Showing papers by "University of Medicine and Dentistry of New Jersey published in 1993"

Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators

Abstract: Objective. —To study the potential usefulness of the 6-minute walk test, a self-paced submaximal exercise test, as a prognostic indicator in patients with left ventricular dysfunction. Design. —Data were collected during a prospective cohort study, the Studies of Left Ventricular Dysfunction (SOLVD) Registry Substudy. Setting. —Twenty tertiary care hospitals in the United States, Canada, and Belgium. Participants. —A stratified random sample of 898 patients from the SOLVD Registry who had either radiological evidence of congestive heart failure and/or an ejection fraction of 0.45 or less were enrolled in the substudy and underwent a detailed clinical evaluation including a 6-minute walk test. Patients were followed up for a mean of 242 days. Outcome Measures. —Mortality and hospitalization. Results. —During follow-up, 52 walk-test participants (6.2%) died and 252 (30.3%) were hospitalized. Hospitalization for congestive heart failure occurred in 78 participants (9.4%), and the combined endpoint of death or hospitalization for congestive heart failure occurred in 114 walk-test participants (13.7%). Compared with the highest performance level, patients in the lowest performance level had a significantly greater chance of dying (10.23% vs 2.99%;P=.01), of being hospitalized (40.91% vs 19.90%;P=.002), and of being hospitalized for heart failure (22.16% vs 1.99%;P Conclusion. —The 6-minute walk test is a safe and simple clinical tool that strongly and independently predicts morbidity and mortality in patients with left ventricular dysfunction. (JAMA. 1993;270:1702-1707)

Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.

Abstract: Background. Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents, it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors, as is often the case in current practice. Methods. We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinically stable while receiving digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor (captopril or enalapril). The patients were randomly assigned in a double-blind fashion either to continue receiving digoxin (85 patients) or to be switched to placebo (93 patients) for 12 weeks

Multiple sclerosis: remyelination of nascent lesions

Abstract: The relationship between plaque pathology and disease duration was examined in 15 patients with multiple sclerosis who died early in the course of their illness. Myelin-stained sections revealed that most plaques examined in patients who died during the first month of their illness showed evidence of ongoing myelin destruction accompanied by a loss of oligodendrocytes. Plaques containing large numbers of oligodendrocytes were not observed in these patients, but were relatively common in patients who died more than 1 month after clinical onset. Remyelination affecting more than 10% of the plaque area was observed in 3 of 82 plaques in 5 patients who died within 10 weeks of clinical onset, in 38 of 105 plaques in 5 patients who died 3 to 10 months after clinical onset, and in 19 of 92 plaques in 5 patients who died 18 months or longer after clinical onset. The study provides new evidence that both oligodendrocytes and myelin are destroyed in new lesions, that this activity ceases completely in many lesions within a few weeks, and that remyelination frequently ensues following repopulation of the plaque by oligodendrocytes. The findings suggest that new lesions normally remyelinate unless interrupted by recurrent activity and that remyelinated shadow plaques are the outcome of a single previous episode of focal demyelination.

Hopelessness, Depression, Suicidal Ideation, and Clinical Diagnosis of Depression

Abstract: The relevance of a clinical diagnosis of depression for explaining the discrepant relationships of hopelessness and depression with suicidal ideation was studied. The Beck Depression Inventory (BDI), Hopelessness Scale (BHS), and the Scale for Suicide Ideation (SSI) were administered to 1,306 (72.8%) patients with at least one DSM-III-R mood disorder and 488 (27.3%) patients without any mood disorders. A multiple regression analysis was conducted, and hopelessness was 1.3 times more important than depression was for explaining suicidal ideation. The interactions of the BDI and BHS with diagnostic group were not significant.

DNA topoisomerase I is involved in both repression and activation of transcription

Abstract: Reconstituted transcription reactions containing the seven general transcription factors, in addition to RNA polymerase II, respond poorly to transcriptional activators. Two factors, Dr2 and ACF, necessary for high levels of transcription in response to an activator have been identified. ACF can enhance basal and activated transcription. Dr2 represses basal transcription, but this can be overcome by transcriptional activators or TFIIA. Dr2 is human DNA topoisomerase I. The DNA relaxation activity of topoisomerase I is dispensable for transcriptional repression. The effect of Dr2 is specific for TATA-box-containing promoters and is mediated by the TATA-binding protein.

Initiation of transcription by RNA polymerase II: a multi-step process

Abstract: Publisher Summary This chapter discusses the initiation of transcription of protein-coding genes. The RNA polymerase II(RNAPII) of the yeast Saccharomyces cerevisiae has been a useful prototype in the study of eukaryotic RNAPII, as features such as function and subunit structure have been highly conserved. The yeast RNAPII is composed of 11 polypeptides with apparent masses ranging from 220 to 10 kDa. This is in contrast to eukaryotic cells, which contain three distinct RNA polymerases, each containing from 8 to 14 polypeptides and responsible for transcribing its own set of genes: RNA polymerase I (RNAPI), which transcribes ribosomal RNA; RNAPII, the RNA polymerase of protein-coding, or class 11, genes; and RNAPIII, which transcribes 5-S rRNA and tRNA genes. In this chapter, only RNAPII is discussed, and only as it pertains to transcription initiation.

The relationship between dementia and elder abuse.

Abstract: OBJECTIVE: Alzheimer's disease and other dementias may be associated with greater risk for physical abuse than other illnesses of the elderly. The authors examined the relationship between dementia and abusive behavior in a group of demented patients and their caregivers. METHOD: An anonymous questionnaire was distributed to 1,000 caregivers who called a telephone help line specializing in dementia. Demographic characteristics of patients and caregivers were assessed, the occurrence of abuse was examined, and caregivers completed the Zarit Burden Interview and the Zung Self-Rating Depression Scale. RESULTS: Questionnaires were completed by 342 caregivers. The mean age of caregivers was 56.1 years; 163 (54.5%) were adult children caring for parents, 111 (37.1%) cared for spouses, and 25 (8.4%) cared for other relatives. Thirty-three caregivers (11.9%) reported that they had directed physically abusive behavior (e.g., pinching, shoving, biting, kicking, striking) toward the dementia patient in their care. These caregivers had been providing care for more years, cared for patients functioning at a lower level, displayed higher burden scores, and displayed higher depression scores than caregivers who reported no abuse. In addition, 92 caregivers (33.1%) reported that the patient directed abuse toward them during the course of providing care. Caregivers who had been abused by patients, in comparison to those who had not, were more likely to direct abusive behavior back toward the patient in their care. CONCLUSIONS: These results support the hypothesis that abuse involving cognitively impaired older adults and their caregivers may be associated with the relatively high psychological and physical demands placed on family members who care for relatives with dementia. Language: en

The hepatic extracellular matrix. II. Ontogenesis, regeneration and cirrhosis.

Abstract: The unique nature of the hepatic extracellular matrix (ECM) is predicted by the special configuration of the space of Disse. Whereas other epithelial organs have two basement membranes (BM) and a substantial ECM interposed between endothelial and epithelial cells, the liver lobule has no BM and only an attenuated ECM, consisting mostly of fibronectin (FN), some collagen type I, and minor quantities of types III, IV, V, and VI. This configuration, together with the abundant fenestrations and gaps of the sinusoidal endothelial cells, seems ideally suited to facilitate the rapid bidirectional exchange of macromolecules normally taking place between plasma and hepatocytes. During organogenesis, the liver anlage is vascularized by continuous capillaries with BM, but by day 13.5 of development (in the rat) the vessels in the immediate proximity of hepatocytes become fenestrated, lacking specialized junctions and BM, suggesting that the hepatocytes produce signals capable of modulating the endothelial phenotype. In regeneration, hepatocyte proliferation precedes vascular proliferation resulting in the formation of hepatocyte clusters that, temporarily, lack sinusoids. Eventually, vascular proliferation follows and the normal hepatocyte-vascular relationships are restored. During this period laminin synthesis by Ito cells is prominent. As soon as hepatocytes become stable, secretion of the sinusoid phenotype-maintaining factors resumes and laminin synthesis and secretion terminates. The interplay between extracellular matrix and liver cells is essential for normal homeostasis and its modification results in derranged hepatic function.

Novel oligonucleotide arrays and their use for sorting, isolating, sequencing, and manipulating nucleic acids

Abstract: A method of sorting mixtures of nucleic acid strands comprising hybridizing the strands to an array of immobilized oligonucleotides, each of which includes a constant segment adjacent to a variable segment. The constant segment of the immobilized oligonucleotides can be made complementary to the ends of strands obtained by digesting a double-stranded nucleic acid with a restriction enzyme and restoring the restriction sites, thereby permitting the sorting of strands according to their variable sequences adjacent to their constant terminal restored restriction sites.

Multiple sclerosis: Pathology of recurrent lesions

Abstract: Recent autopsy studies suggest that remyelinated shadow plaques located in otherwise intact white matter are the outcome of a previous single episode of acute demyelination. In the present study, of 98 remyelinated plaques examined in 15 patients with multiple sclerosis who died between 27 days and 5 years after clinical onset, 15 showed evidence of a superimposed new demyelinating lesion. Inspection of old shadow plaques in a separate series of patients with subacute and long-standing multiple sclerosis revealed that such lesions sometimes exhibit punched-out areas of demyelination and gliosis similar in size and shape to fresh lesions located within or overlapping remyelinated shadow plaques. The findings support magnetic resonance imaging evidence that local recurrence may be as important or more important than progressive edge activity in determining plaque growth and the conversion of nascent lesions into classical demyelinated plaques. The findings also support experimental evidence that recurrent demyelination of the same area of white matter may be one of the factors underlying failed remyelination in multiple sclerosis.

Gingival Recession in Relation to History of Hard Toothbrush Use

Abstract: Gingival recession studies in the U.S. have related primarily to sex and age with little consideration of toothbrush hardness. This preliminary study examined the relation between a history of hard toothbrush use and gingival recession. A total of 182 subjects, male and female, between 18 and 65 years of age, with a minimum of 18 natural teeth, no advanced periodontitis or history of periodontal surgery were examined. Gingival recession was scored as present whenever the free gingival margin was apical to the cemento-enamel junction and root surface was exposed. History of hard toothbrush use was ascertained. Eighty-two subjects had a history of hard toothbrush use, 77 did not, and 23 did not know. The percentage of subjects with recession increased with age from 43% to 81%, with a figure of 63% for all age groups combined. Males tended to show slightly greater levels of recession than females. Regression analysis showed that females had about 4 percentage points less receded surfaces than males. Recession was also found to be more pronounced for subjects with a history of hard toothbrush use, with a mean of 9.4% receded surfaces versus 4.7% for those who had never used a hard brush. For users of hard toothbrushes, the percent of surfaces with recession showed a significant and dramatic increase with increasing brushing frequency; this effect did not exist for those without a history of hard brush use. The relation with age was highly significant, with regression analysis showing that the percent of surfaces with recession tends to increase about 3.5 percentage points per decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system.

Abstract: The extreme S-phase-specific cytotoxicity of camptothecin has been shown to involve active DNA replication. To investigate the role of DNA replication in camptothecin cytotoxicity, we have studied the interaction between the DNA replication machinery and the topoisomerase I-camptothecin-DNA ternary cleavable complex in a cell-free SV40 DNA replication system. The formation of topoisomerase I-camptothecin-DNA-cleavable complexes on the replication template efficiently and irreversibly inhibited DNA replication. Two aberrant forms of replication products were produced whose abundance varied with the concentrations of exogenously added topoisomerase I and camptothecin. At low concentrations of topoisomerase I and camptothecin, the major aberrant DNA replication product was close-to-unit-length-linear DNA, while at higher concentrations the predominant product was close-to-dimer-size-linear DNA. Analysis of these aberrant replication products has suggested a "collision" model in which the interaction between an advancing replication fork and a topoisomerase I-camptothecin-DNA-cleavable complex results in irreversible arrest of the replication fork and the formation of a double-strand DNA break at the fork. Concomitant with fork arrest and fork breakage, the reversible cleavable complex was converted into a topoisomerase I-linked DNA break. We propose that one or several of these events triggers S-phase-specific cell killing and G2-phase cell cycle arrest.

Information Processing Efficiency in Chronic Fatigue Syndrome and Multiple Sclerosis

Abstract: • Objective. —To compare the cognitive performance of subjects with chronic fatigue syndrome (CFS), multiple sclerosis (MS), and healthy controls. All subjects were matched for age, education, and verbal intelligence, as previous neuropsychological studies of CFS had not used appropriate control groups. Design. —Case-control design. All subjects were given a neuropsychological battery and the test scores were compared among the groups. Setting. —Subjects with CFS and subjects with MS were recruited from private and institutional practice and from the community. Healthy subjects were recruited from the community. Patients/Other Participants. —Twelve subjects (all female) with CFS participated in the study. Chronic fatigue syndrome was diagnosed in these patients in accordance with the requirements outlined by the Centers for Disease Control as modified subsequently to not exclude patients with concurrent depression and/or anxiety. All subjects with CFS were referred for a neuropsychological examination to assess persistent cognitive complaints. Eleven subjects (10 female, one male) with the diagnosis of clinically stable MS were chosen from clinics and the community because of complaints of mild to moderate cognitive impairment. The subjects with MS and 11 healthy volunteers (10 female, one male) were matched to the group with CFS by age, education, and estimated verbal intelligence (based on the Vocabulary subtest of the Wechsler Adult Intelligence Scale-Revised). The subjects with MS had a mean Kurtzke Expanded Disability Status Scale score of 4.95 (SD, 1.95;range, 2.0 to 7.5). As a result of the matching procedure, there were no differences among the three groups in age (F[2,31]=0.32), education (F[2,31]=0.80), and verbal intelligence (F[2,31]=0.31). Interventions. —None. Main Outcome Measures. —These measures included the Beck Depression Inventory (BDI), the Paced Auditory Serial Addition Test (PASAT), Digit Span Test, and the Similarities Test of Verbal Abstract Reasoning. Results. —The mean number of correctly identified responses collapsed across the four PASAT trials was significantly different across groups (F[2,31 ]=4.03; P P P P P P r =−.21; MS, r =.13; control, r =.27), or between BDI and Digit Span Test (CFS, r =−.32; MS, r =−.40; control, r =−.19). Results of the PASAT and Digit Span Test were significantly correlated in the CFS group ( r =.71; P r =.06) or control groups ( r =.49). Conclusions. —These results indicate that subjects with CSF and subjects with MS show significant impairment on a test of complex concentration when compared with appropriate controls. The data suggest that subjects with CFS and subjects with MS have difficulty on tasks that require the simultaneous processing of complex cognitive information. Selective impairment in information processing efficiency may lie at the root of other cognitive complaints made by patients with CFS.

Photodynamic inactivation of infectivity of human immunodeficiency virus and other enveloped viruses using hypericin and rose bengal: inhibition of fusion and syncytia formation

Abstract: The mechanism of the antiviral activity of hypericin was characterized and compared with that of rose bengal. Both compounds inactivate enveloped (but not unenveloped) viruses upon illumination by visible light. Human immunodeficiency and vesicular stomatitis viruses were photodynamically inactivated by both dyes at nanomolar concentrations. Photodynamic inactivation of fusion (hemolysis) by vesicular stomatitis, influenza, and Sendai viruses was induced by both dyes under similar conditions (e.g., I50 = 20-50 nM for vesicular stomatitis virus), suggesting that loss of infectivity resulted from inactivation of fusion. Syncytium formation, between cells activated to express human immunodeficiency virus gp120 on their surfaces and CD4+ cells, was inhibited by illumination in the presence of 1 microM hypericin. Hypericin and rose bengal thus exert similar virucidal effects. Both presumably act by the same mechanism--namely, the inactivation of the viral fusion function by singlet oxygen produced upon illumination. The implications of this photodynamic antiviral action for the potential therapeutic usefulness of both hypericin and rose bengal are discussed.

Interaction between an acidic activator and transcription factor TFIIB is required for transcriptional activation

Abstract: How eukaryotic promoter-specific activator proteins (activators) stimulate transcription is a central question. We have previously shown that an acidic activator can directly interact with the general transcription factor TFIIB and increase its stable assembly into a preinitiation complex1,2. We have proposed that this increase in TFIIB assembly is at least part of the mechanism by which an acidic activator functions1,2. A prediction of this hypothesis is that a TFIIB mutant unable to interact with an acidic activator could not support activated transcription, and here we present experiments that verify this prediction. In conjunction with previous studies, our results argue that interaction between an acidic activator and TFIIB is necessary for transcriptional activation.

Multiple functional domains of human transcription factor IIB: distinct interactions with two general transcription factors and RNA polymerase II.

Abstract: Transcription factor IIB (TFIIB) plays a pivotal role in the formation of transcription-competent initiation complexes. TFIIB was found to interact with the TATA-binding protein, the small subunit of TFIIF, and RNA polymerase II. These interactions require distinct domains in TFIIB. Using the gel mobility-shift assay, it was found that the amino terminus of TFIIB was necessary for the formation of complexes containing RNA polymerase II and TFIIF, whereas the carboxy-terminal domain, which is composed of two imperfect direct repeats and includes a putative amphipathic alpha-helix, was sufficient for the formation of complexes containing the TATA-binding protein and TFIIB (DB complex). Protein-protein interaction analyses demonstrate that the amphipathic alpha-helix in TFIIB is important for the interaction with the TATA-binding protein. Specific residues mapping to the carboxyl terminus of the second direct repeat were found to be crucial for the interaction of TFIIB and RNA polymerase II. The interaction with the small subunit of TFIIF was mapped to the amino terminus of TFIIB, which includes a zinc finger.

Delayed and progressive brain injury in closed-head trauma: radiological demonstration.

Abstract: The importance of delayed or secondary brain insults in the eventual outcome of closed-head trauma has been documented in experimental models. To understand this phenomenon in the clinical setting, we studied a series of head-injured patients in whom multiple cranial computed tomographic (CT) scans were obtained. Patients whose follow-up CT studies revealed new intracranial lesions or worsening, compared with admission findings, were considered to have delayed cerebral injury. One hundred forty-nine (44.5%) of 337 consecutively studied patients developed delayed brain injury. There were highly significant associations (P < 0.001) between the appearance of delayed cerebral insults and the severity of the initial brain injury, the need for cardiopulmonary resuscitation in the field, the presence of coagulopathy at admission, and subdural hematoma on the initial CT scan. In addition, delayed injury was associated (P < 0.001) with higher mortality, slowed recovery, and poorer outcome at 6 months. Delayed brain injury was not significantly associated with patient age, sex, injury mechanism, associated injury, the need for endotracheal intubation in the field, early talking, CT abnormality other than intracranial hematoma, or type of residual neurological deficits. We used multiple regression analysis to explore the relationship between severity of injury, delayed insults, and outcome. As expected, the severity of the initial brain trauma contributed significantly to neurological outcome. The presence of delayed cerebral injury makes the outcome dramatically worse for each category of initial injury severity. The relationship between initial and secondary brain injury is discussed.

Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons

Abstract: Objective: To determine the prevalence and predictors of reactivity to tuberculin purified protein derivative (PPD) and skin test anergy in patients with human immunodeficiency virus (HIV) infectio...

Regulation and Heteromeric Structure of the Fibroblast Activation Protein in Normal and Transformed Cells of Mesenchymal and Neuroectodermal Origin

Abstract: The human fibroblast activation protein (FAP), defined by monoclonal antibody F19, is expressed in vivo in reactive stromal fibroblasts of epithelial cancers, subsets of bone and soft tissue sarcomas, and granulation tissue of healing wounds. FAP is generally absent from the stroma of benign epithelial tumors and normal adult tissues. In vitro FAP induction is observed in proliferating cultured fibroblasts and in melanocytes grown with fibroblast growth factor and phorbol ester. In the present study, we show that fibroblast and melanocyte FAP is a cell surface protein comprising noncovalently linked M(r) 95,000 (p95) and M(r) 105,000 (p105) subunits. In contrast, cultured sarcoma and melanoma cell lines express only p95 or are FAP negative. Immunoblot experiments show that p95, but not p105, carries the epitope defined by monoclonal antibody F19. Furthermore, peptide maps of purified p95 and p105 differ, suggesting that they may be distinct gene products. Loss of FAP or a change from p95/p105 to p95 expression accompanies the acquisition of growth factor independence and tumorigenicity in several in vitro test systems, including simian virus 40 transformation of normal fibroblasts, Ha-ras transformation of normal melanocytes, supertransformation of osteosarcoma cells, and enhanced N-MYC expression in variant neuroblastoma cells, whereas serum-starved normal fibroblasts continue to express p95/p105. Thus, fAP expression appears to be linked to the growth factor-dependent proliferative capacity of normal cells and is not merely a secondary event in proliferating cells; furthermore, FAP expression is inversely correlated with growth factor independence and tumorigenicity in transformed cell lines. This distribution pattern is consistent with a role for p95/p105 in mediating extrinsic, growth regulatory signals in normal cells, possibly as a heteromeric cell surface receptor. Such a physiological function may be obviated when oncogenes with cytoplasmic or nuclear sites of action are activated, reducing extrinsic growth factor dependence and permitting down-regulation of FAP in certain transformed cells.

Increases in type III collagen gene expression and protein synthesis in patients with inguinal hernias.

Abstract: ObjectiveThe aim of this study was to determine if alterations in fibrillar collagen synthesis were associated with the development of inguinal hernias.Summary Background DataPrevious work has suggested that alterations in connective tissue accumulation may play a functional role in the development

Prenatal exposure to ethanol alters the postnatal development and transformation of radial glia to astrocytes in the cortex.

Abstract: Postmitotic neurons migrate from a zone(s) near the ventricles to the neocortex. During this migration, neurons associate with radial glia. After serving their role as guides for neuronal migration, the radial glia transform into astrocytes. Prenatal exposure to ethanol causes abnormal neuronal migration. We examined the effects of gestational exposure to ethanol on radial glia and astrocytes. Radial glia were stained immunohistochemically with the antibody RAT-401, and astrocytes were labeled with an antibody directed against glial fibrillary acidic protein (GFAP). The subjects were the offspring of rats fed an ethanol-containing liquid diet (Et), pair-fed a liquid control diet (Ct), or fed chow and water (Ch). During the first postnatal week, radial glial fibers (in Et-treated rats and controls) stretched from the ventricular surface through the developing cerebral wall to the pial surface. In the Et-treated rats, the radial processes were less dense and more poorly fasciculated than they were in the Ch- and Ct-treated rats. Moreover, by postnatal day (P) 5, there was a significant reduction in RAT-401 immunostaining in the Et-treated rats, particularly in the superficial cortex. A similar reduction in control rats did not begin until P10. In all three treatment groups, GFAP-immunoreactive astrocytes were in the cortex throughout the period from P1 to P45. In neonates, GFAP-positive cells were distributed in the marginal zone (layer I) and the intermediate zone (the white matter). The number of GFAP-positive cells in the cortical plate increased steadily with time so that, by P26, GFAP-immunoreactive astrocytes were distributed evenly through all cortical laminae. Interestingly, between P5 and P12, the number of astrocytes was significantly greater in Et-treated rats than in controls. Thus prenatal exposure to ethanol induces the premature loss of RAT-401-positive processes and the precocious increase in GFAP immunostaining. These ethanol-induced changes in glial development indicate that ethanol accelerates the transformation of radial glia into astrocytes. Moreover, the ethanol-induced premature degradation of the network of radial glial fibers may underlie the migration of late-generated neurons to ectopic sites.