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Biomedical subjects

J Adams

Publications and source records attributed to J Adams.

At least 109 records · Page 6Linked to original sources
PubMed2001

Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma.

We have shown that activation of nuclear factor-kappa B (NF-kappa B) promotes cell survival and expression of cytokines such as growth-regulated oncogene-alpha, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC). Activation of NF-kappa B and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-kappa B. In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-kappa B and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-kappa B DNA binding and functional reporter activity at concentrations between 10(-8) and 10(-7) M. Cytotoxicity was observed at 10(-7) M in four murine and two human SCC lines, and followed early cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1--2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg. Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proangiogenic cytokines growth-regulated oncogene-alpha and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-kappa B. We conclude that PS-341 inhibits activation of NF-kappa B pathway components related to cell survival, tumor growth, and angiogenesis in SCC.

Animals↗
PubMed2001

Case-mix adjustment of the National CAHPS benchmarking data 1.0: a violation of model assumptions?

OBJECTIVE: To compare models for the case-mix adjustment of consumer reports and ratings of health care. DATA SOURCES: The study used the Consumer Assessment of Health Plans (CAHPS) survey 1.0 National CAHPS Benchmarking Database data from 54 commercial and 31 Medicaid health plans from across the United States: 19,541 adults (age > or = 18 years) in commercial plans and 8,813 adults in Medicaid plans responded regarding their own health care, and 9,871 Medicaid adults responded regarding the health care of their minor children. STUDY DESIGN: Four case-mix models (no adjustment; self-rated health and age; health, age, and education; and health, age, education, and plan interactions) were compared on 21 ratings and reports regarding health care for three populations (adults in commercial plans, adults in Medicaid plans, and children in Medicaid plans). The magnitude of case-mix adjustments, the effects of adjustments on plan rankings, and the homogeneity of these effects across plans were examined. DATA EXTRACTION: All ratings and reports were linearly transformed to a possible range of 0 to 100 for comparability. PRINCIPAL FINDINGS: Case-mix adjusters, especially self-rated health, have substantial effects, but these effects vary substantially from plan to plan, a violation of standard case-mix assumptions. CONCLUSION: Case-mix adjustment of CAHPS data needs to be re-examined, perhaps by using demographically stratified reporting or by developing better measures of response bias.

Adolescent↗
PubMed2001

ORL nursing: where we have been and where we are going.

In 1873, formal training for nurses in the United States began on the east coast with the formation of hospital-based schools (Schoor & Kennedy, 1999). Upon completion of the two to three year program, graduate nurses took positions in private homes as private duty nurses. Hospitals needed only a few supervisory nurses since student nurses provided most of the patient care. The popularity of private duty nursing continued for many years and was slowly replaced by hospital staff nursing in the 1930s. This article provides an overview of ORL nursing and the advent of certification in ORL specialty nursing.

Certification↗
PubMed2000

Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy.

PURPOSE/OBJECTIVE: To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma. METHODS AND MATERIALS: Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207). RESULTS: Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol. CONCLUSION: Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy.

Adolescent↗
PubMed2000

Fas ligand, Bcl-2, granulocyte colony-stimulating factor, and p38 mitogen-activated protein kinase: Regulators of distinct cell death and survival pathways in granulocytes.

The short life span of granulocytes, which limits many inflammatory responses, is thought to be influenced by the Bcl-2 protein family, death receptors such as CD95 (Fas/APO-1), stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), and proinflammatory cytokines like granulocyte colony-stimulating factor (G-CSF). To clarify the roles of these various regulators in granulocyte survival, we have investigated the spontaneous apoptosis of granulocytes in culture and that induced by Fas ligand or chemotherapeutic drugs, using cells from normal, CD95-deficient lpr, or vav-bcl-2 transgenic mice. CD95-induced apoptosis, which required receptor aggregation by recombinant Fas ligand or the membrane-bound ligand, was unaffected by G-CSF treatment or Bcl-2 overexpression. Conversely, spontaneous and drug-induced apoptosis occurred normally in lpr granulocytes but were suppressed by G-CSF treatment or Bcl-2 overexpression. Although activation of p38 MAPK has been implicated in granulocyte death, their apoptosis actually was markedly accelerated by specific inhibitors of this kinase. These results suggest that G-CSF promotes granulocyte survival largely through the Bcl-2-controlled pathway, whereas CD95 regulates a distinct pathway to apoptosis that is not required for either their spontaneous or drug-induced death. Moreover, p38 MAPK signaling contributes to granulocyte survival rather than their apoptosis.

Animals↗
PubMed2000

Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique.

PURPOSE: Most children with orbital rhabdomyosarcoma will survive their disease. However, conventional photon-radiation treatment, as part of multimodality therapy, results in varying degrees of long-term functional and cosmetic side effects. This report introduces external beam proton radiation therapy (PRT) as a conformal, three-dimensional planned radiation technique for this disease, analyzes normal tissue dosimetry, and describes the technique's application in the first 2 patients. MATERIAL AND METHODS: Between January 1995 and February 1996, 2 patients underwent PRT following biopsy and chemotherapy for orbital rhabdomyosarcoma. Fifty and 55 Cobalt Gray Equivalent (CGE) were delivered to the gross tumor volume and 40 CGE to clinical target volumes in both patients. A relative biologic effectiveness (RBE) of 1.1 was utilized to correlate proton dose calculations with CGE. To achieve dose conformity, a "patch technique" was utilized, where target regions were divided into segments, each treated by a separate proton field. Dose-volume histograms were obtained for target and nontarget regions, including lens, bony orbit, pituitary gland, optic chiasm, optic nerves, lacrimal gland, and ipsilateral frontal and temporal lobes. RESULTS: At 3.4 and 2.5 years after PRT, both patients are clinically and radiographically free of disease. Visual acuity remains excellent, without signs of cataract formation; pituitary function is normal; cosmetically, only mild enophthalmos is noticeable. Doses to 90%, 50%, and 5% of lens volume were kept at less than 1%, less than 2%, and less than 8%, respectively. Fifty percent of lacrimal gland volume received less than 36% of the prescribed dose and 50% of the volume of the optic chiasm, pituitary gland, and hypothalamus were restricted to less than 2%. Proton conformity to orbital contents resulted in between 9% and 36% of the prescribed dose reaching the ipsilateral temporal and frontal lobes immediately adjacent to bony orbit (5% volume). CONCLUSION: PRT can offer excellent sparing of lens and selected intraorbital and ocular normal structures, while maintaining conformal target-dose coverage. The steep dose gradient beyond the orbit minimizes irradiation of normal brain parenchyma, with almost complete sparing of the pituitary gland. Reduction of integral irradiation exposure of the periorbital region will, hopefully, reduce the risk of second malignancy later in life. Reduced radiation dose to specific organs in close proximity to, but not part of the target region promises improved functional outcome and better cosmesis for childhood cancer survivors.

Child↗
PubMed2000

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

Adult↗
PubMed2000

In vitro and in vivo responses to interleukin 12 are maintained until the late SIV infection stage but lost during AIDS.

The in vitro proliferative responses of macaque peripheral blood mononuclear cells (PBMCs) to IL-12 appeared similar before and early after SIV infection, whereas macaque PBMCs sampled during symptomatic stages of SIV infection showed markedly decreased responses. IL-12 was administered to SIVmac239-infected rhesus macaques either during the asymptomatic or the AIDS stage of infection in efforts to evaluate the effect of this cytokine on immune responses, viral loads, and hematopoietic functions in vivo. IFN-gamma secretion levels induced during the asymptomatic or early symptomatic phase were similar to preinfection induced levels, whereas in later AIDS stages this response was lost. The constitutive levels of other measured cytokines were not affected by IL-12 administration in vivo. The frequency and activity of circulating NK cells were markedly enhanced at early stages but not at symptomatic stages of SIV infection. pCTL frequencies were enhanced at early symptomatic stages but not at late AIDS stages. Despite its immunomodulatory effect, IL-12 did not seem to exacerbate or inhibit the replication of SIV in vivo, or the frequency of circulating infected lymphocytes. IL-12 administration was associated with a significant yet subclinical and transient decrease in hematocrit and hemoglobin levels without evidence of hemolysis, hemodilution, or reduction in the frequency of colony-forming unit potential of bone marrow CD34+ cells. This phenomenon may be explained by a functional inhibition of differentiation rather than an altered generation of bone marrow precursors. Thus, these results suggest that IL-12 may benefit HIV-1-infected patients only as long as their immune system retains its capability to respond to cytokine stimulation.

Animals↗
PubMed2000

Right atrial angiographic evaluation of the posterior isthmus: relevance for ablation of typical atrial flutter.

BACKGROUND: Gaining anatomic information about the posterior isthmus is not generally part of flutter ablation procedures. We postulated that right atrial (RA) angiography could rationalize the ablation approach by revealing the conformation of the isthmus. METHODS AND RESULTS: In 100 consecutive patients, biplane RA angiography was performed before ablation to guide catheter contact with the isthmus along its length. Angiography showed a wide variation in the width of the isthmus (17 to 54 mm; 31.3+/-7.9), its angle with the inferior vena cava in the right anterior oblique projection (68 degrees to 114 degrees; 90.3+/-9.0 degrees ), and its lateral position relative to the inferior vena cava in the left anterior oblique projection. A deep sub-Eustachian recess was revealed in 47%, with a mean depth of 4.3+/-2.1 mm (1.5 to 9.4). A Eustachian valve was visualized in 24%. Ablation resulted in bidirectional conduction block (which could be transient) in all, with a median of 2 dragging radiofrequency (RF) applications (2.3+/-2.5 RF applications; 57 degrees C, < or =99 seconds each). Permanent block was achieved in 99%, with a median of 3 RF applications (3.4+/-3.0). The presence of a Eustachian valve or concave isthmus was associated with statistically more RF applications; the same trend was seen for patients with deep pouches. The number of RF applications decreased statistically throughout the study, indicating a learning curve. No patient had a recurrence after a follow-up of 13+/-11 months. CONCLUSIONS: Right atrial angiography reveals a highly variable isthmus anatomy, often showing particular configurations that can make ablation more laborious. Rational adaptation of the ablation approach to these anatomic findings may contribute to successful ablation.

Adolescent↗
PubMed2000

Distinct roles of two conserved Staufen domains in oskar mRNA localization and translation.

Drosophila Staufen protein is required for the localization of oskar mRNA to the posterior of the oocyte, the anterior anchoring of bicoid mRNA and the basal localization of prospero mRNA in dividing neuroblasts. The only regions of Staufen that have been conserved throughout animal evolution are five double-stranded (ds)RNA-binding domains (dsRBDs) and a short region within an insertion that splits dsRBD2 into two halves. dsRBDs 1, 3 and 4 bind dsRNA in vitro, but dsRBDs 2 and 5 do not, although dsRBD2 does bind dsRNA when the insertion is removed. Full-length Staufen protein lacking this insertion is able to associate with oskar mRNA and activate its translation, but fails to localize the RNA to the posterior. In contrast, Staufen lacking dsRBD5 localizes oskar mRNA normally, but does not activate its translation. Thus, dsRBD2 is required for the microtubule-dependent localization of osk mRNA, and dsRBD5 for the derepression of oskar mRNA translation, once localized. Since dsRBD5 has been shown to direct the actin-dependent localization of prospero mRNA, distinct domains of Staufen mediate microtubule- and actin-based mRNA transport.

Actins↗
PubMed2000

RNA recognition by a Staufen double-stranded RNA-binding domain.

The double-stranded RNA-binding domain (dsRBD) is a common RNA-binding motif found in many proteins involved in RNA maturation and localization. To determine how this domain recognizes RNA, we have studied the third dsRBD from Drosophila Staufen. The domain binds optimally to RNA stem-loops containing 12 uninterrupted base pairs, and we have identified the amino acids required for this interaction. By mutating these residues in a staufen transgene, we show that the RNA-binding activity of dsRBD3 is required in vivo for Staufen-dependent localization of bicoid and oskar mRNAs. Using high-resolution NMR, we have determined the structure of the complex between dsRBD3 and an RNA stem-loop. The dsRBD recognizes the shape of A-form dsRNA through interactions between conserved residues within loop 2 and the minor groove, and between loop 4 and the phosphodiester backbone across the adjacent major groove. In addition, helix alpha1 interacts with the single-stranded loop that caps the RNA helix. Interactions between helix alpha1 and single-stranded RNA may be important determinants of the specificity of dsRBD proteins.

Amino Acid Sequence↗
PubMed2000

ATP-induced killing of virulent Mycobacterium tuberculosis within human macrophages requires phospholipase D.

The global dissemination of antibiotic-resistant Mycobacterium tuberculosis has underscored the urgent need to understand the molecular mechanisms of immunity to this pathogen. Use of biological immunomodulatory compounds to enhance antituberculous therapy has been hampered by the limited efficacy of these agents toward infected human macrophages and lack of information regarding their mechanisms of activity. We tested the hypotheses that extracellular ATP (ATPe) promotes killing of virulent M. tuberculosis within human macrophages, and that activation of a specific macrophage enzyme, phospholipase D (PLD), functions in this response. ATPe treatment of infected monocyte-derived macrophages resulted in 3.5-log reduction in the viability of three different virulent strains of M. tuberculosis. Stimulation of macrophage P2X7 purinergic receptors was necessary, but not sufficient, for maximal killing by primary macrophages or human THP-1 promonocytes differentiated to a macrophage phenotype. Induction of tuberculocidal activity by ATPe was accompanied by marked stimulation of PLD activity, and two mechanistically distinct inhibitors of PLD produced dose-dependent reductions in ATPe-induced killing of intracellular bacilli. Purified PLD restored control levels of mycobacterial killing to inhibitor-treated cells, and potentiated ATPe-dependent tuberculocidal activity in control macrophages. These results demonstrate that ATPe promotes killing of virulent M. tuberculosis within infected human macrophages and strongly suggest that activation of PLD plays a key role in this process.

2,3-Diphosphoglycerate↗
PubMed2000

Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch.

OBJECTIVE: While clinical observation has suggested an association between gastroesophageal reflux and laryngeal carcinoma, the nature of this relationship has yet to be defined. The purpose of this study is to determine the carcinogenic potential of acid and pepsin mixtures in the hamster cheek pouch animal model. DESIGN: A blinded intervention study. SUBJECTS: One hundred male Syrian hamsters aged approximately 5 weeks. INTERVENTIONS: A control group of 20 hamsters received application of the carcinogen 9,10-dimethyl-1,2-henzanthracene (DMBA) to their cheek pouch mucosa. One experimental group (n = 20) received applications of DMBA plus hydrochloric acid, and another (n = 20) received DMBA plus an acid and pepsin solution. Latency to squamous cell tumor production, size of tumors, and numbers of tumors were compared among groups. RESULTS: Latency to tumor production and size of tumor were similar among groups, with both experimental and control groups developing tumors of comparable size after 12 weeks of chemical application. However, the number of tumors produced was significantly higher in the DMBA/acid and DMBA/acid/ pepsin groups than in the DMBA only group at 18 weeks, with 23, 27, and 10 tumors in these groups, respectively (P<.02). Likewise, a cumulative dysplasia score was different among groups at 18 weeks with the DMBA/acid and DMBA/acid/pepsin groups scoring higher degrees of dysplasia than the DMBA only group. CONCLUSION: These results suggest that application of acid and acid/pepsin mixtures may promote experimental carcinogenesis in the hamster cheek pouch.

Animals↗
PubMed2000

Structure determination of soybean and wheat glucosylceramides by tandem mass spectrometry.

Glucosylceramide (GluCer) is a major sphingolipid of plant tissue and, thus, abundant in nature and in dietary food sources. The lipid backbones of mammalian GluCer (sphingosine, d18:1(delta4), and ceramide) induce cell death (apoptosis) and inhibit colon carcinogenesis, it is critical to know the structures of GluCer present in plants as a first step toward understanding this potential link between diet and cancer. This study characterized the molecular species of GluCer from soybean and wheat by low-resolution, high-resolution and tandem mass spectrometry. Soybean GluCer was comprised primarily (>95%) of ceramide with 4,8-sphingadiene (d18:2(delta4,delta8)) and alpha-hydroxypalmitic acid (h16:0); the remainder had the same backbone with h18:0, h20:0, h22:0 and h24:0 fatty acids. Wheat GluCer had three major ceramide, d18:2(delta4,delta8) with h16:0, d18:1(delta8) with h16:0 and d18: 2(delta4,delta8) with h20:0, and smaller amounts of other homologs. These backbones differ from those of mammalian sphingolipids, which often have a delta4-double bond (but rarely a delta8-double bond), and have alpha-hydroxy fatty acids in only some cases. Previously unexplained fragmentations that were diagnostic for the type of sphingoid base backbone (i.e. by homolytic cleavage of the doubly allylic C-6-C-7 bond to yield a stable distonic allylic radical cation and an allylic radical neutral) were also identified. Hence this method should be useful in the identification of double bonds in sphingolipids, and structure-function relationships between sphingolipids and colon carcinogenesis.

Glucosylceramides↗
PubMed2000

In vitro and in vivo spin echo diffusion imaging characteristics of synovial fluid: potential non-invasive differentiation of inflammatory and degenerative arthritis.

OBJECTIVE: This study was undertaken to analyse the diffusion characteristics of synovial fluid in degenerative and inflammatory arthropathies. DESIGN AND PATIENTS: Ten in vitro specimens of synovial fluid from patients with both degenerative and inflammatory arthropathy were studied at body temperature with a navigator-corrected spin echo diffusion sequence (B values 0-512 s/mm2), on a Philips 1.5-T Gyroscan. Subsequently synovial fluid from knee joint effusions of 25 patients (10 patients with osteoarthritis, 10 patients with effusions following trauma and 5 patients with effusions secondary to inflammatory arthritis) was evaluated with the same navigator-corrected spin echo diffusion sequence. RESULTS: Both in vitro and in vivo study demonstrated decreased diffusion in patients with effusions secondary to degenerative joint disease (less than 2.40 x 10(-5) cm2/s) relative to patients with effusions accompanying knee trauma (greater than 2.75 x 10(-5) cm2/s) and inflammatory arthritis (in vitro and in vivo greater than 3.00 x 10(-5) cm2/s). CONCLUSION: Synovial fluid in degenerative arthritis shows less diffusion or free water movement than synovial fluid in inflammatory arthritis. Diffusion characteristics of synovial fluid may be used to predict the nature of the underlying form of arthritis in patients presenting with knee joint effusions.

Diagnosis, Differential↗