Clonal analysis of bilateral breast cancer

Forty-nine pairs of bilateral breast tumors (41 synchronous and 8 asynchronous cases) were examined for X-chromosome inactivation status and p53 mutations to address the issue of their clonality. Among 12 cases that were informative for the trinucleotide repeat polymorphism in exon 1 of the androgen receptor gene on the X chromosome, 3 cases were found to have different alleles of the locus inactivated in the right and left breast tumors, indicating that the two tumors arose from distinct transformed cells. Thirteen tumors (13%) from 11 women (22%) contained somatic mutations in exons 5-8 of the p53 gene. In two cases, both breast tumors harbored p53 mutations, but the specific mutations were not identical. Seven synchronous and two asynchronous cases had p53 mutations in one tumor only. A germ line p53 mutation at codon 248, one of the most common p53 mutations in Li-Fraumeni syndrome, was observed in one case. Immunohistochemical analysis of p53 protein with a monoclonal antihuman p53 antibody showed concordant positivity between the right and left tumors in three bilateral breast cancer cases. Our results suggest that at least some bilateral breast tumors originate from distinct cells, but that some bilateral breast tumors may be related through a common p53 abnormality.     

A shape-based machine learning tool for drug design

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.     

The role of anterior ectosylvian cortex in cross-modality orientation and approach behavior

Benzoporphyrin derivative (BPD), a sensitizer currently in clinical trials, was evaluated for the treatment of experimental Greene melanoma implanted in the rabbit iris. To improve tumor targeting, BPD was complexed with low-density lipoprotein (LDL) representing an endogenous carrier system for BPD as previously described. Twelve tumors were irradiated at a sensitizer dose of 2 mg kg-1 body weight using a dye laser at 692 nm. Tumor responses were documented by photography, angiography and light and electron microscopy. All tumors treated with 80 J cm-2 regressed irreversibly. The principal mechanism of tumor necrosis was thrombosis following disruption of endothelial membranes. Ultrastructure data suggested tumor cell damage, although evidence for this being the result of direct PDT-mediated tumor cell death was less clear. These data suggest that BPD-LDL may be used to improve the selectivity of photodynamic tumor therapy possibly by the increased uptake of lipoprotein-delivered sensitizer to neovascular endothelial cells.     

Microbial populations of Botrytis cinerea-inoculated strawberry fruit exposed to four volatile compounds

OBJECTIVE: The authors tested the hypothesis that eye tracking disorder in schizophrenia is associated with neurological signs. METHOD: The subjects were 93 normal comparison subjects and 59 schizophrenic patients. They were evaluated with the Neurological Evaluation Scale, a standardized rating instrument that assesses sensory integration, motor coordination, sequencing of complex motor acts, and other neurological signs. Also, the schizophrenic patients' smooth-pursuit eye movements were tested in response to a 0.3-Hz sinusoidal target by means of infrared oculography. They were divided into those with (N=18) and without (N=41) eye tracking disorder by using a previously described method, which was based on mixture analysis of the distribution of position root mean square error. RESULTS: The patients with eye tracking disorder had significantly worse performance than the patients without eye tracking disorder with respect to sensory integration, and the effect size was moderate to large. In comparison with the normal subjects, both patient subgroups had significantly worse performance on all of the Neurological Evaluation Scale subscales. CONCLUSIONS: Although neurological signs are present generally in schizophrenia, poor sensory integration is particularly pronounced in patients with eye tracking disorder. A review of the literature shows that the two abnormalities have strikingly similar patterns of validators, including 1) familial aggregation, 2) premorbid presence, 3) syndromal specificity, 4) trait status, and 5) association with the deficit syndrome. Poor sensory integration and eye tracking disorder in schizophrenia may be various manifestations of a common, underlying pathophysiological process.     

Relationship of cocaine and other substance dependence to well-being of high-risk psychiatric patients

OBJECTIVE: The co-occurrence of substance dependence disorders was determined in a sample of 160 frequently hospitalized adults with severe mental illness, and the relationship between substance dependence and psychosocial functioning and well-being was examined. METHODS: A structured interview was used to assess subjects for co-occurring current DSM-III-R substance dependence disorders during an acute psychiatric hospitalization. They were administered a structed interview that included the subscales of the Addiction Severity Index, the Center for Epidemiological Studies-Depression Scale, Lehman's Quality of Life Interview, Rosenberg's Self-Esteem Scale, the Mastery Scale, and questions about service needs. RESULTS: Seventy-eight of the subjects (48.8 percent) were diagnosed as having at least one current substance dependence disorder. Most subjects with comorbid substance dependence were polysubstance dependent (55.1 percent), and almost half (44.9 percent) met criteria for cocaine dependence. Subjects who were substance dependent were significantly overrepresented among those diagnosed with bipolar disorder, psychotic disorder not otherwise specified, and major depression. When the analysis controlled for demographic characteristics and primary diagnosis, comorbidity was related to depressive symptoms, adverse life conditions, and diminished life satisfaction in several domains. Substance-dependent subjects were significantly more likely to have been arrested and jailed than nondependent subjects. Cocaine-dependent subjects were significantly less satisfied than all other subjects with their living situation and personal safety and more likely to request assistance for their drug and alcohol use problems. CONCLUSIONS: The findings corroborate high rates of co-occurring substance dependence disorders among frequently hospitalized patients with severe mental illness. They also reveal a high prevalence of cocaine dependence and a dramatic pattern of negative correlates of cocaine dependence. The findings suggest that successful interventions for substance dependence may improve these patients' life circumstances and that psychiatric patients may be particularly receptive to such interventions during hospitalization.     

Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina

Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV-hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Follow-up of TIPS: evaluation of signs of dysfunction with Doppler ultrasonography

The anemia of malignancy is common and is related to several etiologic factors, a major one being relative erythropoietin (Epo) deficiency. Blood transfusions, the traditional therapy, provides a quick solution but is associated with complications. This was the rationale for recombinant human Epo (rHuEpo) in the treatment of anemia of cancer. Over the past few years, about 20 publications have reported the results of rHuEpo in the treatment of cancer-associated anemia in more than 850 patients with a variety of malignancies. In general, more than half of the patients responded with a significant increase in their hemoglobin level, a decrease in blood transfusion requirements, and an improved performance status and quality of life. About 4 weeks are required till the onset of effect. The hormone is well tolerated with minimal adverse effects and subcutaneous injections appear to be the preferred method of administration. Additional studies will hopefully answer several questions including optimal dosage and duration of treatment, Epo resistance, and the possibility of predicting the response.     

Amplitude-dependent modulation of brush border enzymes and proliferation by cyclic strain in human intestinal Caco-2 monolayers

Little is known about the effects of repetitive deformation during peristaltic distension and contraction or repetitive villus shortening on the proliferation and differentiation of the intestinal epithelium. We sought to characterize the effects of repetitive deformation of a physiologically relevant magnitude and frequency on the proliferation and differentiation of human intestinal epithelial Caco-2 cells, a common cell culture model for intestinal epithelial biology. Human intestinal epithelial Caco-2 cells were cultured on collagen-coated membranes deformed by -20 kPa vacuum at 10 cycles/minute, producing an average 10% strain on the adherent cells. Proliferation was assessed by cell counting and 3H-thymidine incorporation. Alkaline phosphatase and dipeptidyl dipeptidase specific activity were measured in cell lysates. Since cells at the membrane periphery experience higher strain than cells in the center, the topography of brush border enzyme histochemical and immunohistochemical staining was analyzed for strain-dependence. Cyclic strain stimulated proliferation compared to static cells. Proliferation was highest in the membrane periphery where strain was maximal. Strain also modulated differentiation independently of its mitogenic effects, selectively stimulating dipeptidyl dipeptidase while inhibiting alkaline phosphatase. Strain-associated enzyme changes were also maximal in areas of greatest strain. The PKC inhibitors staurosporine and calphostin C ablated strain mitogenic effects while intracellular PKC activity was increased by strain. The strain-associated brush border enzyme changes were attenuated but not blocked by PKC inhibition. Thus, strain of a physiologically relevant frequency and magnitude promotes proliferation and modulates the differentiation of a well-differentiated human intestinal epithelial cell line in an amplitude-dependent fashion. PKC may be involved in coupling strain to increased proliferation.     

trans-2-Aryl-N,N-dipropylcyclopropylamines: synthesis and interactions with 5-HT(1A) receptors

Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [(3)H]-8-OH-DPAT from rat brain 5-HT(1A) receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (7l) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT(1A) receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT(1A) receptor affinity. The racemic mixtures of the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high enantiomeric 5-HT(1A) receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT(1A) receptor agonist, stimulating both autoreceptors and postsynaptic receptors.