Length-dependent thermopower of highly conducting Au-C bonded single molecule junctions.

We report the simultaneous measurement of conductance and thermopower of highly conducting single-molecule junctions using a scanning tunneling microscope-based break-junction setup. We start with molecular backbones (alkanes and oligophenyls) terminated with trimethyltin end groups that cleave off in situ to create junctions where terminal carbons are covalently bonded to the Au electrodes. We apply a thermal gradient across these junctions and measure their conductance and thermopower. Because of the electronic properties of the highly conducting Au-C links, the thermoelectric properties and power factor are very high. Our results show that the molecular thermopower increases nonlinearly with the molecular length while conductance decreases exponentially with increasing molecular length. Density functional theory calculations show that a gateway state representing the Au-C covalent bond plays a key role in the conductance. With this as input, we analyze a series of simplified models and show that a tight-binding model that explicitly includes the gateway states and the molecular backbone states accurately captures the experimentally measured conductance and thermopower trends.

Histone deacetylases and cancer: causes and therapies.

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

Artificial enzymes.

Simple chemical catalysts have been designed to achieve some desirable features of enzymes. These novel catalysts are not proteins, but they may incorporate the typical enzyme catalytic groups and they achieve selectivity in their reactions by use of geometric control, as do enzymes. Catalysts that carry out geometrically controlled chlorinations of aromatic rings and steroids have been constructed. Other catalysts achieve the selective synthesis of amino acids, and still others imitate ribonuclease in detailed mechanism and hydrolyze RNA. Optimization of geometries has led to a rate acceleration of over 10(8) in one instance.

In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma.

To test the hypothesis that leukotriene (LT) B4 antagonists may be clinically useful in the treatment of asthma, CP-105,696 was evaluated in vitro, using chemotaxis and flow cytometry assays, and in vivo, using a primate asthma model. CP-105,696 inhibited LTB4-mediated monkey neutrophil chemotaxis (isolated cells, LTB4 = 5 nM) and CD11b upregulation (whole blood, LTB4 = 100 nM) with IC50 values of 20 nM and 16.5 microM, respectively. Using a modification of a previously described in vivo protocol (Turner et al. Am. J. Respir. Crit. Care Med. 1994. 149: 1153-1159), we observed that treatment with CP-105,696 inhibited the acute increase in bronchoalveolar lavage (BAL) levels of IL-6 and IL-8 by 56.9 +/- 13.2% and 46.9 +/- 14.5%, respectively, 4 h after challenge with Ascaris suum antigen (Ag). CP-105,696 tended to reduce the increase in BAL protein levels 0.5 h after Ag challenge by 47.5 +/- 18.3%, but this was not statistically significant. In addition, CP-105,696 prevented the significant 11-fold increase in airway responsiveness to methacholine after multiple Ag challenge. These results suggest that LTB4 partially mediates acute and chronic responses to antigen in an experimental primate asthma model and support the clinical evaluation of LTB4 antagonists in human asthma.

Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase.

PURPOSE: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells. EXPERIMENTAL DESIGN AND RESULTS: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals. CONCLUSIONS: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.

Lithium incorporation in the fibroblasts of manic-depressives.

Lithium incorporation in cultured human skin fibroblasts was measured in a group of 10 manic-depressives and 10 controls. This system was believed to eliminate many of the sources of variability to which measurement of the lithium ratio in erythrocytes (RBCs) is subject. A fibroblast lithium ratio calculated from 1-hr lithium incorporation studies correlated highly with an in vitro RBC lithium ratio in medication-free controls. Manic-depressives and controls did not differ in lithium incorporation or fibroblast lithium ratio, leading to the conclusion that the lithium ratio is probably not a good measure for differentiating the two populations.

Contribution of the depressive perspective to memory function in depression.

The authors used a story recall paradigm to elucidate some aspects of the memory problems of depressive patients. They compared 21 hospitalized depressed patients with a matched group of control subjects for recall of a theme story containing material with positive, negative, and neutral affective tones. The results indicated an overall deficit in the story recall of the depressed patients, most of which could be ascribed to a decrement in recall of the positive themes in the story. Recall of the negative and neutral themes remained intact. These results are consistent with the view that a depressive perspective contributes one component to the memory difficulties of depressed patients.

Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.

Male pattern baldness (MPB) and prostate cancer are common in American males; however, MPB is clinically observable decades earlier. Aging, androgens, and heritability are risk factors for both conditions. We prospectively studied the association between MPB and clinical prostate cancer in a cohort representative of the United States male population. A total of 4,421 men 25-75 years old without a history of prostate cancer were examined for baldness in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. Participants were followed from baseline (1971-1974) through 1992. Incident cases of prostate cancer were identified by interviews, medical records, and death certificates. Age-standardized incidence rates and proportional hazards models were used to examine the association between MPB and clinical prostate cancer. Prostate cancer was diagnosed in 214 subjects over 17-21 years of follow-up. The age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 versus 12.5 per 10,000 person-years). The adjusted relative risk for prostate cancer among men with baldness was 1.50 (95% confidence interval, 1.12-2.00) and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. MPB seems to be a risk factor for clinical prostate cancer.

Long-term recreational physical activity and breast cancer in the National Health and Nutrition Examination Survey I epidemiologic follow-up study.

Our purpose was to study the association between long-term recreational physical activity and breast cancer in the Epidemiological Follow-up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I, 1971-1975). The analytic cohort included 6160 women who were free of breast cancer at the first NHEFS follow-up in 1982-1984 and had interview data on recreational physical activity (low, moderate, and high) in 1982-1984 and 10 years earlier, in 1971-1975. We created categories of long-term (1982-1984 + 1971-1975) recreational physical activity: (a) consistently low; (b) moderate/inconsistent; and (c) consistently high. Data were analyzed using Cox proportional hazard regression models. A total of 138 women developed breast cancer between 1982-1984 and 1992. In women > or =50 years of age in 1982-1984, consistently high (versus consistently low) recreational physical activity was associated with a 67% reduction in breast cancer risk (n = 96 cases; relative risk, 0.33; 95% confidence interval, 0.14-0.82; P for trend = 0.03); in women <50 years of age (n = 42 cases), there was no association. Associations were not modified by body mass index or by weight gain as an adult. High recreational physical activity over the long-term may reduce breast cancer risk in women > or =50 years of age; in this sample, it did so regardless of weight history.

Serological precursors of cancer: malignant melanoma, basal and squamous cell skin cancer, and prediagnostic levels of retinol, beta- carotene, lycopene, alpha-tocopherol, and selenium.

To determine the association between prediagnostic serum levels of retinol, beta-carotene, lycopene, alpha-tocopherol, and selenium and the subsequent risk of malignant melanoma, and basal and squamous cell skin cancer, a nested case-control study among residents of Washington County, MD, was performed. Cases with melanoma (n = 30), basal cell (n = 32), and squamous cell (n = 37) skin cancer who were admitted to hospital for treatment or biopsy of metastatic lesions were each matched by age, sex, and race with two controls. There were no significant associations between serum micronutrient levels and the risk of subsequent skin cancer.

Specific inhibition of leukotriene B4 (LTB4)-induced neutrophil emigration by 20-hydroxy LTB4: implications for the regulation of inflammatory responses.

1. The interaction between leukotriene B4 (LTB4) and its metabolite, 20-hydroxy LTB4 in the control of neutrophil emigration was examined in guinea-pig skin. 2. Leukotriene B4 (10-300 ng) elicited a dose-dependent increase in neutrophil infiltration (as measured by myeloperoxidase activity) 4 h after injection into guinea-pig skin. In contrast, 20-hydroxy LTB4 (30-1000 ng) displayed only weak inflammatory activity in this assay. 3. Although 20-hydroxy LTB4 had low agonist activity, this metabolite caused a potent dose-dependent inhibition of responses to LTB4 (100 ng), when administered systemically (ED50 = 1.3 micrograms kg-1, s.c.) without significantly affecting neutrophil infiltration in response to C5a (2 micrograms). Systemic administration of 20-carboxy LTB4 (10 micrograms) did not affect neutrophil accumulation in response to LTB4 or C5a. In addition, neither 15(S)-hydroxy 5(S)-HPETE(10 micrograms) nor lipoxin A4 (10 micrograms) inhibited responses to LTB4. 4. Addition of 20-hydroxy LTB4 (10(-11)-10(-8) M) to human blood prior to isolation of the neutrophils led to concentration-dependent decrease in the number of LTB4 receptors and decreased chemotactic responsiveness to LTB4 without affecting responses to C5a. Incubation of blood with 20-carboxy LTB4 (10(-8) M) did not reduce LTB4 receptor number of chemotactic responsiveness to LTB4. 5. These data indicate that although 20-hydroxy LTB4 is a weak agonist at LTB4 receptors, it can desensitize neutrophils to the effects of LTB4 via down-regulation of the high affinity receptor and thus provides evidence for a mechanism whereby inflammatory responses may be regulated.

Characterization of the pharmacological profile of the potent LTB4 antagonist CP-105,696 on murine LTB4 receptors in vitro.

1. Binding of [3H]-leukotriene B4 ([3H]-LTB4) to murine spleen membranes (MSM) was determined. 2. Scatchard analyses of [3H]-LTB4 binding indicated the presence of high (KD1 = 1.7 nM) and low (KD2 = 7.5 nM) affinity receptors on MSM with Bmax values of 151 fmol mg-1 protein (Bmax1) and 354 fmol mg-1 protein (Bmax2), respectively. 3. CP-105,696, a potent LTB4 antagonist, inhibited [3H]-LTB4 (0.67 nM) binding to the high affinity receptor on MSM, IC50 = 30.2 nM, Ki = 17.7 nM with a Hill coefficient of 0.93. 4. Scatchard analyses of [3H]-LTB4 binding to MSM in the presence of CP-105,696 indicated that the high-affinity receptor was inhibited in a non-competitive manner and the low-affinity receptor in a competitive manner. 5. Isolated peripheral blood murine neutrophils (MN) responded chemotactically to LTB4, EC50 = 2.5 nM. CP-105,696 blocked this response, IC50 = 2.3 nM. When examined over a full concentration-response range of LTB4, CP-105,696 inhibited chemotaxis in a non-competitive manner. 6. Murine neutrophils in anticoagulated whole blood upregulated the integrin, complement receptor type 3 (CD11b/CD18, Mac-1) in response to LTB4, EC50 = 20 nM and this was inhibited by CP-105,696 in a competitive manner. 7. These results provide evidence that MSM have specific binding sites for LTB4, and as exemplified by CP-105,696, that these receptors may be useful for determining the potency and nature of antagonism of novel LTB4 receptor antagonists.

Alcohol and prostate cancer in the NHANES I epidemiologic follow-up study. First National Health and Nutrition Examination Survey of the United States.

PURPOSE: We prospectively investigated the association between alcohol consumption and prostate cancer in the Epidemiologic Follow-up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I). METHODS: There were two cohorts: 1) Cohort I, followed from baseline (1971-75) through 1992, included 5766 men ages 25-74 years (median follow-up = 17 years); and 2) Cohort II, followed from the first follow-up round for Cohort I (1982-84) through 1992, included the 3868 men in Cohort I free of prostate cancer in 1982-84 (median follow-up = 9 years). Alcohol consumption was assessed at baseline as usual consumption, and at follow-up as usual consumption and as distant past consumption at the ages of 25, 35, 45, and 55. RESULTS: There were 252 incident cases of prostate cancer. Consistent with most previous studies, we found no significant associations between usual total alcohol consumption and prostate cancer in Cohorts I or II [p = non significant (NS)], except for a significant inverse association at the heaviest level of drinking in Cohort II [relative risk (RR) = 0.23, 95% confidence interval (CI) = 0.06-0.95]. Further study of heavy drinkers in Cohort II revealed significant inverse associations between distant past heavy drinking (defined as > 25 drinks/week) and prostate cancer at age 25 (RR = 0.20, 95% CI = 0.06-0.63), age 35 (RR = 0.30, 95% CI = 0.12-0.77), and age 45 (RR = 0.39, 95% CI = 0.17-0.93), but not at age 55 (RR = 0.43, 95% CI = 0.17-1.10). CONCLUSIONS: These results suggest that it may be important to consider distant past alcohol consumption in etiologic studies of prostate cancer. However, our results were based on small numbers of cases who were heavy drinkers and require replication.

The elicitation of a movement disorder by trazodone: case report.

A 65-year-old woman with bipolar disorder and complicated cardiovascular disease who was on maintenance lithium therapy developed a movement disorder following high doses of trazodone for treatment of an acute depression. When the trazodone was reduced, the involuntary movements promptly ceased. Although the movement disorder could not with certainty be attributed to trazodone alone, the drug at least acted as an eliciting agent.

Comparison of one-day and three-day calorie counts in hospitalized patients: a pilot study.

OBJECTIVE: To determine whether a 1-day calorie count can replace the labor-intensive 3-day calorie count commonly, performed in hospitalized patients when estimates of caloric and protein intake are required. DESIGN: Pilot study using prospective, non-concurrent review of medical records. SETTING: Hospital. PARTICIPANTS: Thirty patients (mean age 67 years). RESULTS: Mean 3-day intake (952 +/- 91 calories, 41 +/- 4 g protein) was about half of calculated requirements; first-day intake was similar (918 +/- 116 calories, 40 +/- 5 g protein). The first day had high sensitivity (calories 96%; protein 93%) and positive predictive value (calories 100%; protein 96%). Malnutrition was evident; three-fourths of patients had weights below recommended ranges, and 83% were hypoalbuminemic. CONCLUSIONS: Three-day calorie counts are frequently performed in patients suspected of eating poorly. Results of this pilot study suggest that 1-day calorie counts may be a valid alternative. However, readily available anthropometric and biochemical data may be as good an indicator of inadequate dietary intake.

The importance of dietary protein in healing pressure ulcers.

OBJECTIVE: To determine the effect of dietary protein on healing of pressure ulcers in malnourished patients. DESIGN: Nutritional intervention trial with the non-randomized assignment of patients by pressure ulcer stage and bed type. SETTING: Long-term care facility. PATIENTS: Twenty-eight malnourished patients (age = 72 +/- 18 years, mean +/- SD) with a total of 33 truncal pressure ulcers. Nine patients had stage II ulcers, eight had stage III ulcers, and 16 had stage IV ulcers. METHODS: Patients received liquid nutritional formulas as tubefeedings or meal supplements containing either 24% protein (61 g protein/L; n = 15) or 14% protein (37 g protein/L; n = 13) for 8 weeks. RESULTS: There was a significant decrease in total truncal pressure ulcer surface area of the 15 patients in the 24% protein group (-4.2 +/- 7.1 cm2, P < 0.02), but not in the 13 patients in the 14% protein group (-2.1 +/- 11.5 cm2, P = NS). The change in total ulcer area correlated with both dietary protein intake per kg body weight (rs = -0.50, P < 0.01) and caloric intake per kg body weight (rs = -0.41, P < 0.03). The decrease in stage IV ulcer area in eight patients in the 24% protein group (-7.6 +/- 5.8 cm2, P < 0.02) was significantly greater (P < 0.05) than in eight patients in the 14% protein group (-3.2 +/- 16.4, P = NS). In these 16 patients, the decrease in ulcer size also correlated with dietary protein intake per kg body weight (rs = -0.63, P < 0.01). CONCLUSION: High protein diets may improve the healing of pressure ulcers in malnourished nursing home patients.

Antihydrophobic cosolvent effects in organic displacement reactions.

[formula: see text] Rates of reactions in water can be modified by the presence of antihydrophobic cosolvents such as ethanol and DMSO, which lower the energies of nonpolar surfaces. The rate effects reflect changes both in the solvation of nonpolar surfaces and also in the solvation of polar groups. The effects have been sorted out for some displacement reactions, revealing the geometry of an interesting branching reaction whose two paths show different antihydrophobic effects.

Crisis hospitalization on a psychiatric emergency service.

The availability of short-stay beds for brief admissions to a Psychiatric Emergency Service (PES) is a model that meets a variety of patient and system needs, allowing time to develop alternatives to hospitalization or gain diagnostic clarity, serving a respite function, providing a hospital setting that does not gratify dependency needs, and relieving inpatient census pressures. An eight-bed service for brief inpatient stays of up to 3 days was developed on a PES which serves a large nine-country catchment area in northeastern New York State. Admissions to this unit would otherwise have gone to a medical school teaching hospital psychiatric unit or a state psychiatric center. Fifty-one consecutive admissions were studied. The majority of patients were dischargeable in the short time frame and did not require transfer for longer-term care. The patients as a group showed improvement in psychiatric symptomatology and rated high satisfaction with the program. Most patients were diagnosed with schizophrenia or personality disorder (PD). Suicidality and substance abuse were frequent. The PD patients had a strong association with suicidality and some association with substance abuse, whereas the schizophrenics had more psychiatric symptomatology. PD patients were more likely to be discharged, leading us to propose a rationale for why this group may be uniquely suited to this approach. The study was replicated after a year on another sample of 51 consecutive admissions, confirming the earlier results and providing a 1-year follow-up on the program.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute intoxication and substance abuse among patients presenting to a psychiatric emergency service.

It is common for patients to arrive at the Psychiatric Emergency Service (PES) under the influence of a variety of drugs. The purpose of this study was to 1) determine what impact there was on the PES of patients who arrive after engaging in substance abuse within the 24 hours prior to arrival; and 2) describe some of the parameters associated with substance abuse and mental illness in the PES setting. Consecutive evaluations done at the PES during the study month were reviewed retrospectively utilizing the extensive material collected in the screening chart. Of the 294 evaluations, 32.0% (n = 94) were on patients with acute intoxication and 17.0% (n = 50) had a primary diagnosis of substance abuse or dependence; 49 of 50 presented with active substance abuse. Schizophrenic and personality disorder patients presented with significant levels of acute intoxication (25.2%, 26/103), whereas substance use rate was quite low for patients with affective disorder, adjustment disorder, and other diagnoses. Alcohol was the overwhelming drug of choice by all diagnostic groups, making it difficult to determine group differences in choice of drug. Both the univariate and multivariate studies presented demonstrate that regardless of diagnosis, the impact of substance abusing patients is substantial. They present with high acuity (usually acutely suicidal), require high levels of behavior management, and spend more time in the PES. However, they have much less need for psychiatric hospitalization. In contrast, the patients presenting with psychosis also have a high rate of behavior management needs, but these patients are very likely to be hospitalized. These findings suggest that an important role for the PES is a "filter" to triage patients to the appropriate treatment setting and that this role is fulfilled when the PES is able to provide sufficient time and resources for evaluation and/or stabilization.