higher than uninjured controls. The findings do not support the concept of ischemia as a factor in white matter failure. If toxic pathobiochemical alterations are induced by trauma, it may be possible to reverse these changes by exploiting the preserved white matter blood flow for chemotherapeutic intervention.

Increased serum iodide concentration from iodine absorption through wounds treated topically with povidone-iodine.

Increased serum iodide concentrations secondary to iodine absorption through wounds treated with povidone-iodine dressings is described. Hyperchloremic acidosis and a disparity between serum chloride concentrations determined by two different methods suggested the presence of an unidentified halide. Cardiovascular instability and renal failure occurred concurrent with systemic iodide accumulation. Measurement of serum iodide concentration should be performed when povidone-iodine is used topically in patients with impaired renal function.

Arthroscopically treated tears of the glenoid labrum. Factors influencing outcome.

Labral tears and associated glenohumeral ligament injuries were classified and treated arthroscopically in 83 patients. Transverse labral tears were the most common. Subtle increased glenohumeral translation was noted in 24% of patients. Glenohumeral ligament injury was present in 58% of the shoulders, with the middle and superior ligaments or middle ligaments alone most commonly involved. These ligament injuries were classified into different groups based on severity. Partial excision of the torn labrum was the primary treatment in all patients and was combined with glenohumeral ligament repair in 9 patients. Seventy-eight patients were available for subjective follow-up evaluation (average, 3.2 years), while 53 patients were objectively evaluated (average followup, 2.8 years). There were 14% excellent, 71% satisfactory, and 15% poor results. The main factor associated with poor results was a grade III glenohumeral ligament injury in which only partial excision of the torn labrum was performed. There was a positive correlation between injury to both the superior and middle glenohumeral ligaments and increased anterior translation demonstrated by preoperative stability testing at 60 degrees of humeral abduction in neutral rotation. We believe glenohumeral ligament injury is often associated with labral tears and arthroscopic partial labral excision is only effective in those patients who have grade I or II (less severe) glenohumeral ligament injuries.

Stigma as a barrier to recovery: Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence.

OBJECTIVE: Major depression is undertreated despite the availability of effective treatments. Psychological barriers to treatment, such as perceived stigma and minimization of the need for care, may be important obstacles to adherence to the pharmacologic treatment of major depression. The authors examined the impact of barriers that were present at the initiation of antidepressant drug therapy on medication adherence in a mixed-age sample of outpatients with major depression. METHODS: A two-stage sampling design was used to identify adults with a diagnosis of major depressive disorder, as determined by the Structured Clinical Interview for Diagnosis, who sought mental health treatment at outpatient clinics. Additional instruments were administered to 134 newly admitted adults who had been taking a prescribed antidepressant medication for at least a week to assess perceived stigma, self-rated severity of illness, and views about treatment. The patients were reinterviewed three months later and were classified as adherent or nonadherent on the basis of self-reported estimates of the number and frequency of missed doses. RESULTS: Medication adherence was associated with lower perceived stigma, higher self-rated severity of illness, age over 60 years, and absence of personality pathology. No other characteristics of treatment or illness were significantly related to medication adherence. CONCLUSIONS: Perceived stigma associated with mental illness and individuals' views about the illness play an important role in adherence to treatment for depression. Clinicians' attention to psychological barriers early in treatment may improve medication adherence and ultimately affect the course of illness.

Intracellular enzyme liberation in primate spinal cord injury.

Intracellular lysosomal and nonlysosomal enzymes, as well as tissue edema, were measured in spinal cords of monkeys up to 20 days following a 300 gm-cm open injury. Although edema was maximal between six hours and 11 days, enzyme elevation was delayed. Lysosomal enzyme acid cathepsin increased beginning at five days and the beta-glucuronidase and beta-glycerophosphatase increase began at 11 days. Nonlysosomal enzymes were either not elevated or showed a slight rise. These data suggest that edema, one of the secondary damaging factors in spinal injury, is not a result of release of these intracellular enzymes. Also it appears that intracellular enzymes do not participate in early secondary damaging processes in severe spinal injury.