Overview of genetics for the clinician.
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Child↗
Biomedical subjects
M A Lieberman
Publications and source records attributed to M A Lieberman.
The effects of nursing home placement on family caregivers of patients with Alzheimer's disease.
PURPOSE: This study sought to determine the effects of nursing home placement (NHP) for patients with Alzheimer's disease, compared to maintaining community placement, on changes in family caregiver health and well-being over time. DESIGN AND METHODS: We utilized a 2-year, longitudinal study with one baseline and four follow-up assessments for patients' spouses, adult offspring, and in-laws (married to offspring). Families were recruited from eight clinical outpatient centers, supported by the State of California, and followed in the community over time. A multidisciplinary clinical evaluation was undertaken by the centers, and follow-up assessments included questionnaire and interview data. RESULTS: Family caregiver health and well-being did not improve over time following NHP, and there were no significant differences in health and well-being between family caregivers who placed their ill elder in a nursing home and those who kept the elder at home or in the community. However, female family caregivers and spouses displayed greater declines in health and well-being over time, compared to other family caregivers, regardless of whether or not NHP occurred. IMPLICATIONS: Families considering NHP need to be advised of what may and may not change following NHP. In particular, spouses and female family caregivers may not experience those changes in life satisfaction and well-being that are hoped for. Variation in the effects of NHP may be more related to pre-NHP family processes and relationships than to the severity of the patient's disability, caregiver strain, patient and caregiver demographics, and use of community-based professional services.
Adaptation, Psychological↗
The effects of family conflict resolution and decision making on the provision of help for an elder with Alzheimer's disease.
This study explored how characteristics of multigeneration families of patients with Alzheimer's disease (AD) affected the family's ability to provide help to their ill elder. An intensive patient and family assessment battery was employed with 211 families with an elder with AD, and measures of the amount and kind of help offered by the family group were recorded. Above and beyond control variables, families that used a focused decision-making style and positive conflict resolution methods provided more help than families that did not use these styles and methods. These data suggest the importance of the family system of care in disease management.
Adult↗
A longitudinal study of predictors of nursing home placement for patients with dementia: the contribution of family characteristics.
The caregivers of elderly patients with dementia (N = 164) were followed for 2 years to determine if characteristics of the multigeneration family predicted nursing home placement (NHP) over and above the effects of patient demographics, severity of patient disease, and characteristics of caregivers. Clinical assessment occurred at baseline, and caregivers were assessed by questionnaire and interview at baseline and every 6 months. No patient demographic, severity, or caregiver characteristic significantly predicted NHP. Families scoring high on emotional closeness, high on negative family feelings, and low on family efficiency institutionalized their ill elders at a significantly higher rate than other families, especially at low levels of patient severity. The findings argue that a careful examination of the multigeneration family should increase the prediction of NHP and the relevance of services offered to these families.
Aged↗
Tumor necrosis factor alpha regulates CXC chemokine receptor expression and function.
The alpha chemokine family is central to the participation of neutrophils in the acute inflammatory response. These substances interact with neutrophils through two cell surface receptors, CXCR-1 and CXCR-2 (formally known as IL-8R-1 and IL-8R-2). We investigated the possible regulatory effects of tumor necrosis factor alpha (TNFalpha) pretreatment on CXCR-1 and CXCR-2. To this end, we examined these receptors with flow cytometry, radioligand binding, Northern blot analyzes, calcium mobilization, and chemotaxis experiments on human neutrophils. In flow cytometry experiments, TNFalpha pretreatment substantially decreased cell surface CXCR-2 receptor levels but showed partial recovery at 120 min. On the other hand, CXCR-1 receptor levels had a sharp decline at 15 min and maintained that level to 120 min. Northern blot analyzes showed that mRNA levels of both IL-8 receptors were essentially unchanged after 45 min of TNFalpha pretreatment, but declined markedly following 2 h of pretreatment. Chemotaxis experiments on cells treated with TNFalpha for 5-120 min showed a substantial down-regulation of chemotaxis to IL-8 and GROalpha. This was noted to be much greater than the decline in cell surface receptors. Calcium mobilization experiments revealed minimal inhibition of the IL-8-induced increase in calcium after pretreatment with TNFalpha, but the response to NAP-2 was substantially inhibited. The data demonstrate differential regulation of the IL-8 receptor.
Blotting, Northern↗
Uncoupling of S-phase and mitosis by recombinant cytotoxic necrotizing factor 2 (CNF2).
Cytotoxic necrotizing factor 2 (CNF2) is an exotoxin identified from virulent clinical isolates of Escherichia coli. It has been characterized in adherent cell lines as an inducer of cellular death, hyperploidy (multinucleation), and cytoskeletal reorganization. The molecular mechanism of these actions is unclear. Two cellular mechanisms can be hypothesized to explain the DNA content increase (hyperploidy) induced by the toxin. The first is that the toxin interferes with cytoplasmic division without interfering with normal nuclear cycling, such that DNA is replicated in the absence of cell division. The second is that the toxin drives the nuclear machinery to replicate the DNA multiple times within one cell cycle, without interfering with cytoplasmic division. In order to investigate these phenomena, we have constructed a recombinant CNF2 gene that expresses a toxin with both an epitope tag and a polyhistidine tag. Extracts made from E. coli that express this gene have a high multinucleating activity that colocalizes with the recombinant 115-kDa protein. To distinguish between these hypotheses, we used recombinant CNF2 and several growth conditions (time, partial differentiation, and stage of growth) to establish a relationship between cellular divisions and generation of hyperploidy. It was also determined that the toxin had no effect upon in vitro DNA replication using a Xenopus egg extract system. In aggregate, these data are consistent with the hypothesis that CNF2 is affecting cytoplasmic division and thereby removing the requirement for a completed mitosis before the initiation of another S-phase. These data are discussed in relation to the generation of polyploid cells during megakaryopoeisis and the generation of aneuploid cells during tumorigenesis.
3T3 Cells↗
Megakaryocytic cell line-specific hyperploidy by cytotoxic necrotizing factor bacterial toxins.
Cytotoxic necrotizing factor (CNF) toxins, isolated from certain Escherichia coli strains known to cause intestinal and extra intestinal infections, induce reorganization of the actin cytoskeleton and generate hyperploidy in adherent cell lines. We have examined the effect of CNF toxin on one of the few cell types that naturally increase nuclear DNA content, megakaryocytes. Our studies show that only hematopoietic cells capable of differentiating along the megakaryocyte lineage responded to the CNF2 toxin by becoming polyploid and by reorganizing actin. The K562, HEL, and CHRF-288-11 cell lines can be induced with phorbol ester to differentiate along the megakaryocyte lineage, and these cells also respond to the toxin with increased DNA content and actin cytoskeletal rearrangements. Interestingly, treatment of the K562 and HEL cell lines with CNF2 does not result in an increase in production of the megakaryocytic marker glycoprotein IIIa, unlike phorbol ester treatment. Conversely, two T-cell leukemic cell lines, CEM and Molt4, and the promyelocytic HL-60 cell line, which do not differentiate along the megakaryocyte lineage in response to phorbol myristate acetate, do not respond to CNF2, by increased expression of gpIIIa, increased nuclear DNA content, or actin reorganization. A potential target of these toxins, RhoA, is expressed by both megakaryocytic and nonmegakaryocytic cell lines, as shown by reverse transcription-polymerase chain reaction and Western blot. Although it is clear that the CNF toxins can affect a wide variety of adherent nonhematopoietic cell lines, we propose that the response to CNF, in terms of reorganizing actin structure and increase in DNA content in hematologic suspension cells, correlates with the capability of these target cells to differentiate along the megakaryocytic lineage.
Bacterial Toxins↗
Identification of altered gene expression in skeletal muscle during sepsis using differential display.
Different aspects of muscle metabolism are altered during sepsis and there is evidence that some of these changes may be regulated at the gene level. Differential display is a recently described technique to identify genes whose expression has changed during a biological process. This technique utilizes reverse transcriptase-polymerase chain reaction (RT-PCR) to compare mRNA signals in tissues during two different conditions. We used differential display to test the hypothesis that gene expression is altered in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham-operated. Sixteen hours after CLP or sham operation, extensor digitorum longus muscles were harvested and RNA was extracted. Following differential display, 30 fragments (F1-F30) were identified that appeared to be uniquely expressed in muscles from sham-operated or septic rats. These fragments were reamplified by PCR and used as probes in Northern blot analysis. Messenger RNA levels corresponding to 2 of the 30 fragments (F5 and F24) were confirmed to be increased by Northern blot analysis in septic muscle. Following cloning and sequencing, F5 was found to display significant homology to the gene sequence of the guanine nucleotide releasing protein MSS4. The sequence of F24 did not match any reported gene sequence and may therefore represent a previously unidentified gene. The results support the hypothesis that gene expression is altered in skeletal muscle during sepsis.
Animals↗
Cytokine production by a megakaryocytic cell line.
The regulation of megakaryopoeisis by cytokines is not yet well understood. It is possible that autocrine loops are established during megakaryocyte growth and differentiation, aiding in the maturation of these cells. The CHRF-288-11 human megakaryoblastic cell line has been examined for cytokine production in growing cells and cells stimulated to differentiate by the addition of phorbol esters. It has been demonstrated that these cells produce RNA corresponding to the interleukins IL-1 alpha, 1 beta, 3, 7, 8, and 11, granulocyte-macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (INF-alpha), and basic fibroblast growth factor (bFGF). Additionally, RNA corresponding to the receptors for IL-6, GM-CSF, SCF, INF-alpha, beta, bFGF, and monocyte colony stimulating factor (M-CSF) were also expressed by the cells. The receptor for TNF-alpha was detected immunologically. Analysis at the protein level demonstrated that significant amounts of INF-alpha, TNF-alpha, GM-CSF, SCF, IL-1 alpha, and a soluble form of the IL-6 receptor were produced by the cells. Addition of phorbol esters to CHRF-288-11 cells enhances their megakaryocytic phenotype; such treatment also results in increased secretion of INF-alpha, TNF-alpha, and GM-CSF. These results suggest that potential autocrine loops are established during the differentiation of CHRF-288-11 cells, which may alter the capability of the cell to differentiate. These findings are similar to those recently obtained for marrow-derived megakaryocytes (Jiang et al.) suggesting that CHRF-288-11 cells provide a useful model system for the study of cytokine release during megakaryocyte differentiation.
Cell Line↗
Cloning and characterization of rat density-enhanced phosphatase-1, a protein tyrosine phosphatase expressed by vascular cells.
We have cloned from cultured vascular smooth muscle cells a protein tyrosine phosphatase, rat density-enhanced phosphatase-1 (rDEP-1), which is a probable rat homologue of DEP-1/HPTP eta. rDEP-1 is encoded by an 8.7-kb transcript and is expressed as a 180- to 220-kD protein. The rDEP-1 gene is located on human chromosome 11 (region p11.2) and on mouse chromosome 2 (region 2E). The cDNA sequence predicts a transmembrane protein consisting of a single phosphatase catalytic domain in the intracellular region, a single transmembrane domain, and eight fibronectin type III repeats in the extracellular region (GenBank accession number U40790). In situ hybridization analysis demonstrates that rDEP-1 is widely expressed in vivo but that expression is highest in cells that form epithelioid monolayers. In cultured cells with epitheliod morphology, including endothelial cells and newborn smooth muscle cells, but not in fibroblast-like cells, rDEP-1 transcript levels are dramatically upregulated as population density increases. In vivo, quiescent endothelial cells in normal arteries express relatively high levels of rDEP-1. During repair of vascular injury, expression of rDEP-1 is downregulated in migrating and proliferating endothelial cells. In vivo, rDEP-1 transcript levels are present in very high levels in megakaryocytes, and circulating plates have high levels of the rDEP-1 protein. In vitro, initiation of differentiation of the human megakaryoblastic cell line CHRF-288-11 with phorbol 12-myristate 13-acetate leads to a very strong upregulation of rDEP-1 transcripts. The deduced structure and the regulation of expression of rDEP-1 suggest that it may play a role in adhesion and/or signaling events involving cell-cell and cell-matrix contact.
Amino Acid Sequence↗
Orthodontic tooth movement following guided tissue regeneration: report of three cases.
This report presents three patients with advanced adult periodontitis and in which orthodontic tooth movement was performed subsequent to guided tissue regeneration procedures. Clinical follow-up showed a mean 3.3-mm attachment gain in the deepest preoperative probing depth sites, and radiographs revealed bone fill following guided tissue regeneration procedures with resorbable and nonresorbable membranes, with and without the use of demineralized freeze-dried bone allograft. Orthodontic tooth movement into the regenerated areas was successful. The feasibility of orthodontic tooth movement following successful regenerative procedures is discussed.
Adult↗
The impact of chronic illness on the health and well-being of family members.
Examined is the impact of dementia on the physical and mental health of all family members caring for an ill parent/spouse. The sample included 97 spouses of patients diagnosed with either Alzheimer's disease or vascular dementia, 186 offspring, and 97 offspring spouses or "in-laws." Multiple regression tested the association between severity of the illness and family member health and well-being. Severity was significantly associated with health and well-being for spouses, offspring, and in-laws, regardless of the amount of caregiving, demonstrating the potential cascading effect of the illness through the family. Use of services displayed no direct association with spouse health and well-being, but service utilization interacted with illness severity. The relationship between severity of illness and spouse health was lower under conditions of high service utilization than under conditions of low service utilization.
Adult↗
Sepsis stimulates polyamine biosynthesis in the liver and increases tissue levels of ornithine decarboxylase mRNA.
The influence of sepsis on polyamine metabolism in the liver was studied in rats. Sepsis was induced by cecal ligation and puncture; control rats were sham-operated. Sepsis resulted in increased concentrations in liver tissue of putrescine and spermidine and stimulated activity of the enzymes ornithine decarboxylase (ODC) and s-adenosylmethionine decarboxylase. A similar metabolic response was seen following the subcutaneous injection of 1 mg/kg of endotoxin or following the e intraperitoneal injection of 100 micrograms/kg of human recombinant tumor necrosis factor (TNF)-alpha or interleukin-1 alpha (IL-1 alpha). ODC mRNA levels determined by Northern blots were increased in liver tissue of septic rats, suggesting that the increase in ODC activity may be regulated at the transcriptional level although increased stability of the messenger could give rise to similar results. Treatment of rats with either TNF antiserum, recombinant IL-1 receptor antagonist, or the glucocorticoid receptor antagonist RU 38486, did not prevent the sepsis-induced increase in hepatic ODC activity. The data suggest that sepsis stimulates the biosynthesis of polyamines in liver tissue and that this response to sepsis may not primarily be mediated by TNF, IL-1, or glucocorticoids. The biological role of increased liver polyamines during sepsis, in particular their relationship with the synthesis of acute phase proteins, remains to be determined.
Animals↗
Retroviral mediated gene transfer in megakaryocytic cell lines.
There have been no reports, to date, of successful introduction of foreign DNA into committed megakaryocyte precursor cells. We have successfully infected two megakaryocytic cell lines, one a committed cell line (CHRF-288-11) and the other a bipotential cell line (K562), with a retroviral vector containing the bacterial lacZ gene and a neomycin resistance marker. Modification of standard protocols was required for successful infection of the committed megakaryocyte cell line. Presence of the lacZ transgene was demonstrated at the molecular level by polymerase chain reaction (PCR), and its expression at the mRNA level by reverse transcriptase-PCR. Presence of the bacterial beta-galactosidase was demonstrated by both immunofluorescence and enzyme activity. Treatment of the CHRF-288-11 infected cells with phorbol esters, which induces megakaryocytic differentiation, increases expression of the lacZ transgene. The staining pattern of the lacZ reaction product was perinuclear and punctate in the CHRF-288-11 cells, whereas it was uniform throughout the cytoplasm of the K562 cells, suggesting different sorting mechanisms for bacterial beta-galactosidase in these two cell types. Overall, these results demonstrate the feasibility and provide a method for infecting cultured megakaryocytic cell lines with retroviral of vectors such that a molecular analysis of megakaryocyte differentiation can be accomplished.
Base Sequence↗
The effect of pain from orthodontic arch wire adjustment on masseter muscle electromyographic activity.
Pain has been shown to have an effect on muscle activity even when it does not originate in the muscle itself or in the related joint. The effect of pain from arch wire adjustment on jaw muscle activity is unclear. This study systematically evaluated the effects of orthodontic arch wire adjustment pain on masseter electromyographic (EMG) activity and on the swallowing threshold. The EMG recordings were made on 22 subjects (ages 11 to 15) under three conditions: chewing five peanuts (10 seconds), watching TV chewing gum (15 minutes), and watching TV with no gum (15 minutes). An arch wire adjustment or placebo adjustment was then made. Subjects returned after 48 hours, and the EMG measurements were made under the same conditions. After 3 weeks, subjects received arch wire or placebo treatment in a crossover design with identical recording procedures. The EMG levels while chewing peanuts decreased in 18 of 22 subjects after treatment, compared with 9 of 22 subjects after the placebo. While watching TV with gum, the EMG levels of 20 of 22 subjects decreased after treatment, compared with 9 of 22 subjects after the placebo. The number of chewing strokes before swallowing increased significantly after treatment compared with after placebo. The results suggest that orthodontic pain on teeth tend to reduce muscle activity during function.
Adolescent↗
Alzheimer's disease: the impact of the family on spouses, offspring, and inlaws.
This article reports the findings from a study designed to identify qualities of the multigeneration family system that affected the relationship between the demands of Alzheimer's disease on the family and the health and well-being of (a) spouses, (b) offspring, and (c) offspring's spouses or "inlaws." Members of 97 families of patients with Alzheimer's disease, recruited from four University-affiliated Alzheimer's Centers, completed detailed questionnaires and participated in a 45-minute telephone interview to assess care-strain, personal stress, appraisals of three major domains of family life (World View, Structure/Organization, and Emotion Management), and three health and well-being indices (Anxiety/Depression, Somatic Symptoms, and Well-Being). Multivariate multiple regression equations, run separately for each of the three groups of family respondents and each of the three family domains, indicated: (1) no significant associations between the severity of the elder's disease and family member health and well-being; (2) female family members reported poorer health and well-being than male family members; and (3) caregiver strain was negatively associated with family member health and well-being. Further, appraised family qualities were associated with the health and well-being of the three groups of respondents differently: directly for offspring, interactively with severity of patient disorder for inlaws, and not at all for spouses. The data suggested that some family qualities served a protective function, whereas others exacerbated the negative effects of caregiving by affecting personal health and well-being. The findings are interpreted in terms of the different roles and expectations for care-giving placed on spouses, offspring, and inlaws. It is suggested that programs of intervention for patients with Alzheimer's and other chronic diseases should focus on the multigeneration family as the context for care, rather than only on the primary caregiver.
Activities of Daily Living↗
Induction of the c-ski proto-oncogene by phorbol ester correlates with induction of megakaryocyte differentiation.
Overexpression of v-ski blocks the terminal differentiation of chicken erythroblasts, and in cooperation with v-sea causes transformation of these cells, indicating that c-ski may play a role in regulating either proliferation or differentiation in hematopoietic cells. We examined c-ski expression in four different myeloid cell lines which can be induced to differentiate by exposure to phorbol 12-myristate 13-acetate (PMA). Two of the cell lines are multipotent and have the ability to differentiate into either erythrocytes or megakaryocytes (K562 and HEL cells), one cell line differentiates exclusively into megakaryocytes (CHRF-288-11), and the fourth cell line differentiates into either monocytes or granulocytes (HL-60). Our findings indicate that c-ski mRNA is up regulated by PMA only in those cell lines which respond by differentiating along the megakaryocyte lineage. The extent of differentiation and the observed increase in c-ski mRNA levels are positively correlated with the PMA concentration used to induce differentiation. Experiments in which CHRF-288-11 cells were treated with the protein kinase C (PKC) activator bryostatin 1 indicate that c-ski mRNA induction is not a general effect of PKC activation. The results strongly suggest that c-ski expression is correlated with megakaryocyte maturation.
Bryostatins↗
Expression of tie receptor tyrosine kinase in leukemia cell lines.
The tie receptor tyrosine kinase mRNA was originally identified as an amplified product in reverse transcription-polymerase chain reaction analysis of human K562 leukemia cell RNA. In situ hybridization analysis revealed that the corresponding mouse gene is expressed predominantly in endothelial cells. We have explored tie mRNA and protein expression in tumor cell lines. The 4.4 kb tie mRNA was expressed at high levels in five of five human megakaryoblastic leukemia cell lines studied and in two IL-3-dependent mouse myeloid leukemia cell lines, but not in 42 other leukemia cell lines representing various hematopoietic lineages. Increased expression of tie mRNA and protein was observed upon treatment of the megakaryoblastic leukemia cells with the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA), known to enhance megakaryoblastic markers. Among several cell lines from solid tumors, two fibrosarcomas, one rhabdomyosarcoma and one melanoma cell line were positive for tie mRNA. These results suggest that among hematopoietic lineages tie is predominantly expressed in cells with megakaryoblastic properties and that the tie tyrosine kinase is a receptor for a regulatory factor specific for megakaryoblasts, endothelial cells, and occasional tumor cell lines derived from mesenchymal tissues.
3T3 Cells↗