Health education needs of people with schizophrenia taking clozapine.
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Adult↗
Biomedical subjects
K Miller
Publications and source records attributed to K Miller.
Internet Web resources for anti-tobacco advocacy.
The Internet has recently witnessed growth since it became accessible to the common user in 1990. It is becoming a valuable communications and information resource for the anti-tobacco movement. This article summarizes many valuable resources for the anti-tobacco activist to be found on the World Wide Web today.
Computer Communication Networks↗
Multiple subtypes of phospholipase C are encoded by the norpA gene of Drosophila melanogaster.
The norpA gene of Drosophila melanogaster encodes a phosphatidylinositol-specific phospholipase C that is essential for phototransduction. Besides being found abundantly in retina, norpA gene products are expressed in a variety of tissues that do not contain phototransduction machinery, implying that norpA is involved in signaling pathways in addition to phototransduction. We have identified a second subtype of norpA protein that is generated by alternative splicing of norpA RNA. The alternative splicing occurs at a single exon that is excluded from mature norpA transcripts when a substitute exon of equal size is retained. The net difference between the two subtypes of norpA protein is 14 amino acid substitutions occurring between amino acid positions 130 and 155 of the enzyme. Results from Northern analyses suggest that norpA subtype I transcripts are most abundantly expressed in adult retina, while subtype II transcripts are most abundant in adult body. Moreover, norpA subtype I RNA can be detected by the reverse transcription-polymerase chain reaction in extracts of adult head tissue but not adult body nor at earlier stages of Drosophila development. Conversely, norpA subtype II RNA can be detected by reverse transcription-polymerase chain reaction throughout development as well as in heads and bodies of adults. Furthermore, norpA subtype I RNA is easily detected in retina using tissue in situ hybridization analysis, while subtype II RNA is not detectable in retina but is found in brain. Since only norpA subtype I RNA is found in retina, we conclude that subtype I protein is utilized in phototransduction. Since norpA subtype II RNA is not found in retina but is expressed in a variety of tissues not known to contain phototransduction machinery, subtype II protein is likely to be utilized in signaling pathways other than phototransduction. The amino acid differences between the two subtypes of norpA protein may reflect the need for each subtype to interact with signaling components of different signal-generating pathways.
Alternative Splicing↗
Phospholipase C rescues visual defect in norpA mutant of Drosophila melanogaster.
Mutations in the norpA gene of Drosophila melanogaster severely affect the light-evoked photoreceptor potential with strong mutations rendering the fly blind. The norpA gene has been proposed to encode phosphatidylinositol-specific phospholipase C (PLC), which enzymes play a pivotal role in one of the largest classes of signaling pathways known. A chimeric norpA minigene was constructed by placing the norpA cDNA behind an R1-6 photoreceptor cell-specific rhodopsin promoter. This minigene was transferred into norpAP24 mutant by P-element-mediated germline transformation to determine whether it could rescue the phototransduction defect concomitant with restoring PLC activity. Western blots of head homogenates stained with norpA antiserum show that norpA protein is restored in heads of transformed mutants. Moreover, transformants exhibit a large amount of measurable PLC activity in heads, whereas heads of norpAP24 mutant exhibit very little to none. Immunohistochemical staining of tissue sections using norpA antiserum confirm that expression of norpA protein in transformants localizes in the retina, more specifically in rhabdomeres of R1-6 photoreceptor cells, but not R7 or R8 photoreceptor cells. Furthermore, electrophysiological analyses reveal that transformants exhibit a restoration of light-evoked photoreceptor responses in R1-6 photoreceptor cells, but not in R7 or R8 photoreceptor cells. This is the strongest evidence thus far supporting the hypothesis that the norpA gene encodes phospholipase C that is utilized in phototransduction.
Animals↗
The Bethesda system and Pap smear screening.
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Adult↗
Improved survival of patients with melanoma with an antibody response to immunization to a polyvalent melanoma vaccine.
BACKGROUND: Melanoma vaccine treatment appears to slow the progression of melanoma in some patients, particularly in patients in whom it stimulates cellular antimelanoma immune responses. The relationship of vaccine-induced antibody responses to clinical outcome is less clear. The purpose of this study was to investigate the clinical relevance of antibody responses to melanoma vaccine immunization. METHODS: Eighty-two evaluable patients with surgically resected American Joint Committee on Cancer Stage III malignant melanoma were immunized to a partially purified, polyvalent, melanoma antigen vaccine. Antimelanoma antibodies were measured by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis before vaccine treatment and 1 week after the fourth immunization. RESULTS: Vaccine treatment induced or augmented antibody responses to melanoma in 32 (39%) of the patients. The antibodies were directed to one or more antigens of 38-43, 75, 110, 150 and/or 210 kDs, which previously have been shown to be expressed preferentially in cultured human melanoma cells. The median disease free survival of patients with a vaccine-induced antibody response to one or more of these antigens was 5.4 years compared with 1.4 years for nonresponders (P = 0.06), and 5-year overall survival was 71% compared with 44%, respectively (P = < 0.01). As determined by Cox multivariate analysis, the difference in overall survival was independent of disease severity or of immunologic competence as evaluated by ability to be sensitized to dinitrochlorobenzene. The difference in survival between antibody responders and nonresponders improved with time. CONCLUSIONS: The antibody response to vaccine treatment is an immune marker of vaccine activity that appears to be predictive of a later reduction in the recurrence of melanoma and is unrelated to the vaccine's ability to induce cellular immune responses. This finding suggests that vaccine treatment may be effective in slowing the progression of melanoma in some patients and that the protective effect is mediated partly by vaccine-induced antimelanoma antibodies.
Antibody Formation↗
Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease.
The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.
Adult↗
The function of inducible promoter systems in F9 embryonal carcinoma cells.
Embryonal carcinoma (EC) cells represent an important model for studying the regulation of cellular differentiation during embryonic development and tumor formation. The differentiation of EC cells is associated with changes in the expression of a number of cellular genes, some of which have been implicated directly in the regulation of differentiation. To facilitate further studies of the possible roles of cellular gene products during the differentiation of EC cells, we have used transient transfection assays to compare the function of three promoter systems that direct the conditional expression of recombinant gene constructs. One system employs the mouse mammary tumor virus (MMTV) promoter, which is induced by glucocorticoid hormones. The other two systems are based on chimeric transactivator proteins consisting of the bacterial lac repressor or tet repressor, respectively, fused with a viral transactivation domain. The chimeric proteins function in mammalian cells as sequence-specific activators of transcription that are regulated by either lactose analogs or tetracycline. Transient transfections of mouse F9 EC cells and their differentiated cells with an MMTV promoter-reporter gene construct and a second plasmid encoding the rat glucocorticoid receptor resulted in a dramatic induction of reporter gene expression by glucocorticoid hormone of approximately 200-fold. The conditional expression system based on the tetracycline-responsive transactivator exhibited a similar range of reporter gene expression in response to tetracycline. In contrast, the system based on the lac repressor exhibited a much more limited range of conditional reporter gene expression in our studies. These findings and others discussed in this report suggest that the tetracycline-responsive promoter system may be useful for the conditional expression of recombinant gene constructs in F9 EC cells. Furthermore, data are presented indicating that the human beta-actin promoter should be suitable for stable expression of conditional transactivators, such as the tetracycline-responsive transactivator, in F9 cells before and after differentiation.
Actins↗
A collaborative evaluation of seven alternatives to the Draize eye irritation test using pharmaceutical intermediates.
Much of the data which have been generated on in vitro alternatives to the Draize eye irritation test have dealt with compounds within a specific chemical class or product category. However, in the pharmaceutical industry, it is often necessary to evaluate materials which are not related in structure or properties. It was thus decided to evaluate a diverse series of chemicals in seven in vitro methods for estimating ocular irritation. Thirty-seven test materials were chosen to represent a broad range of pH, solubility, and in vivo irritation potential. Assays were chosen to include as many different types of end points as practical. The group of assays was composed of TOPKAT (assessing structure-activity relationships), bovine corneal opacity-permeability (BCO-P; corneal opacity/toxicity), Eytex (protein coagulation), neutral red uptake (cytotoxicity), MTT in living dermal equivalent (cytotoxicity), Microtox (cytotoxicity in bacteria), and CAMVA (inflammation/toxicity). The results of the study indicated that, in general, the cytotoxicity end points did not correlate well with the in vivo data. The BCO-P, CAMVA, and Eytex assays had the best overall concordance (88.9, 75.8, and 75.0%, respectively) with this set of compounds. Estimation of irritation potential based on structure-activity (TOPKAT) was possible for only approximately 50% of the compounds; however, the assay showed 100% sensitivity (i.e., no false negatives), but low specificity (i.e., negatives correctly identified only 54.5% of the time). These data suggest that for screening of chemicals of diverse structure and properties, the more mechanism-based assays, as opposed to general cytotoxicity assays, hold more promise and should be further evaluated.
Animal Testing Alternatives↗
Photodynamic efficiency of liposome-administered tetramethyl hematoporphyrin in two human bladder cancer cell lines.
The main problems presented by superficial bladder carcinoma, its high recurrence rate and multifocal appearance, require treatment of the bladder as a whole. Photodynamic therapy (PDT) is one such experimental treatment for superficial bladder carcinoma, involving the administration of a photosensitizer that accumulates in the tumor tissue, and subsequent irradiation of the tumor with light. Since the photosensitizers used in PDT suffer from several drawbacks, new photosensitizers are being sought. Drug delivery systems are also being investigated for the administration of hydrophobic photosensitizers and enhancement of photodynamic efficiency and tumor selectivity. In this study we examined a new photosensitizer, tetramethyl hematoporphyrin (TMHP), in two human bladder cancer cell lines. In the first pair of the experiments, TMHP was bound to unilamellar liposomes. Cellular uptake, dark toxicity and photodynamic efficiency were then studied. Fluorescence microscopy showed TMHP localization in the cytoplasm in a perinuclear region, sparing the nucleus. Dark toxicity occurred after incubation of cells with TMHP above a concentration of 20 micrograms/ml. Irradiation was carried out using an argon-pumped dye laser emitting a wavelength of 630 nm at a fluence of 3.6 and 7.2 J/cm2. Before irradiation, cells were incubated with TMHP at concentrations of 2.5 and 5 micrograms/ml for 1 h. Cell survival rates after incubation with 5 micrograms/ml TMHP and irradiation at 7.2 J/cm2 were 15.7% of control cells for Rec and 4.5% for Waf cells. Uptake studies showed a higher intracellular TMHP concentration in Waf than in Rec cells. This correlates with the higher PDT efficiency seen in Waf cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Carcinoma, Transitional Cell↗
Nitroxergic innervation of the human ureterovesical junction.
Nitric oxide synthase (NOS) immunohistochemistry and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry were used to investigate the distribution of nitroxergic, i.e., nitric oxide-synthesizing, neuronal perikarya and processes in the human ureterovesical junction (UVJ). Tissue specimens obtained from two cadaver kidney donors and two patients undergoing radical cystectomy for bladder cancer were examined. Clusters of NOS-immunoreactive neurons were localized in extramural ureterovesical ganglia. NOS-containing nerve fibers traveled within large extramural nerve trunks and marched among smooth muscle bundles. Extramural and intramural blood vessels were encircled by varicose NOS-positive axonal processes. The distribution of NOS immunoreactivity paralleled the staining pattern for NADPH-d activity. Urothelium stained strongly for NADPH-d activity but showed no NOS immunolabeling. Specimens from all four patients investigated showed similar staining patterns. Our results suggest that nitric oxide, a potent smooth-muscle-relaxing neurotransmitter in the autonomic nervous system, plays a physiologic role in opening the human UVJ.
Adult↗
Nitric oxide donor, linsidomine chlorhydrate (SIN-1), in the diagnosis and treatment of erectile dysfunction: critical appraisal and review of the literature.
Recent experimental work has demonstrated that nitric oxide (NO) is the neutrotransmitter responsible for cavernous smooth muscle relaxation. Different studies on the performance of the direct NO-donor linsidomine chlorhydrate (SIN-1) in patients with erectile dysfunction have come to conflicting results ranging from highest praise to complete dismissal. We reviewed all published studies on the use of SIN-1 for intracorporeal injection in erectile failure including our own. To this date, 3 groups published their data. Only the uncontrolled data from Hannover claim good results. The controlled data from Hamburg and Berlin on patients with erectile failure due to venous leakage, to a mixed aetiology in a double-blind fashion and to mixed aetiology with drug increase (1 mg versus 2 mg of SIN-1) showed a significantly worse performance of SIN-1 compared to the standard drug for penile injection, prostaglandin E1. We conclude that there is no place for linsidomine chlorhydrate in either the diagnosis or the treatment of erectile dysfunction.
Animals↗
HLA class II analysis in Jewish Israeli narcoleptic patients.
HLA class II was investigated in eight Jewish narcoleptic patients, representing the total of such patients known in Israel at present, and in three patients suffering from sleep disturbances other than narcolepsy. All (11 out of 11) patients carried the serologic specificities DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB1*1501, DQA1*0102, DQB1*0602 which indicates that the susceptibility gene may be located within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely DRB1*1502, DQA1*0103, DQB1*0601. This study confirms that the incidence of narcolepsy in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked to them are involved in the disease.
Alleles↗
Effects of kanamycin ototoxicity and hair cell regeneration on the DC endocochlear potential in adult chickens.
High doses of aminoglycoside antibiotics cause massive damage to the avian basilar papilla. The resulting functional loss could conceivably arise from the reduction in the DC endocochlear potential (EP) due to impairment of the tegmentum vasculosum (TV) or to shunting of current through the damaged sensory epithelium. To test this hypothesis, the EP was measured in adult chickens after destroying hair cells in the basal half of the cochlea with a high dose (400 mg/kg per day for 10 days) of kanamycin (KM). KM treatment caused an increase in the steady-state EP from +18.1 to +23.3 mV and a decrease in the magnitude of the negative EP from -42.0 to -19.2 mV. The EP showed almost no change between 1 and 2 days and 1 week post-KM treatment. After 4 weeks of recovery, most hair cells had regenerated; however, the steady-state EP was still elevated by 13% and the negative EP was depressed by 37%. These results suggest that functional loss as shown by the large reduction in cochlear microphonic (CM) and the elevated thresholds of compound action potential (CAP) following KM treatment is not due to a reduction in the EP but may arise from functional deficits in the hair cells and/or the auditory nerve.
Animals↗
Evaluation of penile arteries with color-coded duplex sonography: prevalence and possible therapeutic implications of connections between dorsal and cavernous arteries in impotent men.
Penile revascularization for cases of arteriogenic impotence is based on the assumption of hemodynamically relevant connections between the dorsal penile and cavernous arteries. In 325 clinically impotent patients color-coded duplex sonography was performed with the penis flaccid and tumescent after intracavernous injection of 10 micrograms prostaglandin E1. We measured peak flow velocity, end diastolic flow velocity and resistance in the dorsal arteries, deep cavernous arteries and connections perforating the tunica albuginea between the 2 systems. Of our patients 14% had at least 1 such anastomosis with a peak flow velocity exceeding 25 cm. per second after stimulation. Peak flow velocities less than 20 cm. per second were noted only in arteriogenically impotent patients, while those exceeding 25 cm. per second without later rigid erection occurred only in patients with venous occlusive dysfunction and end diastolic flow velocity exceeded 5 cm. per second. We conclude that penile revascularization should be contemplated only if hemodynamically relevant connections are detected, peak flow velocity in the cavernous arteries is less than 20 cm. per second and end diastolic flow velocity is less than 5 cm. per second.
Alprostadil↗
How to predict adverse immune reactions induced by pharmaceutical compounds.
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Animals↗
Experimental delayed postischemic spinal cord hypoperfusion after aortic cross-clamping.
BACKGROUND: As in the brain, recent evidence has suggested a defect in the microcirculation during the reperfusion period after spinal cord ischemia. This investigation was undertaken in order to delineate blood flow dynamics in the postischemic spinal cord of the rat. METHODS: Male Sprague-Dawley rats underwent cross-clamping of the aorta and subclavian arteries (XC) for 11 minutes. Spinal cord blood flow (SCBF) was measured by autoradiography in the gray and white matter of cervical (Ce), thoracic (Th) and lumbar (Lu) regions during XC, 1 h, 6 h and 24 h (XC n = 8, 1 h n = 9, 6 h n = 9, and 24 h n = 11, groups) after XC. Control groups underwent surgical manipulations and SCBF measurement but no XC (Sham 1, n = 8), or clamping of the subclavian arteries only (Sham 2, n = 8). RESULTS: In Ce cord, there was no difference between SCBF of 1 h, 6 h, 24 h and Sham 1. In Th cord, SCBF was reduced during XC (P < 0.003 vs. Sham 2), 1 h, 6 h (P < 0.04 and P < 0.01 vs. Sham 1). In Lu cord, SCBF was not detectable in XC, and depressed in 1 h (P < 0.003) and 6 h (P < 0.003). There was no difference between 24 h and Sham 1 in Ce, Th, and Lu cords. CONCLUSIONS: The study demonstrated a period of delayed postischemic hypoperfusion in the white and gray matter of Th and Lu cord segments lasting 6 h after XC. The phenomenon may play an important role in the ultimate fate of neural elements with borderline viability after ischemic injury.
Animals↗
Significance of preoperative colonoscopy in laparoscopic cholecystectomy.
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Aged↗