Search PubMed⌕ Search

Biomedical subjects

T L Smith

Publications and source records attributed to T L Smith.

At least 19 recordsLinked to original sources
PubMed2003

A 5-year prospective evaluation of DSM-IV alcohol dependence with and without a physiological component.

BACKGROUND: The DSM-III-R removed tolerance and withdrawal as required elements for a diagnosis of alcohol dependence. Although this practice was continued in DSM-IV, the more recent manual asked clinicians to note whether physiological aspects of withdrawal (tolerance and withdrawal) had ever been experienced. Few studies have determined the prognostic meaning of a history of a physiological component to DSM-IV alcohol dependence. METHODS: Face-to-face structured interviews were used to evaluate the course of alcohol, drug, and psychiatric problems during the subsequent 5 years for 1094 alcohol-dependent men and women. These subjects had been classified into subgroups at the time of initial interview regarding evidence of tolerance or withdrawal, and all evaluations were based on DSM-IV criteria. At baseline, the application of DSM-IV diagnostic guidelines resulted in 649 (59.3%) individuals having a history of an alcohol withdrawal syndrome, with or without tolerance (group 1); 391 (35.7%) with histories of tolerance but not withdrawal (group 2); and 54 (4.9%) with no lifetime histories of tolerance or withdrawal (group 3). RESULTS: During the 5-year follow-up, both the broad (group 1 plus 2 versus group 3) and narrow (group 1 versus group 2 plus group 3) definitions of physiological dependence were associated with more alcohol and drug problems. However, for most items, this differential primarily reflected differences between groups 1 and 3, with a less impressive effect by group 2. Although no group differences were noted for the rate of independent major depressive episodes, substance-induced depressions did differentiate among groups, a finding also most closely related to the distinction between groups 1 and 3. CONCLUSIONS: These data support the prognostic importance of noting the presence of a physiological component in alcohol dependence and indicate the potential relevance of limiting the definition of a physiological component to withdrawal.

Adult↗
PubMed2003

A five-year prospective study of diagnostic orphans for alcohol use disorders.

OBJECTIVE: One consequence of the DSM-IV diagnostic system for substance abuse and dependence is that there are individuals who might endorse one or two of the criterion items for dependence but not meet criteria for abuse. These persons have been referred to as "diagnostic orphans." The aim of the analyses presented here is to further understanding about this potentially important group. METHOD: The DSM-IV categorical approach was used to determine alcohol-related diagnoses for 439 young adult men. Structured face-to-face follow-up interviews were administered 5 years later. RESULTS: At the beginning of the evaluation period, 14.6% (n = 64) of the men were alcohol dependent, 18.2% (n = 80) fulfilled criteria for alcohol abuse, 16.4% (n = 72) did not meet criteria for an alcohol use disorder but endorsed one or two of the dependence criteria and 50.8% (n = 223) reported none of the dependence items. At the initial interview, and again 5 years later, the diagnostic orphans reported alcohol and drug use histories that fell between the histories of those with dependence and those with no alcohol-related difficulties. The orphans were most similar to the men with abuse, although they had lower quantities and frequencies of alcohol use, endorsed fewer additional alcohol-related problems and reported less involvement with drugs compared with that group. CONCLUSIONS: Although the diagnostic orphans were more similar to the subjects with alcohol abuse than they were to those with dependence or no diagnosis, the data do not necessarily support combining the orphans with those with abuse. These diagnostic orphans do, however, constitute an important group that carries an enhanced risk for alcohol use disorders and should be closely followed.

Adult↗
PubMed2002

Mood and anxiety symptoms among 140 children from alcoholic and control families.

OBJECTIVE: Children of alcoholics have been reported to have elevated levels of internalizing symptoms, including anxiety and depression. However, many studies have not adequately controlled for the influence of independent (i.e. not substance-induced) parental mood or anxiety disorders and other factors. The present evaluations assess the relationships of the family histories of alcohol use disorders and independent mood and anxiety disorders to internalizing symptoms in children of alcoholic and nonalcoholic subjects. METHOD: A behavioral checklist and a structured interview were administered to the parents of 140 children aged 7-18 years. The fathers of these offspring had been recruited 15 years previously from a university population to participate in a prospective study of 453 men from alcoholic and nonalcoholic families. RESULTS: While a higher score for one of four measures of internalizing symptoms in the children was found to relate to a higher density of alcoholic relatives, this pattern was more robust in children of parents with mood or anxiety disorders. In a hierarchical regression, the family history of alcohol use disorders did not add significantly to the prediction of any of the four internalizing scores in the children after considering the impact of a family history of independent mood and anxiety disorders. CONCLUSIONS: The results indicate that internalizing symptoms in children of alcoholics were more strongly influenced by a positive family history of mood and anxiety disorders than the family history of alcohol use disorders.

Adolescent↗
PubMed2002

Is there an increased rate of additional malignancies in patients with mantle cell lymphoma?

PURPOSE: To examine the frequency of additional neoplasms preceding and following the diagnosis of mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 156 patients with MCL treated on the hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternated with methotrexate and cytosine arabinoside (Hyper-CVAD/M-A) program with or without rituximab from 1994 to 2000 were the subjects of this report. RESULTS: These patients were followed for a median time of 26 months, and a total of 32 (21%) additional neoplasms were diagnosed, 21 preceding the diagnosis of MCL and 11 following MCL. After excluding certain types of non-invasive neoplasms, including basal cell carcinoma, meningioma and cervical intraepithelial neoplasia, we observed seven second malignancies after the diagnosis of MCL, and the 5-year cumulative incidence rate of second malignancy was 11%. The observed-to-expected (O/E) ratio was 7/0.07 = 100 [95% confidence interval (CI) 49.3 to 186.6; P <0.0001]. Of the 21 malignancies diagnosed prior to MCL, 16 were invasive and five non-invasive. There were a total of 10 urologic malignancies occurring before or after the diagnosis of MCL was established. CONCLUSIONS: Our findings suggest that there is an increased incidence of second malignancies in patients with MCL. In addition, the high number of cases with urinary tract cancer in our series may substantiate prior reports describing a possible association between lymphoma and urologic malignancies.

Adult↗
PubMed2002

Recommendations for sentinel lymph node processing in breast cancer.

The status of the sentinel lymph node (SLN) has been shown to accurately reflect the presence or absence of metastases in the axilla in patients with breast cancer. This study was designed to determine the optimal protocol for SLN processing. A total of 173 SLNs from 96 breast cancer patients who had successful SLN localization and underwent completion axillary node dissection were identified. All SLNs were negative for metastases by initial routine histologic evaluation. The nodes were submitted in a total of 300 blocks. Each block was serially sectioned to produce 10 levels. Pan-cytokeratin stain was performed on levels 3 and 8. All other levels were stained with hematoxylin and eosin. Metastases were identified in 22 SLNs from 19 patients by examining all 10 levels. The first two hematoxylin and eosin- or the first cytokeratin-stained levels were positive for metastases in 21 (95.5%) of the 22 positive SLNs. Two additional hematoxylin and eosin-stained and one cytokeratin-stained levels of each SLN correctly identified the status of the node in 94 (97.9%) of 96 patients. Therefore, we recommend that after an initial hematoxylin and eosin-stained section, two additional hematoxylin and eosin-stained sections and one cytokeratin-stained section should be evaluated.

Adult↗
PubMed2002

Prevalence of spasticity post stroke.

OBJECTIVES: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. DESIGN: A cohort study of prevalence of spasticity at 12 months post stroke. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Muscle tone measured at the elbow using the Modified Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modified Barthel Index. RESULTS: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modified Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had significantly lower Barthel scores at 12 months (p < 0.0001). CONCLUSION: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.

Aged↗
PubMed2002

A comparison of alcohol-induced and independent depression in alcoholics with histories of suicide attempts.

OBJECTIVE: Alcohol-dependent men and women are at high risk for two types of major depressive episodes and for suicide attempts. The aim of this study is to compare the characteristics of two groups: (1) alcohol-dependent subjects with histories of suicide attempts and independent mood disorders and (2) a similar population of alcoholics with histories of self harm but who have only experienced alcohol-induced depressions. METHOD: As part of the Collaborative Study on the Genetics of Alcoholism (COGA), semistructured detailed interviews were administered to 371 alcohol-dependent individuals (62% women) with histories of suicide attempts and major mood disorders. Of the total, 145 (39.1%) had ever had an independent depressive episode and 226 (60.9%) had experienced only alcohol-induced depressions. Information was obtained about socioeconomic characteristics, suicidal behavior, independent and induced psychiatric conditions, and aspects of alcohol dependence. RESULTS: Univariate and multivariate comparisons revealed that alcohol-dependent individuals with a history of suicide attempts and independent depression had a higher number of suicide attempts, were less likely to have been drinking during their most severe attempt, and were more likely to have an independent panic disorder. Univariate analyses indicated that these subjects reported a less severe history of alcohol dependence. CONCLUSIONS: The results indicate that a distinction between independent and alcohol-induced mood disorders in alcoholics with a history of suicide attempts may be useful.

Adult↗
PubMed2002

Comparison of 3190 alcohol-dependent individuals with and without suicide attempts.

INTRODUCTION: Suicidal behaviors are often seen in alcohol-dependent individuals. The aim of this study is to identify and confirm risk factors for suicide attempts in a large, family-based sample of alcoholics. METHODS: Semistructured, detailed interviews were administered to 3190 alcohol-dependent individuals as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Information about suicidal behavior, socioeconomic characteristics, psychiatric comorbidity, substance use disorders, and characteristics of alcohol dependence were obtained from alcohol-dependent probands, controls, and their relatives. RESULTS: As determined by both univariate comparison and multivariate logistic regression analysis, alcohol-dependent individuals with a history of suicide attempts were found to have a significantly more severe course of alcohol dependence and a higher prevalence of both independent and substance-induced psychiatric disorders and other substance dependence. First-degree relatives of subjects with suicide attempts showed a significantly higher rate of suicide attempts, even after controlling for additional relevant diagnoses. CONCLUSION: These results support the hypothesis that alcohol-dependent individuals with a history of suicide attempts are more severely impaired. Screening and subsequent treatment of alcohol use disorder, psychiatric comorbidity, and substance use disorders among alcoholics may be crucial in preventing suicide attempts and completions.

Adult↗
PubMed2001

Inflammatory and granulomatous lesions of the larynx and pharynx.

A number of inflammatory and granulomatous lesions can involve the larynx and pharynx. These conditions are generally difficult to diagnose because of the range of symptoms. This article reviews the following conditions: supraesophageal complications of reflux disease, relapsing polychondritis, Wegener granulomatosis, sarcoidosis, tuberculous laryngitis, Teflon (polytetrafluoroethylene fluoropolymer resin; DuPont, Wilmington, DE) granuloma, amyloidosis, rheumatoid arthritis, and systemic lupus erythematosus. The purpose is to provide a brief review of each disease and its manifestations, symptoms, diagnosis, and treatment.

Comorbidity↗
PubMed2001

Female patients with breast carcinoma age 30 years and younger have a poor prognosis: the M.D. Anderson Cancer Center experience.

BACKGROUND: The objective of this study was to analyze the outcome of treatment in young women with breast carcinoma who were treated at a single institution and to develop a clearer understanding of the natural history of the disease in these women. METHODS: One hundred eighty-five women age < or = 30 years in whom a diagnosis of invasive breast carcinoma was made between October 1985 and September 1995 were identified in the Tumor Registry data base. Patient data were obtained by chart review. All female patients with breast carcinoma who were age > 30 years and who were identified in the same data base and received treatment during the same period served as the control population. The stage-stratified overall survival (OS) rate for the study patients was compared with the OS rate for both the control population and patients in the National Cancer Data Base (NCDB). RESULTS: Of 185 patients, 11% presented with Stage I disease, 45% presented with Stage II disease, 38% presented with Stage III disease, and 6% presented with Stage IV disease. Twenty-nine percent of patients with Stage I disease received adjuvant therapy, and 84% of patients with Stage II disease and 96% of patients with Stage III disease received either adjuvant or neoadjuvant chemotherapy. Among patients with Stage I disease, 8 patients underwent mastectomy and 13 patients underwent breast-conserving surgery (BCS). Among patients with Stage II disease, 66 patients underwent mastectomy and 17 patients underwent BCS. Among patients with Stage III disease, 65 patients underwent mastectomy and 5 patients underwent BCS. The 5-year OS rate was 87% for patients with Stage I disease, 60% for patients with Stage II disease, 42% for patients with Stage III disease, and 16% for patients with Stage IV disease. Compared with the control patients and those in the NCDB, there was a trend toward worse OS rates in women age < or = 30 years. CONCLUSIONS: Women who are diagnosed with breast carcinoma at an age < or = 30 years appear to have a poorer prognosis compared with that for their older counterparts.

Adolescent↗
PubMed2001

Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC.

PURPOSE: We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging. PATIENTS AND METHODS: A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy. RESULTS: There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured. CONCLUSION: These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.

Adult↗
PubMed2001

Gemcitabine modulation of alkylator therapy: a phase I trial of escalating gemcitabine added to fixed doses of ifosfamide and doxorubicin.

BACKGROUND: The authors investigated the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) associated with the addition of a biomodulating dose of gemcitabine to an established regimen of ifosfamide and doxorubicin as part of a program to explore the potential of low-dose gemcitabine to modulate the activity of alkylating agents. METHODS: A Phase I trial was carried out in a population of patients with bladder or pelvic carcinoma for whom no standard therapy was available. Doses of ifosfamide and doxorubicin were held fixed at 2 g/m(2) for 4 days and 20 mg/m(2) for 3 days, respectively. Gemcitabine was given on Day 2 and Day 4 at doses of 90 mg/m(2), 150 mg/m(2), and 200 mg/m(2) per dose. RESULTS: A total of 18 patients received 53 courses of therapy. Myelosuppression was dose limiting. Nonhematologic toxicity also was significant, with 10 of 18 patients experiencing toxicity of Grade 3 or greater. For previously untreated patients with an intact performance status, the MTD for gemcitabine in this context was at least 150 mg/m(2) per dose. According to an intent-to-treat analysis, 11 of 18 patients demonstrated a clinically significant response to this regimen. CONCLUSIONS: The regimen of ifosfamide and doxorubicin with the addition of gemcitabine was significantly toxic but has promising activity. Based on the observed activity and the generally reversible nature of the toxicity, the authors have initiated a Phase II trial of this regimen in patients with untreated, metastatic urothelial carcinoma.

Adult↗
PubMed2001

Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors.

The rapid recovery of hematopoiesis after allogeneic blood stem cell transplantation has been attributed to the quality and quantity of hematopoietic progenitors in the blood stem cell grafts from filgrastim-stimulated donors. To determine whether further stimulation with filgrastim after transplantation would affect hematopoietic recovery, a prospective, randomized, controlled study was performed. Forty-two adult recipients of allogeneic blood stem cells from human leukocyte antigen-matched related donors were randomized to receive 10 microg/kg per day filgrastim subcutaneously from day 1 through neutrophil recovery or no growth factor support after transplantation. There was no significant difference between the 2 groups in the number of CD34(+) cells infused (median, 4.8 vs 4.3 x 10(6)/kg). Graft-versus-host (GVHD) disease prophylaxis consisted of tacrolimus and steroids for 9 patients and tacrolimus and minimethotrexate for 33 patients. The group receiving filgrastim had a shorter time to neutrophil levels greater than 0.5 x 10(9)/L (day 12 vs day 15, P =.002) and to neutrophil levels greater than 1.0 x 10(9)/L (day 12 vs day 16, P =.01). The filgrastim group also had a trend for earlier discharge (day 16 vs 20, P =.05). There was no significant difference between the groups in time to platelet recovery, number of transfusions, regimen-related toxicity, infection, incidence of GVHD, relapse, survival, or hospital charges. It can be concluded that the administration of filgrastim after allogeneic blood stem cell transplantation shortens the time to neutrophil recovery. (Blood. 2001;97:3405-3410)

Adolescent↗
PubMed2001

Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.

BACKGROUND: Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. METHODS: 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. FINDINGS: Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29). INTERPRETATION: Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.

Adult↗
PubMed2001

Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.

Acute Disease↗
PubMed2001

Radiofrequency tissue volume reduction: multilesion vs single-lesion treatments for snoring.

OBJECTIVE: To compare the safety and efficacy of single-lesion and multilesion radiofrequency tissue reduction (RFTR) of the soft palate for the treatment of snoring. DESIGN: Prospective, nonrandomized clinical trial. SETTING: University hospital outpatient clinic. PATIENTS: Nonrandomized patients undergoing RFTR to treat socially unacceptable snoring. Of 47 patients, 16 received single-lesion treatments and 31 received multilesion treatments. INTERVENTION: Soft-palate RFTR was performed using a radiofrequency generator. Patients required 1 to 3 treatments based on improvement or withdrawal from the study, and each received 1, 3, or 4 lesions per treatment. Patients who received single-lesion therapy did not cross over into the multilesion group; however, 5 patients in the multilesion group received 4-lesion therapy after a treatment with 3 lesions. MAIN OUTCOME MEASURES: Outcome measures were determined using visual analog scale questionnaires assessing level of snoring (snoring index) and level of pain (pain index) associated with the procedure. Adverse events and complications during treatment were cataloged. Data were collected before the procedure, 6 weeks after each treatment, and an average of 16 months after the last procedure. RESULTS: Single-lesion and multilesion groups showed significant improvement in snoring after RFTR treatments (P<.01 for both). However, compared with the single-lesion group, the multilesion group required fewer treatments (1.94 vs 2.38; P =.05) and was more than twice as likely to be cured after 2 treatments (61% vs 25%; P =.02). A trend toward improved clinical outcomes with increased number of lesions and total energy per treatment was observed when patients treated with 1, 3, or 4 lesions were compared. The 4-lesion group had the most pronounced improvement in snoring index score per treatment, the lowest number of treatments required for cure, and the greatest percentage of patients cured after 2 treatment sessions. Follow-up demonstrated minimal relapse of snoring in the multilesion group at a mean of 16 months. Although there was a statistically significant increase in pain in the multilesion group vs the single-lesion group, this increase did not increase narcotic use or time off work and was considered minimal by reporting patients. CONCLUSION: Multilesion RFTR using higher energy levels per treatment is safe and has increased efficacy without increased complications relative to single-lesion therapy.

Adult↗
PubMed2001

Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha.

Nuclear factor-kappaB (NF-kappa B) is a pleiotropic oxidant-sensitive transcription factor that is present in the cytosol in an inactive form complexed to an inhibitory kappaB (I kappa B) monomer. Various stimuli, including ischemia, hypoxia, free radicals, cytokines, and lipopolysaccharide (LPS), activate NF-kappa B by inducing phosphorylation of I kappa B. Phosphorylation of serine residues at positions 32 and 36 is critical for ubiquitination and degradation of I kappa B alpha with consequent migration of NF-kappa B to the nucleus. Although NF-kappa B is thought to contribute to numerous pathophysiologic processes, definitive assessment of its role has been hindered by the inability to achieve specific inhibition in vivo. Pharmacologic inhibitors of NF-kappa B are available, but their utility for in vivo studies is limited by their relative lack of specificity. Targeted ablation of genes encoding NF-kappa B subunits has not been productive in this regard because of fetal lethality in the case of p65 and functional redundancy in the Rel family of proteins. To overcome these limitations, we have created a viable transgenic mouse that expresses a phosphorylation-resistant mutant of I kappa B alpha (I kappa B alpha(S32A,S36A)) under the direction of a cardiac-specific promoter. Several transgenic lines were obtained with copy numbers ranging from one to seven. The mice exhibit normal cardiac morphology and histology. Total myocardial I kappa B alpha protein level is elevated 3.5- to 6.5-fold with a concomitant 50-60% decrease in the level of I kappa B beta. Importantly, expression of I kappa B(S32A,S36A) results in complete abrogation of myocardial NF-kappa B activation in response to tumor necrosis factor- alpha (TNF-alpha) and LPS stimulation. Thus, novel transgenic mice have been created that make it possible to achieve cardiac-specific and selective inhibition of NF-kappa B in vivo. These transgenic mice should be useful in studies of various cardiac pathophysiological phenomena that involve NF-kappa B activation, including ischemic preconditioning, heart failure, septic shock, acute coronary syndromes, cardiac allograft rejection, and apoptosis.

Amino Acid Substitution↗