Showing papers by "University of Texas Health Science Center at Houston published in 1999"

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

Abstract: A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients.

Abstract: PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information...

The Structure of Ethnic Identity of Young Adolescents from Diverse Ethnocultural Groups

Abstract: The purpose for this study was to examine the structure and construct validity of a measure of ethnic identity among young adolescents from diverse ethnic groups. Students in sixth, seventh, and eighth grades (N = 5,423) from diverse ethnic groups completed the Multigroup Ethnic Identity Measure (MEIM), measures of psychological well-being and a measure of salience of ethnicity. Factor analyses of data for the three largest ethnic groups (European American, African American, Mexican American) yielded a two-factor structure that corresponded to two theoretical approaches to ethnic identity, as hypothesized. Similar patterns in magnitude of loadings were observed across groups, indicating that the MEIM could be used as a global composite index of ethnic identity. Ethnic identity was related positively to measures of psychological well-being such as coping ability, mastery, self-esteem and optimism, and negatively to measures of loneliness and depression. MEIM scores also were moderately strong and positive ...

Size matters: molecular weight affects the efficiency of poly(ethylenimine) as a gene delivery vehicle.

Abstract: Poly(ethylenimine) (PEI) samples of various molecular weights and pHs were used to transfect endothelial cells to achieve levels of gene expression for comparison. PEIs with nominal molecular weights of 600, 1200, 1800, 10,000, and 70,000 Da were examined at pHs of 5. 0, 6.0, 7.0, and 8.0, and the results were recorded in terms of transfection efficiencies at 24, 48, 68, 92, and 120 h post-transfection. Trials were performed on the human endothelial cell-derived cell line EA.hy 926. We found that, for the polymers tested, transfection efficiency increased as the molecular weight of PEI increased. Representative values of PEIs at pH 6 and molecular weight 70,000 produced average transfection efficiencies of 25.6 +/- 7.9% (n = 8) at the greatest average expression levels, while PEI of molecular weight 10,000 yielded efficiencies of only 11.4 +/- 1.7% (n = 6). Transfection efficiencies for molecular weight 1,800 PEI were essentially zero, and PEIs of lower molecular weights produced no transfection at all. In contrast, the pH of the PEI solutions had no discernible effect on transfection. Optimal expression of the green fluorescent protein reporter occurred between 2 and 3 days post-transfection. The amount of reporter expression also was noted, as determined by the brightness of fluorescing cells under UV. The data obtained demonstrate that the molecular weight of the PEI carrier has an effect on transfection efficiency while the pH of the PEI solutions prior to DNA complexation has no such effect.

The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism

Abstract: Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory response. The signaling mechanisms involved were investigated using a tetracycline-controlled expression system to determine the half-lives of interleukin (IL)-6 and IL-8 mRNAs. Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitutively active form of the MAP kinase kinase kinase MEKK1. Destabilization and signal-induced stabilization was transferred to the stable beta-globin mRNA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich region, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF mRNAs. Of the different MEKK1-activated signaling pathways, no significant effects on mRNA degradation were observed for the SAPK/JNK, extracellular regulated kinase and NF-kappaB pathways. Selective activation of the p38 MAP kinase (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A dominant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL-1-induced stabilization. Furthermore, an active form of the p38 MAP kinase-activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whereas a negative interfering MK2 mutant interfered with MAP kinase kinase 6-induced stabilization. These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism.

The Nuclear Factor-κB RelA Transcription Factor Is Constitutively Activated in Human Pancreatic Adenocarcinoma Cells

Abstract: Pancreatic adenocarcinoma is a leading cause of adult cancer mortality in the United States. Recent studies have revealed that point mutation of the K-ras oncogene is a common event in pancreatic cancer, and oncogenesis mediated by Ras may also involve activation of Rel/nuclear factor (NF)-kappa B transcription factors. Furthermore, the c-rel member of Rel/NF-kappa B transcription factor family was first identified as a cellular homologue of the v-rel oncogene, suggesting that other members of the Rel/NF-kappa B family are potentially oncogenes. We therefore investigated the possibility that Rel/NF-kappa B transcription factors are activated in pancreatic cancer. Immunohistochemical analysis, Western blot and Northern blot analysis, electrophoretic mobility shift assays, and chloramphenicol acetyltransferase assays were performed to determine RelA activity in human pancreatic adenocarcinomas and normal tissues and nontumorigenic or tumorigenic cell lines. RelA, the p65 subunit of NF-kappa B, was constitutively activated in approximately 67% (16 of 24) of pancreatic adenocarcinomas but not in normal pancreatic tissues. Constitutive RelA activity was also detected in 9 of 11 human pancreatic tumor cell lines but not in nontumorigenic Syrian golden hamster cell lines. I kappa B alpha, a previously identified NF-kappa B-inducible gene, was overexpressed in human pancreatic tumor tissues and cell lines, and RelA activation could be inhibited by curcumin and dominant-negative mutants of I kappa B alpha, raf, and MEKK1. This is the first report demonstrating constitutive activation of RelA in nonlymphoid human cancer. These data are consistent with the possibility that RelA is constitutively activated by the upstream signaling pathway involving Ras and mitogen-activated protein kinases in pancreatic tumor cells. Constitutive RelA activity may play a key role in pancreatic tumorigenesis through activation of its downstream target genes.

Effects of tissue plasminogen activator for acute ischemic stroke at one year

Abstract: Background In 1995, the two-part National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Study found that patients who were treated with tissue plasminogen activator (t-PA) within three hours after the onset of symptoms of acute ischemic stroke were at least 30 percent more likely than patients given placebo to have minimal or no disability three months after the stroke. It was unknown, however, whether the benefit would be sustained for longer periods. Methods In the NINDS trial, a total of 624 patients with stroke were randomly assigned to receive either t-PA or placebo. We collected outcome data over a period of 12 months after the occurrence of stroke. The primary outcome measure was a “favorable outcome,” defined as minimal or no disability as measured by the Barthel index, the modified Rankin Scale, and the Glasgow Outcome Scale. We assessed the treatment effect using a global statistic. Results Using an intention-to-treat analysis for the comb...

Ganglion cell losses underlying visual field defects from experimental glaucoma

Abstract: PURPOSE. To investigate the relationship between ganglion cell losses and visual field defects caused by glaucoma. METHODS. Behavioral perimetry and histology data were obtained from 10 rhesus monkeys with unilateral experimental glaucoma that was induced by argon laser treatments to their trabecular meshwork. After significant visual field defects had developed, the retinas were collected for histologic analysis. The ganglion cells were counted by light microscopy in cresyl violet-stained retina sections, and the percentage of ganglion cell loss (treated to control eye counts) was compared with the depth of visual field defect (treated to control eye thresholds) at corresponding retinal and perimetry test locations. Sensitivity losses as a function of ganglion cell losses were analyzed for Goldmann III, white and Goldmann V, and short- and long-wavelength perimetry test stimuli. RESULTS. The relationship between the proportional losses of ganglion cells and visual sensitivity, measured with either white or colored stimuli, was nonlinear. With white stimuli, the visual sensitivity losses were relatively constant (approximately 6 dB) for ganglion cell losses of less than 30% to 50%, and then with greater amounts of cell loss the visual defects were more systematically related to ganglion cell loss (approximately 0.42 dB/percent cell loss). The forms of the neural-sensitivity relationships for visual defects measured with short- or long-wavelength perimetry stimuli were similar when the visual thresholds were normalized to compensate for differences in expected normal thresholds for white and colored perimetry stimuli. CONCLUSIONS. Current perimetry regimens with either white or monochromatic stimuli do not provide a useful estimate of ganglion cell loss until a substantial proportion have died. The variance in ganglion cell loss is large for mild defects that would be diagnostic of early glaucoma and for visual field locations near the fovea where sensitivity losses occur relatively late in the disease process. The neural-sensitivity relationships were essentially identical for both white and monochromatic test stimuli, and it therefore seems unlikely that the higher sensitivity for detecting glaucoma with monochromatic stimuli is based on the size-dependent susceptibility of ganglion cells to injury from glaucoma.

Virulence of three distinct Cryptosporidium parvum isolates for healthy adults.

Abstract: The infectivity of three Cryptosporidium parvum isolates (Iowa [calf], UCP [calf], and TAMU [horse]) of the C genotype was investigated in healthy adults. After exposure, volunteers recorded the number and form of stools passed and symptoms experienced. Oocyst excretion was assessed by immunofluorescence. The ID50 differed among isolates: Iowa, 87 (SE, 19; 95% confidence interval [CI], 48.67-126); UCP, 1042 (SE, 1000; 95% CI, 0-3004); and TAMU, 9 oocysts (SE, 2.34; 95% CI, 4.46-13.65); TAMU versus Iowa, P=.002 or UCP, P=.019. Isolates also differed significantly (P=.045) in attack rate between TAMU (86%) and Iowa (52%) or UCP (59%). A trend toward a longer duration of diarrhea was seen for the TAMU (94.5 h) versus UCP (81.6 h) and Iowa (64.2 h) isolates. C. parvum isolates of the C genotype differ in their infectivity for humans.

A Tale of Two Diseases Atherosclerosis and Rheumatoid Arthritis

Abstract: Acute coronary syndromes are responsible for most of the morbidity and mortality caused by coronary atherosclerosis. Both unstable angina and acute myocardial infarction are characterized by coronary thrombosis, usually caused by rupture or fissuring of a coronary plaque. Yet the occurrence of plaque rupture and coronary thrombosis is not related to severity of coronary plaques, and functional factors other than the mere presence of atherosclerotic lesions play an important role.1 2 Recent studies have focused on the inflammatory component of atherosclerosis, trying to highlight the differences between stable and unstable coronary plaques. An increasing body of evidence supports the hypothesis that atherosclerosis shares many similarities with other inflammatory/autoimmune diseases. Indeed, there are surprising similarities in the inflammatory/immunologic response observed in atherosclerosis, in unstable angina, and in rheumatoid arthritis, the prototype of autoimmune disease (Table⇓). However, although our understanding of the molecular and immunological mechanisms of rheumatoid arthritis has greatly progressed, due to the relatively easy access to the diseased tissue (synovium) and to the availability of animal models, the study of the inflammatory and immunological components of atherosclerosis is still in its initial stages. Unfortunately, it is more difficult for cardiologists to follow the evolution of inflammatory response in plaques or make correlations with the clinical course. Furthermore, although mice models of atherosclerosis have been developed in the last few years, there are still no animal models able to reproduce the events occurring in acute coronary syndromes. Thus, the study of the molecular mechanisms of rheumatoid arthritis may give valuable hints for research on the inflammatory/immunological mechanisms of atherosclerosis and acute coronary syndromes. Activation of inflammatory cells (in particular macrophages and mast cells), releasing many collagen-breaking enzymes within atherosclerotic plaques is likely to play an important role in destabilization of plaques.3 Collagen degradation is also an essential …

Prospective Study of Markers of Hemostatic Function With Risk of Ischemic Stroke

Abstract: Background —Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant. Methods and Results —The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0). Conclusions —This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.

Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays

Abstract: Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH pedigrees from Amish, Venezuelan and Utah populations) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles. There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation.

Costs of medical injuries in Utah and Colorado

Abstract: Patient injuries are thought to have a substantial financial impact on the health care system, but recent studies have been limited to estimating the costs of adverse drug events in teaching hospitals. This analysis estimated the costs of all types of patient injuries from a representative sample of hospitals in Utah and Colorado. We detected 459 adverse events (of which 265 were preventable) by reviewing the medical records of 14,732 randomly selected 1992 discharges from 28 hospitals. The total costs (all results are discounted 1996 dollars) were $661,889,000 for adverse events, and $308,382,000 for preventable adverse events. Health care costs totaled $348,081,000 for all adverse events and $159,245,000 for the preventable adverse events. Fifty-seven percent of the adverse event health care costs, and 46% of the preventable adverse event costs were attributed to outpatient medical care. Surgical complications, adverse drug events, and delayed or incorrect diagnoses and therapies were the most expensive types of adverse events. The costs of adverse events were similar to the national costs of caring for people with HIV/AIDS, and totaled 4.8% of per capita health care expenditures in these states.

Glucose for the Heart

Abstract: The homeostasis of plasma glucose levels is essential for survival of the mammalian organism. Since blood glucose concentration is maintained within a narrow range, glucose is a most reliable substrate for energy production in the heart. The importance of glucose metabolism via glycolysis is well appreciated in ischemic and hypertrophied heart muscle,1 2 3 4 but aerobic glucose metabolism for support of normal contractile function has received less attention, mainly because of the well-known fact that fatty acids are normally the predominant fuel for cardiac energy production.2 5 6 We have drawn attention to the heart as a true “omnivore,” ie, an organ that functions best when it oxidizes different substrates simultaneously.7 In light of this concept, we wish to reexamine myocardial glucose metabolism and its relevance to the human heart. In recent years, the tools of molecular and cellular biology have provided new insight into the mechanisms of glucose transport and phosphorylation. Glycogen metabolism has come into greater focus. The regulation of glycolysis is more accurately defined, and the effects of second messengers on myocardial glucose utilization are better known. In view of this background, 2 well-known clinical concepts of myocardial glucose metabolism require critical reevaluation: (1) the diagnostic concept of metabolic imaging with PET and the glucose tracer analogue 18F-2-deoxy-2-fluoro-d-glucose (FDG) and (2) the therapeutic concept of metabolic support for the postischemic heart with glucose, insulin, and K+ (GIK). The simple sugar d-glucose is the most abundant organic molecule in nature. Glucose for the heart is derived either from the bloodstream or from intracellular stores of glycogen (Figure 1⇓). The transport of glucose into the cardiomyocyte occurs along a steep concentration gradient and is regulated by specific transporters. Intracellular glucose is rapidly phosphorylated and becomes a substrate for the …

Y-Chromosome Evidence for a Northward Migration of Modern Humans into Eastern Asia during the Last Ice Age

Abstract: Summary The timing and nature of the arrival and the subsequent expansion of modern humans into eastern Asia remains controversial. Using Y-chromosome biallelic markers, we investigated the ancient human-migration patterns in eastern Asia. Our data indicate that southern populations in eastern Asia are much more polymorphic than northern populations, which have only a subset of the southern haplotypes. This pattern indicates that the first settlement of modern humans in eastern Asia occurred in mainland Southeast Asia during the last Ice Age, coinciding with the absence of human fossils in eastern Asia, 50,000–100,000 years ago. After the initial peopling, a great northward migration extended into northern China and Siberia.

Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.

Abstract: Complex disorders such as diabetes, cardiovascular disease, asthma, hypertension and psychiatric illnesses account for a large and disproportionate share of health care costs, but remain poorly characterized with respect to aetiology. The transmission of such disorders is complex, reflecting the actions and interactions of multiple genetic and environmental factors. Genetic analyses that allow for the simultaneous consideration of susceptibility from multiple regions may improve the ability to map genes for complex disorders, but such analyses are currently computationally intensive and narrowly focused. We describe here an approach to assessing the evidence for statistical interactions between unlinked regions that allows multipoint allele-sharing analysis to take the evidence for linkage at one region into account in assessing the evidence for linkage over the rest of the genome. Using this method, we show that the interaction of genes on chromosomes 2 (NIDDM1) and 15 (near CYP19) makes a contribution to susceptibility to type 2 diabetes in Mexican Americans from Starr County, Texas.

Three-Year Maintenance of Improved Diet and Physical Activity: The CATCH Cohort

Abstract: Objective To assess differences through grade 8 in diet, physical activity, and related health indicators of students who participated in the Child and Adolescent Trial for Cardiovascular Health (CATCH) school and family intervention from grades 3 through 5. Design Follow-up of the 4-center, randomized, controlled field trial with 56 intervention and 40 control elementary schools. Participants We studied 3714 (73%) of the initial CATCH cohort of 5106 students from ethnically diverse backgrounds in California, Louisiana, Minnesota, and Texas at grades 6, 7, and 8. Results Self-reported daily energy intake from fat at baseline was virtually identical in the control (32.7%) and intervention (32.6%) groups. At grade 5, the intake for controls remained at 32.2%, while the intake for the intervention group declined to 30.3% ( P P =.01). Intervention students maintained significantly higher self-reported daily vigorous activity than control students ( P =.001), although the difference declined from 13.6 minutes in grade 5 to 11.2, 10.8, and 8.8 minutes in grades 6, 7, and 8, respectively. Significant differences in favor of the intervention students also persisted at grade 8 for dietary knowledge and dietary intentions, but not for social support for physical activity. No impact on smoking behavior or stages of contemplating smoking was detected at grade 8. No significant differences were noted among physiologic indicators of body mass index, blood pressure, or serum lipid and cholesterol levels. Conclusion The original CATCH results demonstrated that school-level interventions could modify school lunch and school physical education programs as well as influence student behaviors. This 3-year follow-up without further intervention suggests that the behavioral changes initiated during the elementary school years persisted to early adolescence for self-reported dietary and physical activity behaviors.

Sequence and Organization of pXO1, the Large Bacillus anthracis Plasmid Harboring the Anthrax Toxin Genes

Abstract: The Bacillus anthracis Sterne plasmid pXO1 was sequenced by random, "shotgun" cloning. A circular sequence of 181,654 bp was generated. One hundred forty-three open reading frames (ORFs) were predicted using GeneMark and GeneMark.hmm, comprising only 61% (110,817 bp) of the pXO1 DNA sequence. The overall guanine-plus-cytosine content of the plasmid is 32.5%. The most recognizable feature of the plasmid is a "pathogenicity island," defined by a 44.8-kb region that is bordered by inverted IS1627 elements at each end. This region contains the three toxin genes (cya, lef, and pagA), regulatory elements controlling the toxin genes, three germination response genes, and 19 additional ORFs. Nearly 70% of the ORFs on pXO1 do not have significant similarity to sequences available in open databases. Absent from the pXO1 sequence are homologs to genes that are typically required to drive theta replication and to maintain stability of large plasmids in Bacillus spp. Among the ORFs with a high degree of similarity to known sequences are a collection of putative transposases, resolvases, and integrases, suggesting an evolution involving lateral movement of DNA among species. Among the remaining ORFs, there are three sequences that may encode enzymes responsible for the synthesis of a polysaccharide capsule usually associated with serotype-specific virulent streptococci.

Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator–Related Intracerebral Hemorrhage in Acute Ischemic Stroke

Abstract: Background and Purpose—Five pretreatment variables (P 300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated 33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. Results—Symptomati...

A Nonhyperthermophilic Common Ancestor to Extant Life Forms

Abstract: The G+C nucleotide content of ribosomal RNA (rRNA) sequences is strongly correlated with the optimal growth temperature of prokaryotes. This property allows inference of the environmental temperature of the common ancestor to all life forms from knowledge of the G+C content of its rRNA sequences. A model of sequence evolution, assuming varying G+C content among lineages and unequal substitution rates among sites, was devised to estimate ancestral base compositions. This method was applied to rRNA sequences of various species representing the major lineages of life. The inferred G+C content of the common ancestor to extant life forms appears incompatible with survival at high temperature. This finding challenges a widely accepted hypothesis about the origin of life.

Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy.

Abstract: Objective To determine the incidence and prognostic significance of documented eradication of breast cancer axillary lymph node (ALN) metastases after neoadjuvant chemotherapy. Summary Background Data Neoadjuvant chemotherapy is the standard of care for patients with locally advanced breast cancer and is being evaluated in patients with earlier-stage operable disease. Methods One hundred ninety-one patients with locally advanced breast cancer and cytologically documented ALN metastases were treated in two prospective trials of doxorubicin-based neoadjuvant chemotherapy. Patients had breast surgery with level I and II axillary dissection followed by additional chemotherapy and radiation treatment. Nodal sections from 43 patients who were originally identified as having negative ALNs at surgery were reevaluated and histologically confirmed to be without metastases. An additional 1112 sections from these lymph node blocks were obtained; half were stained with an anticytokeratin antibody cocktail and analyzed. Survival was calculated using the Kaplan‐Meier method. Results Of 191 patients with positive ALNs at diagnosis, 23% (43 patients) were converted to a negative axillary nodal status on histologic examination (median number of nodes removed 5 16). Of the 43 patients with complete axillary conversion, 26% (n 5 11) had N1 disease and 74% (n 5 32) had N2 disease. On univariate analysis, patients with complete versus incomplete histologic axillary conversion were more likely to have initial estrogenreceptor‐negative tumors, smaller primary tumors, and a complete pathologic response in the primary tumor. The 5-year disease-free survival rates were 87% in patients with preoperative eradication of axillary metastases and 51% for patients with residual nodal disease after neoadjuvant chemotherapy. Of the 39 patients with complete histologic conversion for whom nodal blocks were available, occult nodal metastases were found in additional nodal sections in 4 patients (10%). At a median follow-up of 61 months, the 5-year disease-free survival rates were 87% in patients without occult nodal metastases and 75% in patients with occult nodal metastases. Conclusions Neoadjuvant chemotherapy can completely clear the axilla of microscopic disease before surgery, and occult metastases are found in only 10% of patients with a histologically negative axilla. The results of this study have implications for the potential use of sentinel lymph node biopsy as an alternative to axillary dissection in patients treated with neoadjuvant chemotherapy.

Discovery of Some of the Biological Effects of Nitric Oxide and Its Role in Cell Signaling (Nobel Lecture)

Abstract: A unique simple molecule with an array of signaling functions: NO. The free radical nitric oxide not only mediates a long list of biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis from GTP, but can also interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids, and other molecules. Furthermore, NO can function as an intracellular messenger, an autacoid, a paracrine substance, a neurotransmitter, or a hormone that can be carried to distant sites for effects.

Combination of EGFR, HER-2/neu, and HER-3 Is a Stronger Predictor for the Outcome of Oral Squamous Cell Carcinoma Than Any Individual Family Members

Abstract: In a series of 111 patients with squamous cell carcinoma (SCC), we used immunohistochemistry to examine the expression levels of four epidermal growth factor receptor (EGFR) family members (EGFR, HER-2/neu, HER-3, and HER-4). Expression of the EGFR members was not significantly associated with tumor size. However, their expressions (except for HER-4) were significantly associated with the presence of lymph node metastasis, and all of them were significantly associated with distant metastasis. We further examined the association between the expression levels of the EGFR members and the survival rates in 47 oral SCC patients whose detailed clinical follow-ups were available. The expression of all EGFR members was significantly associated with shortened patient survival, and the association was strongest for HER-2/neu. Furthermore, the combination of HER-2, HER-3, and EGFR but not HER-4 significantly improved the predicting power. The expression level of HER-2/neu was significantly correlated with that of EGFR or HER-3. Similar coexpression patterns were also observed in three oral SCC cell lines studied, but not in four other head and neck SCC cell lines. Taken together, these results indicated that expression levels of EGFR, HER-2/ neu, and HER-3 may help predict the outcome of patients with oral SCC.

Systemic lupus erythematosus in three ethnic groups: III A comparison of characteristics early in the natural history of the LUMINA cohort:

Abstract: Aim: To determine and contrast the socioeconomic-demographic and clinical features of patients with recent onset (5 y) systemic lupus erythematosus (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA, C).Subjects and methods: SLE cases (American College of Rheumatology criteria) (incident (n ‘ 56), prevalent (n ‘ 173)), were enrolled in a longitudinal study at The University of Alabama at Birmingham, The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston. Socioeconomic-demographic, clinical, immunological, behavioral and psychological data were obtained using validated instruments and standard laboratory techniques, and compared.Results: 70 H, 88 AA and 71 C SLE patients constitutethis cohort. H and AA patients were younger and of lower socioeconomic-demographic status. They also had evidence of more frequent organ system involvement (renal, cardiovascular), more auto-antibodies, more active disease (after adjusting for dis...

Early Clinical and Radiological Predictors of Fatal Brain Swelling in Ischemic Stroke

Abstract: Background and Purpose—Early identification of acute stroke patients at risk of fatal brain swelling is necessary to facilitate implementation of aggressive therapies. Initial clinical, laboratory, and CT characteristics that may be used as selection criteria were analyzed to determine predictors of herniation and neurological death. Methods—Data from the placebo arm of the Lubeluzole-International-9 trial were reviewed to identify patients with fatal brain edema. Early clinical, laboratory, and radiographic parameters were evaluated in a case-control design. Initial CT scans were analyzed for early ischemic abnormalities by 2 blinded investigators. Results—Twenty-three patients died from brain swelling, with minimum baseline National Institutes of Health Stroke Scale (NIHSS) scores of 20 (n=12; mean, 23.2±1.8) with left and 15 (n=11; mean, 17.6±2.2) with right hemispheric infarctions (P=0.0001). A sample of 112 subjects with comparably severe strokes, but who did not die from brain swelling, was selected...

Biologic Rhythms in the Immune System

Abstract: In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24 h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.

The genetics revolution and the assault on rheumatoid arthritis.

Abstract: Reading the daily headlines proclaiming the current revolution in human genetics and the imminent completion of the Human Genome Project (1), it is often difficult to restrain one’s excitement, and also easy to overlook the formidable challenges that remain for understanding the role of genes in human disease. This challenge is particularly germane to multifactorial diseases in which multiple genes contribute to disease risk, along with other factors, and in which heterogeneity of disease etiology and phenotype complicate the analysis. Both of these conditions hold for rheumatoid arthritis (RA), the most common, and still poorly understood, form of inflammatory arthritis. When thinking about the causes of biologic phenotypes, the simple dichotomy of nature versus nurture has been replaced by a more subtle view, in which both genes and environment interact over time and contribute to disease. It is also important to recognize that nongenetic factors do not simply consist of exposure to environmental influences such as infection or diet, but also include stochastic processes that may occur quite early in development as well as close in time to the onset of disease. This is probably a significant reason for the relatively low concordance of autoimmunity in monozygotic (MZ) twins (2–6). In addition, disease must be viewed as a phenomenon that occurs in populations as well as individuals, and thus the historical and evolutionary factors that have shaped populations need to be taken into account for us to achieve full understanding. This interactive approach to appreciating the role of genetics in complex human disease is illustrated in Figure 1. The main practical result of this more complex model is the realization that genetic associations with disease are very unlikely to yield simple one-to-one correlations between genes and phenotypes. Rather, there will be considerable noise obscuring these relationships which can only be resolved by obtaining large numbers of observations. The need for large collaborative studies in RA is clear. The purpose of this discussion is to review the current status of RA genetics and the approaches being used to increase our knowledge of this genetically complex disorder.