Long-term blood glucose monitoring with implanted telemetry device in conscious and stress-free cynomolgus monkeys.

AIMS: Continuous blood glucose monitoring, especially long-term and remote, in diabetic patients or research is very challenging. Nonhuman primate (NHP) is an excellent model for metabolic research, because NHPs can naturally develop Type 2 diabetes mellitus (T2DM) similarly to humans. This study was to investigate blood glucose changes in conscious, moving-free cynomolgus monkeys (Macaca fascicularis) during circadian, meal, stress and drug exposure. MATERIALS AND METHODS: Blood glucose, body temperature and physical activities were continuously and simultaneously recorded by implanted HD-XG telemetry device for up to 10 weeks. RESULTS AND DISCUSSION: Blood glucose circadian changes in normoglycemic monkeys significantly differed from that in diabetic animals. Postprandial glucose increase was more obvious after afternoon feeding. Moving a monkey from its housing cage to monkey chair increased blood glucose by 30% in both normoglycemic and diabetic monkeys. Such increase in blood glucose declined to the pre-procedure level in 30 min in normoglycemic animals and >2 h in diabetic monkeys. Oral gavage procedure alone caused hyperglycemia in both normoglycemic and diabetic monkeys. Intravenous injection with the stress hormones, angiotensin II (2 µg/kg) or norepinephrine (0.4 µg/kg), also increased blood glucose level by 30%. The glucose levels measured by the telemetry system correlated significantly well with glucometer readings during glucose tolerance tests (ivGTT or oGTT), insulin tolerance test (ITT), graded glucose infusion (GGI) and clamp. CONCLUSION: Our data demonstrate that the real-time telemetry method is reliable for monitoring blood glucose remotely and continuously in conscious, stress-free, and moving-free NHPs with the advantages highly valuable to diabetes research and drug discovery.

Renal transplantation in the inbred rat. 3. A study of heterologous anti-thymocyte sera.

Heterologous rabbit anti-rat thymocyte sera, its immunoglobulin G fraction, and the bivalent and univalent antibody fragments obtained by pepsin digestion are potent immunosuppressive reagents when tested in a system of renal allotransplantation between the LBN F(1) hybrid and Lewis rat strains. The AT F(ab')(2) is not lymphocytotoxic in vitro but has agglutinating ability, while the AT Fab' neither agglutinates nor is cytotoxic to rat lymphocytes, but will inhibit the in vitro reaction. The AT IgG and the F(ab')(2) are more immunogenic in their host than normal rabbit IgG and F(ab')(2), probably due to increased delivery of the antibody to the immune system. Donor pretreatment studies demonstrate that a cross-reacting, highly immunogenic antibody with anti-lymphocyte specificity may bind to renal sites and be transferred to the new host after transplantation. In addition, the crude unabsorbed anti-thymocyte antisera may induce a nephritis characteristic of immune complex disease which can be eliminated by complete absorption with serum proteins. Further in vivo and in vitro evidence is presented that the AT IgG contains small amounts of antibody to glomerular basement membrane antigens and may induce an autologous phase-nephrotoxic nephritis. The amount of in vivo binding by AT IgG to GBM was reduced by subcutaneous rather than intravenous administration. Most of the rabbit antisera tested contain antibody in low titer to sheep erythrocytes and in vivo experiments indicate that the nature of the immunodepressive effect of AT globulin to sheep erythrocytes is due in part to the passive transfer of antibody and is not necessarily due to a specific anti-lymphocyte effect.

Non-competitive resource exploitation within mosquito shapes within-host malaria infectivity and virulence.

Malaria is a fatal human parasitic disease transmitted by a mosquito vector. Although the evolution of within-host malaria virulence has been the focus of many theoretical and empirical studies, the vector's contribution to this process is not well understood. Here, we explore how within-vector resource exploitation would impact the evolution of within-host Plasmodium virulence. By combining within-vector dynamics and malaria epidemiology, we develop a mathematical model, which predicts that non-competitive parasitic resource exploitation within-vector restricts within-host parasite virulence. To validate our model, we experimentally manipulate mosquito lipid trafficking and gauge within-vector parasite development and within-host infectivity and virulence. We find that mosquito-derived lipids determine within-host parasite virulence by shaping development (quantity) and metabolic activity (quality) of transmissible sporozoites. Our findings uncover the potential impact of within-vector environment and vector control strategies on the evolution of malaria virulence.

Effect of phorbol esters on alloimmune cytolysis.

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) profoundly affects cytolytic T-lymphocyte activity. Alloimmune C57BL/6 (H-2b anti-H-2d) cytolytic splenocytes treated with TPA, 0.3 to 3.0 ng/ml, killed specific P815 (H-2d) targets significantly better than did untreated controls as measured in 4-hr 51Cr release microcytotoxicity assay. Higher concentrations of TPA in the 30- to 100-ng/ml range significantly inhibited cytolytic function. The non-tumor-promoting analog, 4 alpha-phorbol-12,13-didecanoate, failed to affect killing at all doses tested. TPA-induced augmentation of cytolytic function requires an immunologically sensitized splenocyte population, since normal nonimmunized splenocytes treated with TPA did not kill target cells. Furthermore, treatment of splenocytes with anti-Thy 1,2 antibody and complement abrogated killing, indicating that T-lymphocytes mediate the killing. The TPA-induced effect does not require macrophage-like cells, since augmented killing occurred despite the removal of glass-adherent or iron-phagocytosing cells. Finally, the cytolytically augmented effector cells remain immunologically specific, since the nonspecific targets, syngeneic EL4 (H-2b) and third-party L929 (H-2k), are not killed. Thus, low levels of TPA augment the cytolytic ability of alloimmune T-lymphocytes against their specific target cells.

Mutagen exposures and chromosome 3 aberrations in acute myelocytic leukemia.

Thirteen patients with acute myelocytic leukemia (AML) and with clonal aberrations involving chromosome 3 were studied. Three patients had monosomy 3, four had trisomy 3, and six had structural aberrations of chromosome 3. In the majority of cases chromosome 3 aberrations were parts of complex karyotypes, but in two patients, the abnormalities appeared as single aberrations, one as an interstitial deletion del(3)(p13p21) and the other as monosomy 3. All breakpoints of chromosome 3 were found in the fragile site regions 3p14.2, 3q21 and 3q26-27. All patients with monosomy 3 or structural aberrations of chromosome 3 and one of the four patients with trisomy 3 had been exposed to mutagens, such as occupational exposures to organic solvents and/or petroleum products or treatments with irradiation or antineoplastic agents. The association among mutagen exposure, structural chromosome 3 aberrations and fragile sites in AML may indicate that targeting of the mutagens to these sites is of importance for the etiology of the disease. Leukemia (2000) 14, 112-118.

Ecotin is a potent inhibitor of the contact system proteases factor XIIa and plasma kallikrein.

Ecotin, a serine protease inhibitor found in the periplasm of Escherichia coli, has been characterized as a potent reversible tight-binding inhibitor of the human contact activation proteases factor XIIa (FXIIa) and plasma kallikrein, having Ki values of 89 pM and 163 pM, respectively. Ecotin also inhibited human leukocyte elastase (HLE) with high affinity (Ki = 55 pM). The association rate constants kon for FXIIa and kallikrein were 5.3 x 10(5) M-1.s-1 and 2.9 x 10(5) M-1.s-1, respectively. The dissociation rate constant koff for kallikrein, measured in the presence of HLE to prevent reassociation, was 6.3 x 10(-5) s-1; the koff for ecotin with FXIIa was 4.7 x 10(-5) s-1. Both FXIIa and kallikrein cleaved ecotin slowly at pH 5.0, identifying Met-84 as the P1 residue. The potent anticoagulant effect by ecotin is explained by the coincident inhibition of FXIIa, kallikrein, and FXa and suggests that it may be useful in the study of inflammatory or thrombotic disorders such as sepsis or cardiopulmonary bypass.

Comparison of preoperative characteristics of men and women undergoing coronary artery bypass grafting (the Post Coronary Artery Bypass Graft [CABG] Biobehavioral Study).

A cohort of 759 coronary artery bypass grafting (CABG) patients (269 women and 490 men) was enrolled in the prospective POST CABG Biobehavioral Study at 5 clinical centers in the United States and Canada. Sociodemographic and medical data were obtained by interview and from medical charts. Health-related quality of life and psychosocial data were ascertained preoperatively by interview and questionnaire for those patients whose condition allowed preoperative assessment and was compared among patients from hospitals enrolling both male and female patients (143 women and 267 men). Women enrolled in the Biobehavioral Study were older than men (65.4 +/- 9.0 vs 61.8 +/- 9.7 years, p < 0.001) and more likely to have a preoperative medical condition which precluded biobehavioral evaluation (47% vs 34%, p < 0.001). Women were less likely to be high school graduates (59% vs 74%, p < 0.001), were less likely to be earning > or = $25,000 per year (39% vs 69%, p < 0.001), and were married less often at the time of surgery (59% vs 85%, p < 0.001). Fewer women than men were able to perform basic self-care activities (p < 0.001) and social activities (p < 0.001). Women were also less able to perform the more demanding activities required for independent living, recreation, and maintaining a household (p < 0.001). Women were also more anxious (p = 0.01) and reported more depressive symptoms (p < 0.001) than men. These data suggest that plans for perioperative and convalescent care for women undergoing CABG should take into account their less favorable medical and psychosocial status relative to men.

A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia.

In the light of previous findings that treatment of leukemia patients with DNA-linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin-DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL.

Cytokines in human breast cancer: IL-1alpha and IL-1beta expression.

We hypothesize that interleukin 1alpha (IL-1alpha) and interleukin 1beta (IL-1beta) are present and tumor cell associated in human breast cancer (HBC) specimens. To test our hypothesis: a) immunologic analysis was performed on HBC histologic sections for IL-1alpha (n=49) and IL-1beta (n=42) distribution; and b) homogenates of HBC tumors were analyzed for levels of IL-1alpha (n=82), IL-1beta (n=101) and interleukin 8 (IL-8) (n=103) expression. Immunohistochemical analysis demonstrated the presence of IL-1alpha and IL-1beta in tumor cells in patients with invasive cancer and ductal carcinoma in situ. Quantitative analysis confirmed the presence and positive correlation of IL-1alpha and IL-1beta to IL-8, a known angiogenic factor, in cancer specimens. These studies demonstrate that tumor-associated IL-1alpha+, IL-1beta are present in the tumor microenvironment and may play a pivotal role in regulating breast tumor growth and metastasis.

Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue.

UNLABELLED: Recently, we demonstrated the presence of Interleukin-8 (IL-8) in human breast cancer (HBC) tissue. We hypothesize that the IL-8 receptors are present and play a role in tumor cell and vascular endothelial cell (VEC) activation (e.g. proliferation and angiogenesis). MATERIALS AND METHODS: Immunohistochemical analysis for IL-8 receptors (IL-8RA and IL-8RB) was performed on 43 malignant and 8 benign breast tissue samples. RESULTS: Tumor cells expressed IL-8RA and IL-8RB in all of the malignant specimens. Only 50% of the benign ductal epithelial cell (DEC) samples expressed these receptors. The majority of small vessel endothelial cells (SVEC) expressed IL-8RA and IL-8RB, while large vessel endothelial cells (LVEC) showed primarily IL-8RB expression. CONCLUSIONS: Our results demonstrate that tumor and VEC express the IL-8 receptors and likely play a role in regulating tumor and VEC activation which controls proliferation, angiogenesis and metastasis in HBC.

Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma.

BACKGROUND: Interleukin 8 (IL-8) is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies. We hypothesize that IL-8 plays an important role in the cellular proliferation and angiogenesis seen in head and neck squamous cell carcinoma (HNSCC) and set out to identify its receptors, IL-8RA and IL-8RB. METHODS: Immunohistochemical analysis was performed on specimens from 38 HNSCC patients with stage I to IV disease and control tissues. RESULTS: All of cancer specimens demonstrated positive staining for IL-8RA. The IL-8RA staining of microvessel endothelial cells was seen in 51%. The IL-8RB pattern was similar to the IL-8RA pattern in that 97% of cancer sections demonstrated positive cancer cell staining, and 74% of the specimens demonstrated positive staining for microvessel endothelial cells. CONCLUSION: Our studies demonstrate that IL-8 receptors are expressed by cancer cells and microvessel endothelial cells in HNSCC, suggesting that IL-8 may act in an autocrine/paracrine fashion to stimulate cellular proliferation and angiogenesis.

Decreased expression of transforming growth factor beta receptors on head and neck squamous cell carcinoma tumor cells.

BACKGROUND: Transforming growth factor beta (TGF-beta) has antiproliferative effects on normal and neoplastic cells that express specific TGF-beta receptors. We hypothesize that diminished expression of TGF-beta and/or its receptors may contribute to the uncontrolled proliferation of head and neck squamous cell carcinoma (HNSCCA) cancer cells. METHODS: Using immunohistochemical techniques, we characterized the expression of TGF-beta isoforms and TGF-beta receptors, TGF-beta(RI) and TGF-beta(RII), in HNSCCA. Tumor production of TGF-beta was evaluated in culture supernatants from a cytokine-stimulated HNSCCA tumor line (HTB-43). RESULTS: All control specimens displayed strong cell-associated staining of TGF-beta as well as both receptors. Forty-seven of 47 cancer specimens exhibited positive staining for TGF-beta in the tumor matrix. Forty of the 47 cancer specimens demonstrated no expression of TGF-beta(RI), and 43 of the 47 expressed no TGF-beta(RII). Only interleukin 1 alpha (IL-1 alpha) and IL-1 beta induced significant TGF-beta expression from the HTB-43 cells. CONCLUSIONS: Decreased expression of TGF-beta receptors may play a significant role in the pathogenesis of HNSCCA by allowing uncontrolled cell proliferation.

Enhanced tumor cell expression of tumor necrosis factor receptors in head and neck squamous cell carcinoma.

BACKGROUND: To determine if tumor necrosis factor (TNF) receptors are upregulated in tumor cells, we measured the distribution and levels of TNF-alpha and TNF-beta, and TNF receptors RI and RII, in head and neck squamous cell carcinoma (HNSCC) tumor specimens and normal control specimens. METHODS: HNSCC and control tissue specimens were analyzed qualitatively using immunohistochemistry and quantitatively using immunoassays. RESULTS: Immunohistochemical analysis revealed that TNF-alpha, TNF-beta, TNF RI, and TNF RII antigens were associated predominately with tumor cells in the tissue. Quantitative analysis of TNF factors and receptors in tissue homogenates (mean levels +/- standard error of the mean, in pg/mg of total protein) indicated that: (1) TNF-alpha levels in cancer patients were not statistically different from levels in normal tissues (7.27 +/- 0.91 versus 4.62 +/- 1.33, respectively, P < 0.11); (2) TNF-beta levels in cancer patients were one third of those in normal tissue (5.07 +/- 1.83 versus 16.06 +/- 3.26, respectively, P < 0.01); and (3) both TNF RI and TNF RII levels were consistently elevated two- to four-fold in the cancer tissue when compared to normal tissue levels (1,228.72 +/- 125.67 versus 650.33 +/- 187.70, P < 0.01; and 823.39 +/- 95.90 versus 230.03 +/- 153.01, P < 0.002, respectively). CONCLUSIONS: In HNSCC, enhanced expression of TNF receptors on the cancer cells occurs and is likely to contribute to the regulation of TNF and its activation of tumor cells within the tumor microenvironment; targeting these receptors in cancer cells may provide a new approach to controlling tumor growth and metastasis.

Interleukin-1 receptor antagonist in head and neck squamous cell carcinoma.

BACKGROUND: We hypothesized that in head and neck squamous cell carcinoma, the overexpression of protumorigenic interleukin-1 (IL-1) activity within the tumor tissue is a result of decreased expression of the specific antagonist or inhibitor (ie, IL-1 receptor antagonist) by the tumor cells. Ultimately, this local overexpression of IL-1 activity increases tumor growth and metastasis. DESIGN: To test our hypotheses, immunologic analysis for IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist was performed on histologic sections and tumor homogenates of human head and neck squamous cell carcinomas. SETTING: University teaching hospital. PATIENTS OR OTHER PARTICIPANTS: Normal and tumor specimens were obtained from patients undergoing surgical resections of the head and neck for benign and malignant disease. RESULTS: Immunohistochemical analysis demonstrated the presence of IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist within tumor cells and inflammatory cells in the tumor stroma in 19 of 19 tumor specimens. Quantitatively, IL-1 alpha was present in 19 of 19 tumor specimens (1.97 +/- 0.46 ng/mg of total protein [mean +/- SD]) and 5 of 9 normal specimens (0.23 +/- 0.12 ng/mg of total protein). All specimens contained IL-1 beta in detectable quantities (1.60 +/- 0.29 ng/mg of total protein in tumor specimens and 0.189 +/- 0.04 ng/mg of total protein in normal specimens). All specimens contained IL-1 receptor antagonist (368.87 +/- 57.63 ng/mg of total protein in tumor specimens and 585.10 +/- 166.03 ng/mg of total protein in normal specimens). The mean total IL-1/IL-1 receptor antagonist ratio was 13.26 +/- 2.31 in patients with cancer compared with 0.997 +/- 0.26 in normal patients. CONCLUSIONS: The increased IL-1 index in the cancer state compared with the normal state reflects an imbalance of IL-1 and IL-1 receptor antagonist, which may contribute to unrestricted growth and metastasis of head and neck squamous cell carcinoma.

Optical flow, spatial orientation, and the control of posture in the elderly.

Stabliographic techniques were used to better understand the role of the visual system in the perceptual motor activity of older people as it relates to the maintenance of postural control. The central research question was to determine the sensitivity of the subject's visual system to changes in three standard conditions of optical flow generated by an experimental moving room. Any movement that was present as a function of this optical flow field was recorded on a force platform and expressed in movement of a computed center-of-pressure variable. Movement of the center of pressure was recorded in a baseline condition and in the experimental conditions, and the data were analyzed with respect to differences in the three conditions of optical flow and between both younger and older subjects. The older subject group exhibited less stability than the younger subjects in response to the baseline conditions; and, after adjusting for baseline movement, the center-of-pressure motions of younger and older subjects, in response to the experimental conditions, were compared. No reliable differences were present between younger and older subjects for the radial optical flow condition; in the lamellar flow condition, older subjects moved significantly more than younger subjects; and, in the combined condition (global), the movement of the older subjects was significantly greater than that of the younger subjects for all motion variables recorded. The results are interpreted and discussed both in terms of their implication for falling in the elderly and in the context of an ecological interpretation of the role of vision in maintaining postural stability while both stationary and in motion.

Sensitivity and specificity of saliva thiocyanate and cotinine for cigarette smoking: a comparison of two collection methods.

Saliva samples returned by mail were compared to duplicates returned by interviewers in terms of the sensitivity and specificity of cotinine and thiocyanate analyses performed on those samples to detect tobacco use. Compared to the samples returned by interviewers, those returned through the mail were slightly lower in specificity but similar in sensitivity. These findings confirm that saliva samples do not deteriorate during transit via the postal service, although substantial questions remain that concern the validity of such samples in the evaluation of cessation programs.

Behavioral treatment of obesity with monetary contracting: two-year follow-up.

Reported is a 2-year follow-up of a behavioral weight reduction program for men using monetary contracts of varying size and group versus individual contingencies. Although initial weight losses were large, in the absence of an effective maintenance program weight losses at two years were modest, similar to those obtained with less effective initial weight loss procedures. Group contracts were significantly more effective in producing long term loss than individual contracts. Reported behaviors associated with weight loss at 2 years are presented.

Calorie requirements in weight loss: an estimate based on self-reported food intake in middle-aged men.

Twenty-eight men participating in a weight reduction program self-recorded foods eaten and calorie consumption for a 15-week period. These food records were examined to estimate calorie needs during weight loss as a function of age, entry weight, height and physical activity level. Only entry weight was significantly associated with calorie need. A predictive equation for calorie need is offered for setting individual calorie intake goals for patient-assessed calorie intake.

Peer review of nursing research proposals.

The grant review process that operationalizes peer review for the critique, scoring, approval, and selection of research grants for funding may intimidate a novice reviewer. This article describes the peer review panel and process of grant review, specifies the role and responsibilities of the reviewer in the review session, and presents considerations for the evaluation of proposals and the preparation of a written critique. A sample critique is provided.

Reviews and summaries of research related to AACN 1980 research priorities: clinical topics.

This article reviews and summarizes the research conducted following publication of the 1980s American Association of Critical-Care Nurses' clinical research priorities. Original research conducted on the clinical priority topics between 1981 and 1991 was included. Review articles, doctoral dissertations, theses and abstracts were excluded unless judged to provide important information on the topic. Following the statement of each priority, progress in the area is summarized. Limitations and measurement issues are discussed as appropriate. Recommendations for future research are provided, and progress in the area is summarized.