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Biomedical subjects

D Weiner

Publications and source records attributed to D Weiner.

At least 19 recordsLinked to original sources
PubMed2001

Identification of gene clusters differentially expressed during the cellular injury responses (CIR) to cisplatin.

The goal of this study was to identify changes in mRNA levels in tumour cells after a toxic exposure to cisplatin (IC(99)dose). Using suppression-subtractive hybridization (SSH) 2 cDNA libraries were created, an UP library (202 cDNA fragments) and a DOWN library (153 cDNA fragments). Using reversed Northern hybridization 16 and 30 fragments were truly differentially expressed in the UP and DOWN libraries, respectively. Most prominent in the UP library were the mitochondrial and injury response clusters and in the DOWN library the cytoskeletal, protein synthesis and signalling clusters. These distinct clusters potentially represent an expression profile of the cisplatin-induced cellular injury response.

Antineoplastic Agents↗
PubMed2001

Nicotine affects the signaling of the death pathway, reducing the response of head and neck cancer cell lines to DNA damaging agents.

BACKGROUND: Growing evidence suggests that tobacco can affect the responsiveness of cancer cells to treatment, particularly those of head and neck cancer. This article describes the effects of nicotine on the signaling of the death pathway, resulting in a decreased cytotoxicity of various anticancer agents such as cisplatin and gamma-radiation. METHODS: Colony-forming assays (CFA), using the head and neck cancer cell lines UMSCC10b and UMSCC5 and DNA fragmentation assays, were used to determine the effect of nicotine on cytotoxicity of various anticancer agents, whereas PCR and a JNK activity test were used to study the effect of nicotine on message expression levels and activity of the JNK signaling pathway. RESULTS: Nicotine consistently reduced the cytotoxic effect of DNA-damaging agents, such as cisplatin, UV, and gamma radiation, in UMSCC10b cells, increasing their IC(50) values by twofold, 1.7-fold, and 1.8-fold, respectively. These results were confirmed in a second squamous cell carcinoma cell line (UMSCC5), demonstrating an increase in IC(50) values for cDDP by twofold and 1.9-fold in the UMSCC10b andUMSCC5, respectively. In addition, nicotine reduced the DNA fragmentation 48 h after cDDP exposure in UMSCC10b and UMSCC5 cell lines by 30% and 33%, respectively. The latter, however, was not the result of an effect of nicotine on either the uptake of cDDP or repair of the cDDP-DNA-adducts. To further substantiate the adverse effect of nicotine, the JNK and gadd153 signaling pathways were studied. JNK activity was decreased by 1.8-fold, as well as the expression of its downstream target c-jun (1.9-fold), when tumor cells were exposed to cisplatin in the presence of nicotine. In addition, the gadd153 message was affected and reduced by 1.8-fold. CONCLUSIONS: Nicotine adversely affects the cytotoxicity of DNA-damaging agents. Nicotine does not interfere with the repair of the damage but directly affects the signaling of the death pathway, reducing the signaling of the JNK1 pathway. The latter results in a decrease in efficacy of the anticancer treatment in tumors exposed to nicotine.

Antineoplastic Agents↗
PubMed2000

Acute increase in blood flow to the rat bladder subsequent to partial bladder outlet obstruction.

Partial obstruction of the rat bladder outlet initiates a multi-step process during which the bladder progressively loses its functional ability. The first step in this progression is bladder hypertrophy; the organ dramatically increases in size and weight to compensate for the effects of obstruction. Unoperated female rats, age-matched, sham-obstructed rats, and rats that received a partial bladder outlet obstruction were studied. During the first 24 hours after partial bladder outlet obstruction, relative bladder blood flow was measured using a fluorescent microsphere infusion technique and laser Doppler imaging. Nitric oxide synthase (NOS) activities of control and obstructed rat bladder tissues were determined using an enzymatic assay that measures the conversion of (3)H-L-arginine to (3)H-L-citrulline. Using the microsphere infusion technique, a significant increase in blood flow to the obstructed rat bladder was observed during the first 24 hours after partial bladder outlet obstruction. Relative bladder blood flow increased approximately sixfold at 4 and 6 hours post-obstruction and remained elevated through 24 hours of obstruction. Sham operations (evaluated after 6 hours after surgery) resulted in a minor increase in blood flow that did not reach statistical significance. Relative blood flow to the spleen, measured in the same rats, was not significantly changed. Laser Doppler measurements also identified a significant increase in rat bladder blood flow after outlet obstruction and showed that increased blood flow could be detected as early as 1 hour post-obstruction. Interestingly, despite the significant differences in bladder blood flow between control and early post-obstructed rat bladders, NOS activities of control and obstructed rat bladders were comparable. The increase in bladder blood flow precedes the urothelial, fibroblast and smooth muscle cell hyperplasia, and the smooth muscle hypertrophy that occurs after obstruction. We propose that, in response to surgical induction of partial outlet obstruction, acute up-regulation of bladder blood flow may be an initiating factor for subsequent bladder cell proliferation and smooth muscle hypertrophy. Neurourol. Urodynam. 19:195-208, 2000.

Animals↗
PubMed1999

Pain in nursing home residents: an exploration of prevalence, staff perspectives, and practical aspects of measurement.

OBJECTIVE: To help rectify the underdiagnosis of chronic pain in frail nursing home residents by developing a new feasible pain self-report instrument, the structured pain interview; to use this new tool to estimate pain prevalence and staff's knowledge of residents' pain in two nursing homes; and to compare the performance differences of the structured pain interview and the commonly used 0-10 scale. DESIGN: Cross-sectional survey. SETTING: One 120-bed VA-affiliated and one 125-bed university-affiliated, community-based nursing home in Durham, North Carolina. PATIENTS: One hundred fifty-eight chronic care nursing home residents without aphasia, acute illness, persistent vegetative status, or severe hearing impairment and 3 1 nursing home nurses. OUTCOME MEASURES: Pain prevalence according to resident self-report and nurse report; stability of response to the structured pain interview and 0-10 scale over 1 month; agreement between residents and nurses on the structured pain interview and 0-10 scale. RESULTS: Fifty-eight percent of the VA and 45% of the community nursing home residents reported pain. Forty-two percent at the VA and 20% at the community home were unable to respond to the 0-10 scale, compared with 7.5% and 14% using the structured pain interview. Stability of response to the structured pain interview at 1 month was 0.56 at the VA (nurse-resident agreement 0.38) and 0.72 in the community (nurse-resident agreement 0.07), which was very comparable to the 0-10 scale. CONCLUSIONS: We have developed a highly feasible tool for examining pain prevalence in nursing homes. This tool uncovered considerable miscommunication regarding pain between residents and staff. Improvement in pain communication between nursing home residents and staff is needed, so that more effective pain treatment programs can be developed for this vulnerable population.

Attitude of Health Personnel↗
PubMed1998

Evaluating persistent pain in long term care residents: what role for pain maps?

The purpose of this study was to examine the utility of the pain map as a pain assessment tool in frail nursing home residents. The study was conducted in two phases. In Phase 1, nursing home staff's knowledge of the locations of resident pain complaints was examined. We found significant deficiencies in this knowledge. In Phase 2, we examined the following test characteristics of pain extensity (number of painful body areas annotated on pain map): (1) test-retest reliability, (2) convergent validity as compared with pain intensity measured by a pain thermometer (modified vertical verbal descriptor scale) and an 11 point numerical graphic rating scale (NGRS), and (3) predictive validity with depression, functional impairment and self-rated health. Pain map scoring was performed by counting the number of involved body areas (i.e., numbered segments) using an established scoring template. Test-retest reliability by body area was excellent. Pain extensity was modestly associated with pain thermometer-scored pain intensity but not with NGRS-scored pain intensity. Pain extensity also demonstrated modest predictive validity with self-rated health, but not with depression or functional impairment. The advantage of knowing where residents hurt is that this allows staff to target their assessment and thus determine the functional implications of residents' pain. It appears that pain maps add a useful dimension to pain assessment in residents of long term care facilities.

Adult↗
PubMed1997

A basic compositional requirement of agents having heparin-like cell-modulating activities.

Heparin has been recognized as possessing a large variety of cell-modulating activities. Using compositionally simple, structurally rigid, and low molecular weight saccharide molecules (cyclodextrins), we demonstrated that these activities depend primarily on a single, gross compositional parameter: a minimum intramolecular density of neighboring anionic (sulfate) groups. This same critical parameter is shown to be involved in achieving cell-modulating behavior as diverse as angiogenesis, endothelial proliferation, inhibition of smooth muscle cell growth, and cell protection against virus invasion. Physical chemical evidence is presented that associates this property with multi-ionic complex formation between the clusters of anionic and cationic sites on the complexing partners. These observations revive early suggestions of the decisive role of electrostatic complexation capabilities of glycosaminoglycans like heparin; taken together with numerous observations on heparinoids and other agents reported in diverse specialized fields of cell biology and medicine, they provide evidence that molecular agents of critical anionic (sulfate) density (MACADs) represent a broad class of molecules that, in contrast to proteins, do not rely on structural detail for their cell biological activities, but function by ionic complexation with proteinic agents (e.g. growth factors), thereby modifying their structure-specific activities.

Alcian Blue↗
PubMed1997

Antigens produced in plants by infection with chimeric plant viruses immunize against rabies virus and HIV-1.

The coat protein (CP) of alfalfa mosaic virus was used as a carrier molecule to express antigenic peptides from rabies virus and HIV. The antigens were separately cloned into the reading frame of alfalfa mosaic virus CP and placed under the control of the subgenomic promoter of tobacco mosaic virus CP in the 30BRz vector. The in vitro transcripts of recombinant virus with sequences encoding the antigenic peptides were synthesized from DNA constructs and used to inoculate tobacco plants. The plant-produced protein (virus particles) was purified and used for immunization of mice. Both antigens elicited specific virus-neutralizing antibodies in immunized mice.

AIDS Vaccines↗
PubMed1997

Interleukin-10 downregulates the intracerebral immune response in chronic Toxoplasma encephalitis.

The expression of the immunosuppressive cytokine interleukin (IL)-10 in the normal and Toxoplasma gondii-infected murine brain was analysed. Microglia/macrophages expressed IL-10 at the mRNA and protein level in the normal brain. In Toxoplasma encephalitis (TE), CD4+ and CD8+ T-cells also contributed to the upregulated IL-10 production. Neutralization of endogenous IL-10 in chronic TE reduced the intracerebral parasitic load and increased the number of immune cells and the production of protective cytokines. These findings indicate that intracerebral expression of IL-10 interferes with the immune response in TE and may contribute to parasite persistence in the brain.

Animals↗
PubMed1997

Synthetic CD4 exocyclics inhibit binding of human immunodeficiency virus type 1 envelope to CD4 and virus replication in T lymphocytes.

CD4 functions as a major T-cell surface receptor for human immunodeficiency virus by binding the human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 with relatively high affinity. We have developed constrained aromatically modified analogs of the secondary structures of the first domain of CD4 in order to analyze surfaces involved in binding of gp120. Complementarity determining-like regions (CDRs) of the D1 domain of CD4 were reproduced as synthetic aromatically modified exocyclic (AMEs) forms. The exocyclic CDR3.AME(82-89), derived from the CDR3 (residues 82-89) region of CD4 D1 domain, specifically inhibited binding of recombinant gp120 to both recombinant soluble CD4, and CD4+ Jurkat cells, and blocked syncytium formation and virus particle production caused by HIV-1 infection. We have previously shown that the CDR3.AME analog binds to the CD4 CDR3 region and creates a disabled CD4 heterodimer. We propose that the AME prevents the formation of an essential homodimeric surface needed for efficient HIV binding. Additionally the disabled CD4 receptor may be less able to signal the cell to allow HIV replication and HIV infection. Such compounds may represent a new receptor specific approach to modulate biological functions.

Amino Acid Sequence↗
PubMed1997

Quality of care.

Explore the source record for details and available documents.

Female↗
PubMed1996

Pain measurement in elders with chronic low back pain: traditional and alternative approaches.

Pain evaluation typically relies upon the use of self-report instruments. The validity of these tools is questionable in many older adults, however, particularly those with cognitive impairment. Rating of pain behavior (e.g. grimacing, sighing) by an objective observer represents an alternative pain assessment strategy which has been validated in subjects of heterogeneous ages. The purpose of this study was to examine, in a group of community-dwelling elderly with low back pain and lumbosacral osteoarthritis, the concurrent validity of observational pain behavior rating techniques as compared with self-report instruments and the degree to which pain and pain behavior relate to disability. Thirty-nine cognitively intact subjects, age > 65 years, without depression, other sources of pain, or other known spinal pathology underwent the following measures: (1) pain self-report using the verbal 0-10 scale, vertical verbal descriptor scale, Arthritis Impact Measurement Scales and McGill Pain Questionnaire; (2) pain behavior was sampled during two protocols, one, identical to that used by Keefe and Block (Behav. Ther., 13 (1982) 363-375), that required subjects to sit, stand, walk, and recline for 1-2 minute periods (which we have labelled the traditional protocol), and a second, more demanding protocol that was designed to simulate activities of daily living that place a premium on axial movement (the 'ADL' protocol); (3) disability was assessed using the Roland questionnaire, a 6 month global disability question and the Jette Functional Status Index; and (4) radiographic evaluation of the lumbosacral spine; osteoarthritis was quantitated using a previously validated scoring system. Interrelationships among pain, pain behavior and disability measures were tested using canonical correlations. Self-reported pain was associated with pain behavior frequency; the association was stronger when the ADL protocol was used, as compared with the traditional protocol. The association between pain and disability was modestly strong with both self-report instruments and pain behavior observation when the ADL protocol was used, but not when the traditional protocol was used. Our findings suggest that pain behavior observation is a valid assessment tool in the elderly. In addition, it seems that observation of elders during performance of activities of daily living may be a more sensitive and valid way of assessing pain behavior than observing pain behavior during sitting, walking, standing, or reclining.

Activities of Daily Living↗
PubMed1996

Pathogenesis of slipped capital femoral epiphysis: current concepts.

Since Ambrose Paré in 1572 initially described what is believed to be the first case of slipped capital femoral epiphysis (SCFE), a virtual plethora of unproven theories has evolved in the ensuing years. The most currently popular theories embrace a framework of biomechanical events versus biochemical events having impact at the time of puberty. The zone of slipping always occurs primarily through the zone of hypertrophy in a corrugated undulating fashion. All investigative studies show that the growth plate at the time of puberty is weakened in SCFE. The final common pathway appears to be a mechanical failure of the growth plate, due to a weakened state, to resist displacement. The commonly encountered large body mass coupled with an increasingly oblique physis lying in a relative degree of retroversion creates a mechanical environment that, coupled with delicate alterations in the hormonal balance of thyroid hormone, growth hormone, testosterone, and estrogen, render the plate intrinsically suspectible to displacement by rather innocuous forces occurring in a shear plane. Ultrastructure studies of SCFE demonstrate a significant alteration in anatomy and physiology in all active metabolic areas of the growth plate. It is the author's concept that SCFE is a generalized metabolic disorder of puberty resulting from a series of pubertal mishaps with a multifactorial basis ordinarily caused by a relative imbalance of hormones, coupled with biomechanical events.

Adolescent↗
PubMed1996

Interferon-gamma receptor-deficiency renders mice highly susceptible to toxoplasmosis by decreased macrophage activation.

Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of macrophages. Macrophages are of critical importance in toxoplasmosis, and insufficient macrophage activation cannot be compensated by other immune mechanisms.

Adoptive Transfer↗
PubMed1995

Systemic immunization induces protective CD4+ and CD8+ T cell-mediated immune responses in murine Listeria monocytogenes meningoencephalitis.

The immune mechanisms underlying immunization-induced protection of mice from lethal central nervous system (CNS) listeriosis were evaluated by immunohistochemistry, flow cytometry of leukocytes isolated from the brain, reverse transcription-polymerase chain reaction analysis of intracerebral (i.c.) tumor-necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-1 beta, IL-10, granulocyte/macrophage colony-stimulating factor, and inducible nitric oxide synthase mRNA expression, and T cell depletion experiments. The data demonstrate that active immunization of mice prior to an i.c. infection with Listeria monocytogenes prevents the development of a fatal necrotizing encephalitis and accelerates the recruitment of an increased number of alpha beta T cell receptor (TcR)+ CD4+ and CD8+ T cells, gamma delta TcR+ T cells, B cells, granulocytes and macrophages to the brain compared to non-immunized animals. In addition, immunization induced a pronounced activation of i.c. macrophages and microglial cells as shown by an increased expression of MHC class II antigens. In parallel, transcript levels for all cytokine mRNA analyzed were higher in the brains of immunized mice. The protective effects of immunization were completely abolished by depletion of CD4+, CD8+, or both T cell subsets. All groups of T cell-depleted immunized mice developed a fatal necrotizing encephalitis with an increased i.c. bacterial load. In addition, cytokine mRNA synthesis was significantly impaired. The severity of disease was only slightly different between CD4+, CD8+ and CD4+/CD8+ T cell depleted mice, indicating that both subsets of T cells are required for an effective i.c. immune response to L. monocytogenes. This is in marked contrast to systemic listeriosis, and points to CNS-specific features of the immune response.

Animals↗