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Biomedical subjects

J Alexander

Publications and source records attributed to J Alexander.

At least 145 records · Page 8Linked to original sources
PubMed1999

Novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system.

BACKGROUND: Central baroreflex failure in Shy-Drager syndrome and traumatic spinal cord injuries results in severe orthostatic hypotension and often confines the patient to the bed. We proposed a novel therapeutic strategy against central baroreflex failure: implementation of an artificial feedback control system able automatically to regulate sympathetic vasomotor tone, that is, a bionic baroreflex system (BBS). With the use of a rat model of central baroreflex failure, we developed the BBS and tested its efficacy. METHODS AND RESULTS: Our prototype BBS for the rat consisted of a pressure sensor placed into the aortic arch, stimulation electrodes implanted into the greater splanchnic nerve, and a computer-driven neural stimulator. By a white noise approach for system identification, we first estimated the dynamic properties underlying the normal baroreflex control of systemic arterial pressure (SAP) and then determined how the BBS computer should operate in real time as the artificial vasomotor center to mimic the dynamic properties of the native baroreflex. The open-loop transfer function of the artificial vasomotor center was identified as a high-pass filter with a corner frequency of 0.1 Hz. We evaluated the performance of the BBS in response to rapid-progressive hypotension secondary to sudden sympathetic withdrawal evoked by the local imposition of a pressure step on carotid sinus baroreceptors in 16 anesthetized rats. Without the BBS, SAP rapidly fell by 49+/-8 mm Hg in 10 seconds. With the BBS placed on-line with real-time execution, the SAP fall was suppressed by 22+/-6 mm Hg at the nadir and by 16+/-5 mm Hg at the plateau. These effects were statistically indistinguishable from those of the native baroreflex system. CONCLUSIONS: These results suggest the feasibility of a BBS approach for central baroreflex failure.

Animals↗
PubMed1999

[Chlorination of drinking water--possible cancer risk from a by-product].

In a recent study, 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX; CAS no 77439-76-0) which is formed during chlorination of water containing organic substances, was found to be carcinogenic in the rat, at multiple sites in both sexes. MX is known as a potent bacterial mutagen. Epidemiological studies have suggested an association between chlorinated water consumption and a moderate increase in the risk of cancer. Although MX is a strong mutagen in prokaryotes, its genotoxic effects in mammalian cells are not so large, and more variable results are obtained. Very low concentrations of MX are found in drinking water (ng/L), whereas the genotoxic and carcinogenic effects in experimental animals of this compound are detectable at relatively high doses (mg/kg body weight). Relative to the risk for infectious diseases from the consumption of contaminated drinking water, the possible cancer risk associated with MX exposure appears to be low. Even so, efforts should be made to reduce disinfection byproduct formation by removing organic matter before chlorination.

Animals↗
PubMed1999

Utilization of MHC class I transgenic mice for development of minigene DNA vaccines encoding multiple HLA-restricted CTL epitopes.

We engineered a multiepitope DNA minigene encoding nine dominant HLA-A2.1- and A11-restricted epitopes from the polymerase, envelope, and core proteins of hepatitis B virus and HIV, together with the PADRE (pan-DR epitope) universal Th cell epitope and an endoplasmic reticulum-translocating signal sequence. Immunization of HLA transgenic mice with this construct resulted in: 1) simultaneous CTL induction against all nine CTL epitopes despite their varying MHC binding affinities; 2) CTL responses that were equivalent in magnitude to those induced against a lipopeptide known be immunogenic in humans; 3) induction of memory CTLs up to 4 mo after a single DNA injection; 4) higher epitope-specific CTL responses than immunization with DNA encoding whole protein; and 5) a correlation between the immunogenicity of DNA-encoded epitopes in vivo and the in vitro responses of specific CTL lines against minigene DNA-transfected target cells. Examination of potential variables in minigene construct design revealed that removal of the PADRE Th cell epitope or the signal sequence, and changing the position of selected epitopes, affected the magnitude and frequency of CTL responses. Our results demonstrate the simultaneous induction of broad CTL responses in vivo against multiple dominant HLA-restricted epitopes using a minigene DNA vaccine and underline the utility of HLA transgenic mice in development and optimization of vaccine constructs for human use.

Amino Acid Sequence↗
PubMed1999

Pan DR binding sequence provides T-cell help for induction of protective antibodies against Plasmodium yoelii sporozoites.

Pan-DR epitope (PADRE) peptides have demonstrated the capacity to deliver help for antibody responses in vivo. They were also found, fortuitously, to be able to provide significant helper T-cell activity in vivo. This suggested that linear constructs, containing the PADRE epitope, might be as efficient at generating an immune response as large multivalent antigens. Plasmodium falciparum and P. yoelii PADRE constructs were capable of inducing a high titre IgG antibody response that recognized intact sporozoites. We now report that these antibodies can inhibit sporozoite invasion of hepatocytes in vitro and that mice immunized with the PyCSP-PADRE linear construct were protected when challenged with P. yoelii sporozoites.

Amino Acid Sequence↗
PubMed1999

Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans.

Theradigm-hepatitis B virus (HBV) is an experimental lipopeptide vaccine designed to stimulate induction of HBV-specific CTL responses in HLA-A2 individuals. Previous studies had demonstrated high immunogenicity in healthy volunteers, but comparatively weak CTL responses in chronically infected HBV patients. Herein, we examined helper T lymphocyte (HTL) responses in chronically infected patients. Despite normal proliferation and IL-2 secretion, IL-12 and IFN-gamma secretion in vitro in response to the vaccine was reduced compared with healthy volunteers. A similar pattern of cytokine secretion was observed following mitogen stimulation, suggesting a general altered balance of Th1/Th2 responses. Further analysis indicated that HTL recall responses to whole tetanus toxoid protein were reduced in chronically infected subjects, and reduced responsiveness correlated with the outcome of Theradigm-HBV immunization. Finally, experiments in HBV transgenic mice indicated that the nonnatural Pan DR HTL epitope, PADRE, is capable of inducing high levels of IFN-gamma secretion and that its inclusion in a lipopeptide incorporating an immunodominant Ld-restricted CTL epitope resulted in breaking tolerance at the CTL level. Overall, our results demonstrate an alteration in the quality of HTL responses induced in chronically infected HBV patients and suggest that use of a potent HTL epitope may be important to overcome CTL tolerance against specific HBV Ags.

Animals↗
PubMed1999

[Heterocyclic amines in cooked meat].

The age adjusted incidence of cancer has increased on average 1% annually since the beginning of this century, and cancer is now one of the most prevalent causes of death. Diet is suggested to be responsible for about 30-70% of all cancer cases. The heterocyclic amines (HCA) produced during processing of meats and fish at temperatures above 150 degrees C are candidate dietary causes. Amounts in food range from less than 1 ng/g in cooked meat or fish up to over 300 ng/g in well done flame grilled chicken breast meat. The most important parameters determining HCA amounts are cooking temperature and cooking time. 20 different HCAs are identified from cooked or grilled meats and fish. HCAs are causing cancer in various organs in mice, rats and cynomolgus monkeys. It is of interest to note that in rats, PhIP, the most abundant heterocyclic amine in cooked food, causes colon, prostate and mammary cancer, which are the most prevalent cancers in humans. Epidemiological studies show a correlation between intake of red meat and colon, mammary and prostate cancer. Based on the adverse effects of HCA, a reduced intake is recommended and practical advice on how this can be done is given.

Amines↗
PubMed1999

Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans.

It is now generally accepted that IFN-gamma, secreted by Th1 cells, is the most potent cytokine leading to macrophage activation and host resistance against infection with the intracellular protozoan parasite Leishmania. It is also established that IL-12 is a critical cytokine involved in the differentiation and expansion of Th1 cells. Therefore, the ability of Leishmania parasites to actively suppress IL-12 production by host macrophages may be an important strategy for parasite survival. Here we report that a major parasite cell surface molecule, phosphoglycan (PG), of Leishmania could selectively inhibit the synthesis of IL-12(p40, p70) by activated murine macrophages. Furthermore, synthetic PG (sPG) was able to inhibit IL-12 release in a dose-dependent manner. Inhibition was dependent on the galactose(beta1-4)mannose(alpha1)-PO4 repeating units and not the glycophosphoinositol lipid anchor of lipophosphoglycan. At the concentration used, sPG had no effect on the release of TNF-alpha or IL-6 in activated macrophages. The inhibition of IL-12(p40) production was at the transcriptional level, but was not mediated through NF kappaB inhibition. These data demonstrate that PG may be an important molecule for the establishment and survival of the parasite in permissive hosts.

Animals↗
PubMed1999

Evaluation of a mathematical model to predict intrapulmonary shunt non-invasively.

PURPOSE: We have previously published a mathematical model of oxygen transport. Using several physiological assumptions, the model provides a non-invasive estimate of intrapulmonary shunt. During a larger study of lung injury in a pig model, we had the opportunity to check the validity of our assumptions and the accuracy of the model's predictions. METHODS: We used six female pigs, average weight 12.8 kg. Following general anesthesia, tracheostomy and insertion of pulmonary venous and arterial lines, lung injury was induced by repeated saline lung lavage. Using hemodynamic measurements made at different levels of inspired oxygen, intrapulmonary shunt was calculated both by the traditional shunt equation and also by our mathematical model based on non-invasive measurements of FIO2 and SaO2. RESULTS: There was good agreement between the two methods of shunt calculation. Using linear regression the correlation coefficient was 0.95. Bland and Altman analysis showed a bias of -0.8 and precision of 12%. CONCLUSION: In a controlled setting, intrapulmonary shunt can be estimated from non-invasive measurements to a reasonable degree of accuracy. However, the calculation requires too many assumptions to be of general clinical value. The equations used provide a validated physiological model that acts as a useful tool for teaching cardiorespiratory physiology.

Animals↗
PubMed1999

A survey of women's experiences of vaginal loss from 24 hours to three months after childbirth (the BLiPP study).

OBJECTIVE: To describe the range of normal vaginal loss as reported by women from 24 hours after delivery until three months postnatally. SETTING: Two health districts in the south of England. METHODS: A prospective survey of women's experiences and expectations of the duration, amount and colour of vaginal loss after childbirth. The term vaginal loss includes all types of fluid loss from the vagina following childbirth. FINDINGS: Five hundred and twenty-four women were recruited to the survey in 1995. Vaginal loss, as reported by the women, was considerably more varied in duration, amount and colour than descriptions in current midwifery textbooks. The median number of days reported for the duration of vaginal loss was 21 days and the interdecile range (10th to 90th percentile) was 10-42 days. For colour of lochia, women overall reported their vaginal loss to be more predominantly red/brown in colour and the traditional descriptions of the timing and colour phases of lochia rubra, serosa and alba are not supported by the majority of the women's experiences. Primiparous women were significantly more likely to report feelings of surprise or shock about their experiences of vaginal blood loss after the birth (odds ratio 4 [95% Confidence Interval 2-9]). Seven primiparous women (2%) were unaware that they would have a blood loss at all after the birth. IMPLICATIONS FOR PRACTICE: The findings from this survey have been used to develop information leaflets for women and health professionals about vaginal loss following childbirth. These leaflets include descriptions of normal ranges for the colour, amount and duration of vaginal loss in the first three months after childbirth.

Adolescent↗
PubMed1999

Feeding outcome in breast-fed term babies supplemented by cup or bottle.

OBJECTIVE: To describe the feeding method at discharge from midwifery care of term babies supplemented either by cup or bottle while in hospital. DESIGN: A retrospective review of the obstetric and midwifery records of 531 consecutively born babies. SETTING: A large maternity unit, with an integral General Practitioner Unit, in an inner city in the south of England. PARTICIPANTS: 63 term breast-feeding babies; 30 supplemented by cup and 33 supplemented by bottle. MAIN OUTCOME MEASURE: Breast feeding on discharge from midwifery care. FINDINGS: There were no significant differences between the bottle and cup supplementation groups in relation to feeding outcome (OR 1 94 95% CI 0.61, 6.31), or in the length of time from the beginning of supplementation to leaving hospital (median difference 1 95% CI 0, 1) or discharge from midwifery care (median difference 0 95% CI, -1, 1). Babies who received supplements of expressed breast milk, as opposed to artificial milk, were more likely to be supplemented by cup (OR 4 29, 95% CI 0.9, 26.91; p = 0.05), but were not more likely to be discharged from midwifery care breast feeding (OR 3.79, 95% CI 0.69, 38.36). CONCLUSION: Owing to the small scale and retrospective nature of this survey, its results must be viewed with caution. However, given the apparent lack of evidence in this area, prospective work should be undertaken to examine the most appropriate method of supplementation for term babies. Generalisation from work related to babies in special care baby units is no longer acceptable.

Bottle Feeding↗
PubMed1999

Cissampelos sympodialis Eichl. leaf extract increases the production of IL-10 by concanavalin-A-treated BALB/c spleen cells.

The effect of the aqueous fraction of the ethanol extract of Cissampelos sympodialis Eichl. (Menispermaceae) leaves (AFL) on Concanavalin-A (Con-A)-activated spleen cell proliferation and cytokine (IL-2, IL-4, IL-10 and IFN-gamma) secretion were analyzed. BALB/c spleen cells were treated, in vitro, with different concentrations, ranging from 6.25 to 400 microg/ml of AFL either in the presence or the absence of 5 microg/ml of the mitogen Con-A. It was observed that concentrations of the AFL higher then 50 microg/ml were toxic to the cells and concentrations ranging from 6.25 to 50 microg/ml decreased the lymphocyte proliferative response in the presence of the mitogen. This inhibition of mitogen induced proliferation was not reverted by the addition of exogenous recombinant IL-2. The AFL did not significantly inhibit IL-2 secretion. In the presence of AFL there was a reduction in the levels of secreted IFN-gamma while the production of both IL-10 and IL-4 were increased. AFL did not induce the production of any of the cytokines analyzed, in the absence of Con-A. It is suggested that increased IL-10 production down regulates IFN-gamma secretion and T cell proliferative responses.

Animals↗
PubMed1999

Characterization of metabolites of benz(j)aceanthrylene in faeces, urine and bile from rat.

1. The excretion of benz[j]aceanthrylene (B[j]A) and the biotransformation products found in faeces, urine and bile of rat exposed to [3H]-labelled B[j]A have been studied. 2. About 95% of the administered radioactivity was excreted within 7 days, 79% via faeces and 16% via urine, and most of the radioactivity in urine and faeces was excreted within 2 days. 3. The B[j]A metabolites excreted between days 1 and 2, including those excreted in bile during the first 5.5 h in a separate experiment, were further characterized by HPLC, UV and electrospray/atmospheric pressure chemical ionization mass spectrometry. 4. In faeces, bile and urine, hydroxylated B[j]A metabolites predominated. The major metabolites in faeces were B[j]A-1,2-dihydrodiol-8-hydroxy and B[j]A-1,2-dihydrodiol-10-hydroxy. These metabolites were found as conjugated metabolites in the bile. The glucuronide conjugate of B[j]A-1,2-dihydrodiol-10-hydroxy was also a major metabolite in urine. Two sulphate conjugates of oxidized B[j]A were detected in bile, a sulphate conjugate of a B[j]A-dihydrodiol-phenol and B[j]A-1,2-dihydrodiol-10-sulphate. Trans-B[j]A-1,2-dihydrodiol was detected in urine, faeces and bile. 5. These findings support the hypothesis that epoxidation at the cyclopenta ring is an important biotransformation pathway for B[j]A in vivo. In addition to the characterized metabolites, a large fraction of polar compounds, possibly glutathione conjugates, was also excreted in urine and bile.

Animals↗
PubMed1999

Neonatal exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice.

We examined whether the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) could increase intestinal tumorigenesis in neonatal C57BL/6J-Min/+ mice, a murine model for familial adenomatous polyposis. Min/+ mice are heterozygous for a nonsense mutation in the adenomatous polyposis coli gene and spontaneously develop multiple intestinal adenomas, primarily in the small intestine. Neonatal Min/+ mice (3-6 days old) were exposed to PhIP via breast milk from lactating dams given 8 s.c. injections of 50 mg/kg PhIP three times a week or to 8 s.c. injections of 25 or 50 mg/kg PhIP directly, over the same period. At the age of 11 weeks, the number, diameter and location of the intestinal tumors were scored. Remarkably, a 2- to 4-fold increase in the number of small intestinal tumors was seen in Min/+ mice exposed to PhIP via breast milk (P < 0.001). To our knowledge, this is the first time PhIP has been reported to induce tumors following exposure via breast milk from PhIP-exposed dams. Upon direct exposure to 50 mg/kg PhIP, a 6- to 9-fold increase in the number of small intestinal tumors was observed (P < 0.001). The diameter of the PhIP-induced small intestinal tumors was slightly increased (P < 0.001). In the colon, a 3- to 4-fold increase in the number of tumors was seen in Min/+ mice exposed to PhIP via breast milk (P = 0. 004). Direct exposure to 50 mg/kg PhIP caused a 2- to 6-fold increase in the number of colonic tumors (P = 0.014). The PhIP-induced colonic tumors were located more distally and displayed a smaller diameter than the tumors from the controls (P < 0.05). In contrast to a previous study, where PhIP showed only a moderate tumorigenic effect in adult Min/+ mice, the present study demonstrates a strong tumorigenic effect of PhIP in neonatally exposed Min/+ mice, even after exposure via breast milk from PhIP-exposed dams.

Animals↗
PubMed1999

Psychiatric comorbidity associated with DSM-IV ADHD in a nonreferred sample of twins.

OBJECTIVE: To test the external validity of the dimensions and subtypes of DSM-IV attention-deficit/hyperactivity disorder (ADHD) by assessing the prevalence of psychiatric comorbidity. METHOD: Eight- to 18-year-old twins with ADHD (n = 105) and without ADHD (n = 95) were recruited through local school districts. Comorbid disorders were assessed by structured diagnostic interviews with the parent and child and by a behavioral rating scale completed by the child's classroom teacher. RESULTS: Symptoms of inattention were associated with lower intelligence and higher levels of depression, whereas symptoms of hyperactivity-impulsivity were associated more strongly with symptoms of oppositional defiant disorder (ODD) and conduct disorder (CD). All DSM-IV subtypes were associated with higher rates of ODD and CD in comparison with controls, and the combined type was associated with more disruptive behavior disorder symptoms than the other 2 subtypes. The combined type and predominantly inattentive type were associated with more symptoms of depression than controls or the predominantly hyperactive-impulsive type. CONCLUSIONS: These results provide support for the discriminant validity of the dimensions and subtypes of DSM-IV ADHD and suggest that clinicians should carefully screen for comorbid disorders as part of a comprehensive assessment of ADHD.

Adolescent↗
PubMed1999

Decision-making activity and influence of nurse executives in top management teams.

This study assesses the impact on decision-making when introducing the nurse executive into the top management team (TMT) in Veterans Affairs Medical Centers. Results indicate that nurse executives formally elevated to the TMT were no more likely to perceive greater involvement in decision-making than non-TMT nurse executives or nurses informally appointed to the TMT. However, nurse executives in all categories perceived themselves as more involved in strategic decisions than other TMT members.

Decision Making, Organizational↗
PubMed1999

Outcomes for community health nursing practice.

OBJECTIVE: The purpose of this study was to develop an easy, practical list of outcomes amenable to community health nursing interventions. This study sought to answer the following question: What outcomes are sensitive to nursing interventions in the community health setting? SUMMARY BACKGROUND DATA: Nursing literature discusses many client outcomes. However, available outcome lists are not always sensitive to nursing interventions by community health nurses. Nurses need a precise list to measure client outcomes resulting from contact between nurses and clients in a variety of community health settings. METHODS AND SUBJECTS: The study used a modified Delphi technique to ensure adequate response from the subjects. Initially, focus groups generated items for the Delphi questionnaires. Using items from the focus groups, the researchers developed three rounds of questionnaires. In each round, nurses stated a level of agreement with each item as an outcome for community health nurses. Twenty-two community health nurses in one Southeastern state participated in four focus groups. One hundred fifty-two community health nurses returned round 1 questionnaires, 68 nurses returned round 2 questionnaires, and 48 nurses returned round 3 questionnaires. RESULTS: The researchers grouped the outcomes into four domains: client's psychosocial components of care, client's physiologic components of care, nursing intervention/implementation components of care, and environmental/community safety components of care. CONCLUSIONS: The findings produced an easy, practical list of 48 nursing outcomes for use in decision making and research by community health nurses in all settings.

Community Health Nursing↗
PubMed1999

The effects of managed care on physician and clinical integration in hospitals.

OBJECTIVE: To empirically estimate the effects that managed care has had on physician and clinical integration in urban hospitals. DATA SOURCES: The 1993 Hospital-Physician Relationship Survey conducted for the Prospective Payment Assessment Commission, augmented with data from a variety of secondary sources. The entire 1,495 responding hospitals were used to construct measures of integration; 591 responding hospitals in urban areas were used for the managed care analysis. STUDY DESIGN: Factor analysis was used to reduce 23 integration variables into 5 physician and 3 clinical integration factors. Two-stage least-squares regression techniques were used to estimate the effects of endogenous managed care. Models were estimated for all urban hospitals and for hospital subsets based upon ownership, multi-hospital system status, and teaching. PRINCIPAL FINDINGS: Other things equal, physician involvement in hospital management and governance increased with managed care involvement; to a lesser degree, the use of physician organization arrangements and other joint ventures also increased. Practice management and support services were lower in hospitals with high managed care activity. Larger hospitals, investor owned, system, and non-teaching hospitals had larger managed care revenues. Managed care revenues were lower in more concentrated hospital markets. CONCLUSIONS: The relationship between managed care and physician and clinical integration is relatively modest. Much of the realignment under managed care has been limited to certain types of efforts. Those efforts can best be described as foundation-building rather than comprehensive or fundamental.

Data Collection↗