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Biomedical subjects

J M Phillips

Publications and source records attributed to J M Phillips.

At least 19 recordsLinked to original sources
PubMed2000

Nondepleting anti-CD4 has an immediate action on diabetogenic effector cells, halting their destruction of pancreatic beta cells.

The induction of tolerance in a primed immune system is a major aim for therapy in autoimmunity and transplant rejection. In this paper, we investigate the action of the nondepleting anti-CD4 Ab, YTS 177. Although this Ab is nondepleting, we have demonstrated a direct action in vivo on activated effector cells. We show that the Ab inhibits transfer of insulin-dependent diabetes mellitus by the CD4+ Th1 clone BDC2.5 to nonobese diabetic mice. Furthermore, we show that this Ab acts directly on diabetogenic effector cells because it prevented BDC2.5-induced insulin-dependent diabetes mellitus in nonobese diabetic-scid recipients in the absence of other T cells. The Ab halts the diabetic process even when it is administered after the BDC2.5 cells have infiltrated the pancreas and destruction of islets is already underway. This is accompanied by an immediate decrease in proinflammatory cytokine production with cessation of beta cell destruction and disappearance of infiltrating cells from the pancreas, leaving any remaining beta cells intact. These data suggest that Abs such as this may be effective not only because they induce regulatory T cells but also because they are able to directly prevent effector cell function.

Adoptive Transfer↗
PubMed2000

Cholinergic neurotransmission influences covert orientation of visuospatial attention in the rat.

RATIONALE: Both monkey and human studies have suggested that attentional orienting may be mediated by the cholinergic neurotransmitter system. OBJECTIVES: The purpose of the present study was to examine whether the cholinergic agonist (nicotine) and/or antagonist (scopolamine) influence covert orientation in the rat. METHODS: Rats carried out a visual reaction time task to measure covert orienting of attention following systemic administration of nicotine or scopolamine. RESULTS: Nicotine reduced reaction times, abolishing the validity effect by differentially speeding the reaction times for invalidly cued targets. Conversely, scopolamine increased the validity effect by disproportionately lengthening reaction times to invalidly cued targets. CONCLUSIONS: Taken together, these data indicate that cholinergic transmission represents an important neurochemical substrate of visuospatial attention, specifically influencing disengagement or movement of attention.

Animals↗
PubMed2000

Anticipatory errors after unilateral lesions of the subthalamic nucleus in the rat: evidence for a failure of response inhibition.

The nature of anticipatory responding in rats with unilateral subthalamic nucleus lesions was examined. Rats were trained to respond toward visual targets that were preceded by 1 of 4 different cues. For normal rats, a cue invokes an involuntary attentional orienting that enhances processing of the target at the location of attention. The cue is also a salient stimulus to which a response must be suppressed. Therefore, this task was used to investigate possible attentional impairments, as well as the ability of a lesioned rat to suppress competing motor programs. Responding under target control was not affected by the lesion. There was an increase in anticipatory responses before target onset, which could be accounted for by a failure to inhibit contralateral responses.

Animals↗
PubMed1999

Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection.

BACKGROUND: The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts. METHODS: We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes. RESULTS: None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection. CONCLUSIONS: These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.

Amino Acid Substitution↗
PubMed1999

Attentional orienting is impaired by unilateral lesions of the thalamic reticular nucleus in the rat.

The thalamic reticular nucleus (TRN) has been implicated in attentional processes based on its anatomical, electrophysiological, and neurochemical relationships with the sensory nuclei of the thalamus and corresponding sensory areas of cortex. This study examined the possibility that the TRN is involved in covert orienting of attention. Attention can be summoned to a spatial location in the absence of an overt orienting response. The reaction time to a visual target is faster when attention has been drawn to the location of the target by a preceding cue in that location (valid cue) compared with when the cue misdirects attention (invalid cue) away from the location of the subsequent target. This reaction time difference is referred to as the "validity effect." Rats were trained to perform such a reaction time task with visual cues and targets presented in poke holes to either side of the rat's head, which had to be maintained centrally and still. If the rat made an overt orienting response to the cue, the trial was aborted. Unilateral lesions were made by injection of ibotenic acid in the TRN. After surgery, there was no bias apparent in their responding; they were as likely to initiate responses and were equally accurate to either side. There was, however, a complete abolition of the validity effect for responses to contralateral targets. The data are discussed in terms of a role for the TRN in attentional processing.

Animals↗
PubMed1999

Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice.

The nonobese diabetic (NOD) mouse, a spontaneous animal model for insulin-dependent diabetes mellitus, displays a tendency in common with human diabetic populations to develop autoimmune thyroiditis although incidence and severity of thyroid lesions vary widely among different colonies around the world. A congenic strain of NOD mice bearing I-Ak on a NOD background (NOD-H2(h4)) has recently been derived and displays a much greater tendency to develop thyroiditis and autoantibodies to mouse thyroglobulin (MTg) although it is free of diabetes. Both thyroid infiltrates and autoantibody formation are accelerated and enhanced in NOD-H2(h4) mice by increased iodine intake. The effect of increased iodine intake on NOD mice themselves has not been directly investigated although a recent study of these animals given high or low doses of iodine showed no follicular destruction unless the mice were first rendered goitrous by iodine deprivation. We found that dietary iodine increased both the incidence and the severity of thyroid lesions in our NOD mice although autoantibodies to MTg were absent. NOD background genes appear to be essential for the development of these lesions, which were maximal after 4 weeks of iodine administration and showed no significant regression when the iodine was stopped. Furthermore, our studies show for the first time that both CD4(+) and CD8(+) T cells are necessary for the development of this accelerated but essentially spontaneous murine thyroid disease.

Animals↗
PubMed1999

Integrating cancer risk assessment into a community health nursing course.

BACKGROUND: Because the state of Maryland has the fourth highest cancer death rate among the states and the District of Columbia, a community-based hospital identified the need to develop a cancer prevention, screening, and education program for the community at large and the employees. Subsequently, as a prerequisite for graduation, Community Health Nursing Students (CHN) conducted a project with the goal of assessing hospital employee cancer risk status and presenting a hospital-based cancer education program. METHOD: Data regarding employee cancer risk status were gathered using a modified 31-item cancer-risk-assessment guide; risk factors for cancers of the lung, colon-rectum, skin, prostate, breast, and cervix were identified. RESULTS: Overall, the employees were at a high to moderate risk of developing cancers of the cervix, followed by cancers of the skin and breast, and at lowest risk of developing cancer of the lung, followed by cancers of the prostate and colon-rectum. CONCLUSION: The findings provided baseline data for the development of employee-focused cancer education and screening programs.

Adult↗
PubMed1999

Pregnancy loss rates following second trimester genetic amniocentesis.

Data from 3,953 consecutive second trimester genetic amniocenteses were analysed to determine pregnancy loss rates up to 6 weeks after the procedure. Information was prospectively collected on a cohort of 3,685 women in 3,896 singleton and 50 twin pregnancies, from 2 operating sites in Perth, Western Australia, using 9 operators over the 6-year period, 1989 to 1995. Complete information regarding pregnancy outcome was obtained for 3,643 of the 3,685 women (98.9%). There were 27 identified singletons and 1 set of twins lost within 6 weeks following amniocentesis. The overall pregnancy loss rate in this cohort was 29 of 3,911 (0.74%). The pregnancy loss rate associated with genetic amniocentesis is not excessive in comparison to the calculated background pregnancy loss rate of 1%, and it is suggested that each prenatal diagnostic team should determine their own complication rates for the purpose of counselling prior to amniocentesis.

Abortion, Spontaneous↗
PubMed1999

Prenatal diagnosis of hepatic mesenchymal hamartoma.

A case of hepatic mesenchymal hamartoma diagnosed prenatally with ultrasound and confirmed histologically post-delivery is presented. Although histologically benign, this lesion resulted in fetal demise secondary to congestive cardiac failure in the third trimester. The development of non-immune hydrops in association with a fetal hepatic mesenchymal hamartoma is a poor prognostic sign for perinatal survival.

Adult↗
PubMed1999

Breast cancer screening and African American women: fear, fatalism, and silence.

PURPOSE/OBJECTIVES: To explore the beliefs, attitudes, and practices related to breast cancer and breast cancer screening among low- and middle-income African American women. DESIGN: Qualitative study using focus group methodology. SAMPLE/SETTING: 26 African American women, age 40-65, selected from three employment groups, recruited from a community-based center and a local teacher's union in a moderate-sized urban area. METHODS: Three 90-minute focus group discussions exploring breast cancer beliefs, attitudes, and practices were audiotaped, transcribed verbatim, and analyzed using thematic context analysis techniques. FINDINGS: When breast cancer was discussed, fear was the predominant feeling expressed in all groups. This fear was a primary reason not to engage in breast cancer screening. Unemployed women and service workers emphasized the role of violence in causing breast cancer, whereas teachers discussed injury and sex as causing breast cancer. All participants stressed that breast cancer is seldom discussed within the African American community. Teachers added that this secrecy within the African American community leads to breast cancer being viewed as a white woman's disease. CONCLUSIONS: Despite initiatives promoting breast cancer awareness. African American women still hold misconceptions regarding the etiology of breast cancer and fatalistic perspectives regarding breast cancer outcomes, perhaps because breast cancer is discussed infrequently. Because pain, fear, and fatalism were discussed in all groups, future research should address the influence of these factors to increase screening behaviors. IMPLICATIONS FOR NURSING PRACTICE: Because unemployed women, service workers, and teachers differed in their beliefs about breast cancer and breast cancer screening, nurses must be mindful of the need to tailor Interventions to address the needs of both low- and middle-income African American women.

Adult↗
PubMed1999

Reaction time performance following unilateral striatal dopamine depletion and lesions of the subthalamic nucleus in the rat.

The akinesia resulting from Parkinson's disease or striatal dopamine depletion in experimental animals can be ameliorated or reversed by inactivation of the subthalamic nucleus. This inactivation might be effective by restoring balance to the basal ganglia motor circuits. Alternatively, new movement-related deficits might be introduced which mask the original impairments (e.g. hyperkinesia might replace hypokinesia). In the present study, striatal dopamine depletion was effected unilaterally, in order to dissociate generalized effects, e.g. hyperkinesia, from response-specific initiation effects. Rats were trained in a lateralized visual reaction time task and then assigned to one of four groups: striatal dopamine depletion; cell body lesion of the subthalamic nucleus; combined striatal dopamine depletion and subthalamic nucleus lesion; or control. As expected, rats with striatal dopamine depletion exhibited slower reaction time and a bias to respond to the ipsilateral side. The subthalamic nucleus lesion resulted in no reaction time change (in particular, there was no evidence of faster reaction times), but there was an increase in anticipatory responding. The group with the combined striatal dopamine depletion and subthalamic nucleus lesion had no reaction time impairment. This group showed an increase in anticipatory errors and a contralateral response bias. These data demonstrate that lesions of the subthalamic nucleus do not merely cancel the akinesia which follows striatal dopamine depletion by the addition of a hyperkinetic impairment. Rather, there appears to be a change in the balance of the motor system.

Animals↗
PubMed1998

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein.

Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin fibroblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) fibroblasts. We found that structural and numerical aberrations in chromosomes were significantly increased in F5E6 cells during aging in vitro and fluorescence in situ hybridization (FISH) analysis using chromosome-specific probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages > 16, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was confirmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo fibroblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal beta-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce beta-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerase-negative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P < 0.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.

Cell Line↗
PubMed1998

Thymus-dependent monoclonal antibody-induced protection from transferred diabetes.

It is well established that long-term protection from insulin-dependent diabetes mellitus (IDDM) can be afforded to non-obese diabetic (NOD) mice by a short course of non-depleting (nd) anti-CD4 monoclonal antibodies (mAb). Since it is increasingly apparent that the CD8+ T cell plays a prominent role in the development of IDDM, we have investigated the effect of an anti-CD8 mAb (YTS 105) of the same isotype in both spontaneous and induced IDDM in NOD mice. Treatment with YTS 105 for 3 weeks was able to prevent the transfer of IDDM for a long period, and also substantially reduced spontaneous IDDM in female NOD mice. The role of the thymus in tolerance induction by these antibodies was studied. In the adult transfer model, thymectomized NOD mice, unlike their euthymic counterparts, were not protected long-term by treatment with YTS 105, and began to become overtly diabetic shortly after treatment. This was also true when the nd anti-CD4 mAb was used. Protection from spontaneous disease was not affected in the same way by thymectomy. The reasons for the observed effect of the thymus in the transfer model, and the differences between the two models that may explain the contrasting results are discussed.

Animals↗
PubMed1998

Excitotoxic lesions of the subthalamic nucleus ameliorate asymmetry induced by striatal dopamine depletion in the rat.

We investigated the effect of unilateral dorsal striatal dopamine depletion (by intrastriatal infusion of 6-OHDA), ibotenic acid lesions of the subthalamic nucleus (STN) and combined dopamine depletion and STN lesions on sensorimotor asymmetry using a test of somatosensory asymmetry [T. Schallert et al., Pharmacol. Biochem. Behav. 16 (1982) 455-462]. The unilateral striatal dopamine depletion resulted in a somatosensory asymmetry. This asymmetry was ameliorated in the rats with combined dopamine depletion and STN lesion. indicating the potential beneficial nature of STN inactivation in rats with striatal dopamine depletion.

Animals↗
PubMed1997

Laparoscopic-assisted vaginal hysterectomy: American Association of Gynecologic Laparoscopists' 1995 membership survey.

A questionnaire was mailed to all members of the AAGL to determine the current performance of laparoscopic-assisted vaginal hysterectomy (LAVH), and to assess the relative frequencies of techniques and complications. Answers of the 1092 members who responded were entered into a database computer program and analyzed. The analysis revealed 14,911 LAVHs performed by 767 members. Complication rates appeared to be in the same range as those reported for vaginal hysterectomy and total abdominal hysterectomy. Inferior epigastric injury was the most common complication. Physicians showed a shift in their practices away from abdominal hysterectomy after they learned LAVH.

Female↗
PubMed1997

alpha-Cell neogenesis in an animal model of IDDM.

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Animals↗