Picture story. Agony and antagonism.
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Binding Sites↗
Biomedical subjects
T L Smith
Publications and source records attributed to T L Smith.
Picture story. Carefully coordinated copper chemistry.
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Animals↗
Factors affecting mobilization of CD34+ cells in normal donors treated with filgrastim.
BACKGROUND: Multiple days of apheresis are required for some normal peripheral blood progenitor cell (PBPC) donors, to ensure a sufficient collection of CD34+ cells for allografting. It would be of practical value to be able to identify the patients with poor mobilization on the basis of simple pretreatment clinical or hematologic variables. STUDY DESIGN AND METHODS: Clinical characteristics and laboratory data for 119 normal PBPC donors who underwent apheresis on Days 4 to 6 of treatment with granulocyte-colony-stimulating factor (filgrastim) were analyzed for correlations with CD34+ cell yield from the first day of apheresis. RESULTS: The CD34+ cell yield was significantly lower in donors who were more than 55 years of age, who underwent apheresis on Day 4 of filgrastim therapy, or who were not obese. There were weak direct correlations between CD34+ cell yield and the baseline white cell count, preapheresis white cell count, and preapheresis mononuclear cell count, and there was a weak inverse correlation with age. Twenty-one donors (18%) were considered to have poor mobilization (< 20 x 10(6) CD34+ cells/L blood processed). In the multivariate analysis, the only significant factor was age greater than 55 years, which conferred a 3.8 times greater risk (95% CI, 1.1-13.7) of poor mobilization (p = 0.04). However, poor mobilization occurred in all age groups, so the predictive value of the model was low. CONCLUSION: Donor variables correlated with CD34+ cell yield only weakly, so no particular clinical characteristic can be used to exclude an individual as a PBPC donor if he or she is otherwise suitable for the apheresis procedure.
Adolescent↗
Comparison of induced and independent major depressive disorders in 2,945 alcoholics.
OBJECTIVE: Depressive episodes among alcohol-dependent men and women are heterogeneous in causation and clinical course. This study tested three hypotheses regarding the rates and clinical characteristics of two potential subtypes of these affective states: those that appear to be substance-induced mood disorders and those that are independent major depressive episodes. METHOD: Semistructured, detailed interviews were administered to 2,945 alcohol-dependent subjects as part of the Collaborative Study on the Genetics of Alcoholism. With the use of a time line method for determining the type of mood disorder among probands, relatives, and comparison subjects, individuals with histories of the two types of mood disorders were compared. RESULTS: Major depressive episodes with an onset before the development of alcohol dependence or during a subsequent long abstinence period (i.e., independent depressions) were observed in 15.2% of the alcoholics, while 26.4% reported at least one substance-induced depressive episode. According to a logistic regression analysis, the subjects with independent (as compared to substance-induced) major depressive episodes were more likely to be married, Caucasian, and female, to have had experience with fewer drugs and less treatment for alcoholism, to have attempted suicide, and, on the basis of personal interviews with family members, to have a close relative with a major mood disorder. CONCLUSIONS: These results support the contention that it is possible to differentiate between what appear to be substance-induced and independent depressive episodes in alcoholics. Such differentiation might be important for establishing prognosis and optimal treatment.
Adult↗
Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer.
PURPOSE: Most of the data about high-dose chemotherapy (HDCT) for metastatic breast cancer are derived from phase II studies. The interpretation of these data depends on comparisons with data from properly selected historical control patients treated with standard therapy under similar circumstances. We report the long-term results of patients with metastatic breast cancer who were eligible for HDCT but were treated with doxorubicin-containing standard-dose chemotherapy. PATIENTS AND METHODS: Prospectively collected data from 18 successive doxorubicin-containing protocols for the treatment of metastatic breast cancer were evaluated. Using common eligibility criteria for HDCT, we identified patients who would have been candidates for HDCT. We analyzed response rates, progression-free survival (PFS), and overall survival (OS) for all patients, potential HDCT candidates, and noncandidates. RESULTS: A total of 1,581 patients was enrolled onto the 18 studies. Six hundred forty-five were HDCT candidates, and 936 were noncandidates. The complete response rate was 27% for HDCT candidates and 7% for noncandidates; median PFS was 16 and 8 months and median OS was 30 and 17 months, respectively. Survival rates for HDCT candidates and noncandidates, respectively, were 21% and 6% at 5 years and 7% and 2% at 10 years. CONCLUSION: This study suggests that encouraging results of single-arm trials of HDCT could partially be due to selection of patients with better prognoses and further stresses the importance of completing ongoing randomized trials of HDCT to assess the relative efficacy of HDCT in patients with metastatic breast cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Assessing the risk for alcoholism among sons of alcoholics.
OBJECTIVE: A low level of response (LR) to alcohol has been shown to predict a high future risk for alcoholism. Studies to date have incorporated both alcoholism family history positive (FHP) and negative (FHN) subjects, but no prospective investigation has evaluated the predictive power of LR among the higher risk FHP individuals alone. If LR can be adequately evaluated without considering FHN controls, future studies of this high risk group can be done more efficiently. METHOD: As part of a larger study, at an average of over 8 years after original testing, alcoholic outcomes were evaluated with personal interviews for 133 white sons of alcoholic fathers. The development of alcoholism for men whose LR scores at about age 20 fell into the lower third of intensity was compared to the development of alcoholism for men whose LR scores fell above the median. RESULTS: The high and low extremes on LR resulted in an 85.0% sensitivity and 58.9% specificity regarding the prediction of future alcoholism in sons of alcoholics. These results remained robust even after controlling for the quantity and frequency of alcohol intake at the time of original testing. CONCLUSIONS: The data indicate that future research on the relationship between LR and the risk for alcoholism in FHPs can be carried out with a single intoxicating dose of alcohol and without FHN controls.
Adolescent↗
The relationship between Self-Rating of the Effects of alcohol and alcohol challenge results in ninety-eight young men.
OBJECTIVE: The level of intensity of response to a drug is likely to influence the future pattern of intake of the substance. This article evaluates a simple Self-Rating of the Effects (SRE) of alcohol form, and reports the relationship between a person's estimate of the amounts of alcohol usually required for four possible effects during three different time frames and his subjective feelings reported during an alcohol challenge. METHOD: SRE forms and results of a challenge with 0.9 ml/kg (0.72 g/kg) of ethanol were available for 18 to 29 year old drinking, but not alcohol dependent, men (N = 98). A subset of 40 subjects completed a second SRE form approximately 1 year later. RESULTS: The correlation between the two SRE administration was .82 (p < .0001), and the results on the SRE were internally consistent, with a higher number of drinks associated with more intense alcohol effects. Focusing on the subjective feelings reported at the 60-minute timepoint during the alcohol challenge, 11 of the 12 alcohol effect categories on the SRE correlated in the predicted direction, including eight that were statistically significant. Evaluating all seven timepoints during the drinking experiment, the average number of drinks on the SRE correlated significantly with the Subjective High Assessment Scale (SHAS) total score at all but the final timepoint. Sons of alcoholics and controls demonstrated similar levels of correlation between SRE and alcohol challenge results. Finally, the SRE correctly identified 79% of the individuals whose levels of response to alcohol fell into the lowest third of intensity during the alcohol challenge, and it correctly classified 60% to 67% of the alcohol challenge subjects who did not fall into that low response category. CONCLUSIONS: The SRE is a simple and reliable measure of a person's estimate of the number of drinks required to achieve a response. The form might be helpful in educating people about the intensity of their response to alcohol and might be useful as a point of discussion in curricula focusing on genetic aspects of alcoholism. When alcohol challenges are not possible in a research protocol, the SRE might help identify a less heterogeneous subgroup of individuals at high risk for alcoholism who have a common mechanism increasing their vulnerability.
Adolescent↗
Periods of abstinence following the onset of alcohol dependence in 1,853 men and women.
OBJECTIVE: Data from both laboratory experiments and retrospective histories of alcoholics indicate that alternations between periods of abstinence and heavy drinking are common in the course of alcoholism. This article examines the prevalence, chronological characteristics and clinical features associated with periods of abstinence in a large sample of alcohol dependent men and women. METHOD: As part of the Collaborative Study on the Genetics of Alcoholism (COGA), semistructured personal interviews were used to gather data on the course of alcoholism in 1,853 alcohol dependent men and women. Data were evaluated regarding the characteristics of alcoholics with and without periods of abstinence lasting 3 or more months, and the course of these periods over time were evaluated separately for subjects with one, two, three or four episodes of abstention. RESULTS: Despite a relatively high threshold of 3 months for defining an abstinence period, 62.3% of the subjects had at least one such episode, including 55.6% of the 1,853 alcoholics for whom complete data were available. Those alcohol dependent subjects with periods of abstention had an average (+/- SD) of 1.7 +/- 0.99 such periods, and 43% of abstainers had two or more. Logistic regression analyses revealed that the predictors of history of abstention were female gender (odds ratio [OR] = 1.78), older age at interview (OR = 1.04 per year), younger age of onset of alcoholism (OR 0.93 per year), ever having been married (OR = 1.45), the number of DSM-III-R dependence items endorsed (OR = 1.03 per item) and attendance in AA (OR = 2.82). Among abstainers, a period lasting 5 or more years was predicted by older age (OR = 1.03 per year) and AA participation (OR = 3.23), but also by more years of alcoholism (OR = 1.06 per year), white racial background (OR = 1.79) and the absence of history of having been a proband (OR = 3.39). CONCLUSIONS: Periods of abstinence of 3 or more months were commonly observed in the course of alcohol dependence. This information is important for clinicians who need to avoid inappropriate stereotypes of alcoholism and who wish to educate their alcohol dependent patients about the course of this disorder.
Adult↗
Mycobacterial infections: new threats from old disease.
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Adolescent↗
Management of vasospastic disorders of the hand.
Vasospastic disorders of the upper extremity are common and often difficult to treat. Using the proposed classification system (Table 2) allows management based upon pathologic condition, physiologic staging, and response to treatment. Identifying patients in this way also helps in determining which treatments are most appropriate. The basic approach to management includes environmental and behavioral modifications including cessation of tobacco use, protection of hands, and avoidance of situations that trigger the vasospastic response. Pharmacologic therapy may provide good results in a majority of patients. Surgical intervention is reserved for patients with vaso-occlusion, ischemia, and refractory symptoms in spite of attempts at medical management. Surgical options include vascular reconstruction, peripheral sympathectomy, or a combination of techniques. The goal of medical and surgical management is to increase total or nutritional blood flow in the digits.
Hand↗
The Self-Rating of the Effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism.
AIMS: A low level of response (LR) to alcohol is a characteristic of sons of alcoholics and predicts an elevated future alcoholism risk. A 12-question Self-Rating of the Effects (SRE) of alcohol form has been shown to correlate cross-sectionally with a designation of a low LR determined by alcohol challenges. DESIGN: This study evaluates the potential usefulness of the SRE as a retrospective measure of both the response to alcohol and of subsequent alcoholism in two samples. SETTING: All subjects were studied in the United States, most in California. PARTICIPANTS: First, 94 sons of alcoholics and controls completed the SRE 15 years after an alcohol challenge, and SRE values were compared to their prior LR results and their alcoholic outcomes. Secondly, the relationship between SRE results and alcoholic status was determined in 551 men and women alcoholics, their relatives, and controls. MEASUREMENTS: Subjects were evaluated with face-to-face interviews. FINDINGS: Despite the interval of 15 years, the correlation between the SRE and the subjective high feelings on the alcohol challenge was between -0.3 and -0.4. For those 94 subjects the full SRE correlated with a diagnosis of alcohol dependence at 0.5, a figure that remained at 0.3 even when only the estimates related to the earliest drinking experiences were considered. For the 551 men and women, the correlation between the SRE and alcohol dependence diagnoses was 0.6, including 0.3 for the estimates of the first five times of drinking. All major findings in both samples remained robust when the recent drinking history or the number of items endorsed was considered, or when the most severe alcohol problem, passing out, was deleted from the analysis. CONCLUSIONS: When alcohol challenges are not possible, these retrospective reports indicate that the SRE is a potentially useful surrogate for determining a subgroup of people who might carry a low level of response to alcohol and a subsequent elevated risk for alcoholism.
Adult↗
The effect of contusion and cryotherapy on skeletal muscle microcirculation.
OBJECTIVE: The most common treatment of soft tissue contusions is ice application (cryotherapy). The physiological basis for this therapy is assumed to be cold-mediated vasoconstriction resulting in decreased edema formation and a reduction in overall morbidity. This proposed mechanism has not been tested. The present research examined the hypothesis that cryotherapy following contusion is effective because it reduces microvascular perfusion and subsequent edema formation. EXPERIMENTAL DESIGN: The microcirculatory responses to contusion were studied with and without cryotherapy in a chronically instrumented rat model. Initial studies evaluated the immediate effects of cryotherapy on arteriolar and venular diameters and microvascular perfusion (using laser Doppler floxmetry). Variables were measured before and immediately after 20 minutes of cryotherapy. Two additional studies monitored the same microvascular parameters longitudinally in four sets of chronically instrumented animals. Groups of rats studied had contusion or sham contusion with ice treatment or no ice treatment. Measurements were performed repeatedly before and after treatment for 24 hours or 96 hours after contusion/sham contusion. RESULTS: The acute microvascular effects of cryotherapy were vasoconstriction and decreased perfusion. However, when cryotherapy was used as a treatment following contusion/sham contusion, there were no long-lasting microvascular effects of cryotherapy either in the presence or absence of contusion. CONCLUSIONS: These results indicate that cryotherapy of striated muscle following contusion does not reduce microvascular diameters or decrease microvascular perfusion. Alternate mechanisms of action for cryotherapy treatment need to be investigated.
Animals↗
Bilirubin sensitized photooxidation of human plasma low density lipoprotein.
Previous investigations have shown that the bile pigment bilirubin can act as peroxyl radicals scavenger and transition metals trap, but also as a peroxidant, to erythrocyte ghost membranes through 1O2-driven photooxidation. In the present study we examined the changes occurring in the lipoprotein particle following bilirubin-sensitized photooxidation of isolated plasma LDL. The oxidative stress resulted in increased TBA reactivity, diene formation, free cholesterol oxidation, apo B fragmentation and enhanced uptake of the modified particle by the mouse macrophage scavenger receptors as well as the decrease binding to the native B, E-receptor on fibroblasts. The marked increase in TBARS production in D2O-enriched medium and the inhibition of lipid peroxidation of azide is consistent with singlet oxygen involvement in the oxidation process. The apo B-bound Cu2+ appears to become redox active during photooxidation since the presence of EDTA in the reaction mixture greatly reduced protein fragmentation. It was also found that BHT inhibited almost completely the lipid peroxidation, as determined by the TBA reaction but could not totally abolish the formation of 5 alpha-hydroxycholesterol, which is the main product formed by the direct attack of 1O2 on cholesterol. The results of this work strongly suggest that, through photooxidation by light-activated bilirubin, the lipoprotein particle may be modified in the blood stream as well, besides being modified in the well known oxidation site within the arterial wall. Our findings provide the rationale for extending these studies to clinical investigations, which aim at developing strategies for minimizing damage to arterial tissue following phototherapy of hyperbilirubinemic newborns or cancer patients after systemic administration of photosensitizers.
Animals↗
Role of operator subsites in Arc repression.
By binding to adjacent subsites in its 21 base-pair operator, Arc represses transcription from two divergent promoters, Pant and Pmnt, in the immunity I operon of bacteriophage P22. Arc dimers bind to each subsite with nanomolar affinities and interact through protein-protein interactions to stabilize binding further. Here, we show that an Arc dimer bound to a single subsite reduces the rate of RNA polymerase open-complex formation and represses transcription from Pant and Pmnt promoter variants to varying degrees. Occupancy of the subsite proximal to the Pant-35 region results in significantly greater repression than occupancy of the- 10 proximal subsite. For repression of Pmnt, Arc bound at the- 10 proximal subsite is more effective than Arc bound at the- 35 proximal subsite. Because of the divergent orientations of the two promoters, the-35 proximal site in Pant is the same as the- 10 proximal site in Pmnt. Thus, in both cases, the same operator subsite is primarily responsible for repression of transcription initiation.
Base Sequence↗
Increased Na(+)-dependent high affinity uptake of glutamate in astrocytes chronically exposed to ethanol.
The effects of ethanol exposure on the Na(+)-dependent high affinity uptake of [3H]glutamate were determined in primary cultures of astrocytes prepared from neonatal rat cerebral cortex. Acute exposure to 100 mM ethanol had only marginal effects on [3H]glutamate uptake. However, chronic exposure of astrocytes to 50 or 100 mM ethanol for 4 days elicited a dose-dependent increase in the maximal uptake capacity, Vmax, for glutamate with no significant effect on the Km for this process. Because Na(+)-dependent glutamate uptake by astrocytes is considered a principal mechanism for the clearance of brain extracellular glutamate, the present results suggest that the ethanol-induced upregulation of glutamate transport may modulate glutamatergic transmission in certain disease states such as alcoholism.
Animals↗
Dual regulation of open-complex formation and promoter clearance by Arc explains a novel repressor to activator switch.
In studies of variants of the P(ant) promoter of bacteriophage P22, the Arc protein was found not only to slow the rate at which RNA polymerase forms open complexes but also to accelerate the rate at which the enzyme clears the promoter. These dual activities permit Arc, bound at a single operator subsite, to act as an activator or as a repressor of different promoter variants. For example, Arc activates a P(ant) variant for which promoter clearance is rate limiting in the presence and absence of Arc but represses a closely related variant for which open-complex formation becomes rate limiting in the presence of Arc. The acceleration of promoter clearance by Arc requires occupancy of the operator subsite proximal to the -35 region and is diminished when Arc bears a mutation in Arg-23, a residue that makes a DNA-backbone contact in the operator complex.
DNA Footprinting↗
Ethnicity and cure rates of Texas children with acute lymphoid leukemia.
BACKGROUND: Ethnic differences in the survival of children treated for acute lymphoid leukemia (ALL) have been described in several locations. Children of African, Polynesian, Native American, and Mexican ancestry had a less favorable outcome than children of European ancestry when treated in a similar manner by the same physicians and nurses. METHODS: We reviewed the medical records of the 94 European-American (E-A) and 84 Mexican-American (M-A) Texas children registered and treated in national collaborative ALL therapy trials at the M. D. Anderson Cancer Center in Houston between 1974 and 1985 and followed through June 1994. Information was collected regarding age, sex, presenting clinical features, risk for relapse grouping, protocol assignment, event free survival, and the financial status of their families. Cure was defined as initial continuous complete remission for more than seven years and cessation of therapy for more than four years. Presenting characteristics of E-A and M-A children were compared, and then related to cure rates by univariate and multivariate analyses. Event free survival rates of E-A and M-A children were determined together and by sex. RESULTS: Comparing presenting features, financial status as identified by pay code was significantly less for M-A children. Other features were not significantly different. By univariate analysis, an age of 2 to 6 years, female sex, initial white blood cell count below 10,000/microL, low risk grouping, registration on the most recent protocol, and full pay status were significantly associated with higher cure rates. By multivariate analysis, male gender, high risk group, and registration on earlier protocols were found to be significantly associated with a low cure rate. Event free survival and cure rate were lower for M-A children, but the differences were not statistically significant. CONCLUSIONS: Further study of larger numbers of patients, including contemporary immunophenotypic and genotypic characterization of ALL, is needed for better definition of possible ethnic differences. Ethnicity and financial status should be included in the analysis of clinical trials of ALL therapy.
Child↗
An 8-year follow-up of 450 sons of alcoholic and control subjects.
BACKGROUND: Between 1978 and 1988, 453 sons (age range, 18-29 years) of alcoholic and control subject were evaluated for their level of reaction (LR) to alcohol. This article presents the results of the 8.2-year follow-up of 450 of these men. The three goals were (1) to attempt to replicate results of the follow-up of the first 223 subjects, (2) to evaluate the potential impact of the quantity and frequency of drinking at the time of the original study on the relationship between LR and alcoholic outcome (ALC), and, most importantly, (3) to test if the relationship between family history (FH) and ALC might be mediated by LR in a subset of the sample. METHODS: Face-to-face structured follow-up interviews were carried out with the subjects and separately with an additional informant, and blood samples, as well as urine specimens, were obtained for determination of state markers of heavy drinking and drug toxicology screens. RESULTS: First, the rate of development of DSM-III-R abuse and dependence on alcohol was 14.1% and 28.6%, respectively, for family history positive (FHP) subjects, compared with 6.6% and 10.8%, respectively, for family history negative (FHN) men. Second, neither consideration of the quantity nor the frequency of drinking at the time of the original study, nor their combination, effectively diminished the relationships between LR and ALC. Third, among men who drank and demonstrated the 15% highest and lowest scores of LR at about the age of 20 years (ie, 30% of the relevant population), the correlation between FH and ALC was greatly reduced when LR was considered, but the correlation between LR and ALC was not greatly diminished when the impact of FH was evaluated. CONCLUSIONS: In this sample of moderately functional white men, the development of alcoholism occurred in relationship to an FH of alcoholism, but alcohol abuse or dependence was unrelated to prior psychiatric disorders. For this group, LR at the age of 20 years was associated with future alcoholism in a manner that was independent of the drinking practices at the time of the original study. At least among those men with clearly high and low LR scores, these data are consistent with the conclusion that LR might be a mediator of the alcoholism risk.
Adolescent↗