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Biomedical subjects

L A Kennedy

Publications and source records attributed to L A Kennedy.

At least 19 recordsLinked to original sources
PubMed2001

Community involvement at what cost?--local appraisal of a pan-European nutrition promotion programme in low-income neighbourhoods.

In the UK, government has committed itself to improving health and reducing inequalities in health. For the first time, issues such as food poverty will be addressed by tackling the causes of poverty and wider determinants of ill health. The time has never been better, therefore, for health and local authorities to work collaboratively to promote and improve health. Community involvement is also paramount to sustainable programmes. However, such a dramatic shift in policy and greater emphasis on public health requires health professionals themselves to adopt a different approach. The World Health Organization (WHO) recommends a health promotion approach as a framework for action. But despite the existence of this framework there is little evidence that a wider understanding of health promotion and the necessary practical experience has been achieved. This has weakened the potential impact of health promotion and has possibly encouraged inappropriate use of health promotion principles in practice. The European Food and Shopping Research Project (SUPER project) was established under the WHO European network of Healthy Cities to help local projects implement the principles of health promotion (WHO, 1986). This paper describes the SUPER project and its implementation in Liverpool (1989-1997), where levels of unemployment, deprivation and ill health are amongst the highest in the UK. Participation in SUPER is appraised to identify the various benefits and obstacles involved and to identify links with progress at the local level. This appraisal is discussed and the use, and potential misuse, of participatory appraisal techniques to elicit information and mobilize communities is examined.

Community Health Planning↗
PubMed2001

Three-dimensional microscopic image reconstruction of prostatic adenocarcinoma.

CONTEXT: Routine microscopy provides only a 2-dimensional view of the complex 3-dimensional structure that makes up human tissue. Three-dimensional microscopic image reconstruction has not been described previously for prostate cancer. OBJECTIVES: To develop a simple method of computerized 3-dimensional image reconstruction and to demonstrate its applicability to the study of prostatic adenocarcinoma. METHODS: Serial sections were cut from archival paraffin-embedded prostate specimens, immunostained using antikeratin CAM5.2, and digitally imaged. Computer image-rendering software was used to produce 3-dimensional image reconstructions of prostate cancer of varying Gleason grades, normal prostate, and prostatic intraepithelial neoplasia. RESULTS: The rendering system proved easy to use and provided good-quality 3-dimensional images of most specimens. Normal prostate glands formed irregular fusiform structures branching off central tubular ducts. Prostatic intraepithelial neoplasia showed external contours similar to those of normal glands, but with a markedly complex internal arrangement of branching lumens. Gleason grade 3 carcinoma was found to consist of a complex array of interconnecting tubules rather than the apparently separate glands seen in 2 dimensions on routine light microscopy. Gleason grade 4 carcinoma demonstrated a characteristic form of glandular fusion that was readily visualized by optically sectioning and rotating the reconstructed images. CONCLUSIONS: Computerized 3-dimensional microscopic imaging holds great promise as an investigational tool. By revealing the structural relationships of the various Gleason grades of prostate cancer, this method could be used to refine diagnostic and grading criteria for this common tumor.

Adenocarcinoma↗
PubMed2000

Tacrolimus: an alternative for graft-versus-host disease prevention.

OBJECTIVE: To evaluate the efficacy of tacrolimus for prevention of graft-versus-host disease (GVHD) in patients receiving allogeneic bone marrow transplants. DATA SOURCES: Published literature was identified through MEDLINE (January 1990-December 1998) using the key words tacrolimus, FK506, graft-versus-host disease, and bone marrow transplant. DATA SYNTHESIS: GVHD associated with allogeneic bone marrow transplant is a serious life-threatening complication. An evaluation of studies using tacrolimus for prevention of GVHD was conducted. CONCLUSIONS: Tacrolimus is effective for the prevention of GVHD in allogeneic bone marrow transplant. Further studies need to be conducted to optimize the dosage schedule and to determine therapeutic ranges, efficacy, and safety.

Graft vs Host Disease↗
PubMed1995

A quantitative technique for reporting surface degradation patterns of UHMWPE components of retrieved total knee replacements.

A quantitative method of reporting surface degradation of the ultra-high molecular weight polyethylene (UHMWPE) tibial component from retrieved total knee replacements (TKR) was developed. Specific features include a qualitative assessment expressing the patterns in which the damage was detected as well as a quantitative summary of the observed degradation mechanisms. In addition, a method of measuring lower limb alignment changes with time is described and related to the observed damage patterns. Two case studies are presented. One case illustrated that changes in alignment resulted from factors other than wear. The damage observed on the tibial plateau appeared to occur subsequent to the changes in alignment. The second case illustrated that the wear of the UHMWPE tibial insert lead to the changes in the overall lower limb alignment. The methods described provide additional information regarding TKR failure mechanisms compared to reporting methods currently available. In particular, the collection of temporal alignment data at clinical follow-up visits enhanced the assessment of the retrieved TKR.

Biocompatible Materials↗
PubMed1992

Manipulation of dopamine receptors alters hypoxic pulmonary vasoconstriction in isolated perfused rat lungs.

Using an isolated, perfused rat lung model, we examined the hypoxic pulmonary vasoconstriction (HPV). We studied the alterations in HPV induced by the selective DA1 receptor agonist, fenoldopam, the selective DA1 antagonist, SCH 23390, as well as a combination of these agents. Fenoldopam significantly attenuated HPV. SCH 23390 had no effect on HPV, but was ableto block the effect of fenoldopam. These data confirm the presence of vasodilatory DA1 receptors in the pulmonary vascular bed. The data further suggest that ongoing DA1 activity may be important in counterbalancing some pathologic pulmonary hypertensive states.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid beta-protein precursor.

Alzheimer's amyloid beta-protein precursor contains a Kunitz protease inhibitor domain (APPI) potentially involved in proteolytic events leading to cerebral amyloid deposition. To facilitate the identification of the physiological target of the inhibitor, the crystal structure of APPI has been determined and refined to 1.5-A resolution. Sequences in the inhibitor-protease interface of the correct protease target will reflect the molecular details of the APPI structure. While the overall tertiary fold of APPI is very similar to that of the Kunitz inhibitor BPTI, a significant rearrangement occurs in the backbone conformation of one of the two protease binding loops. A number of Kunitz inhibitors have similar loop sequences, indicating the structural alteration is conserved and potentially an important determinant of inhibitor specificity. In a separate region of the protease binding loops, APPI side chains Met-17 and Phe-34 create an exposed hydrophobic surface in place of Arg-17 and Val-34 in BPTI. The restriction this change places on protease target sequences is seen when the structure of APPI is superimposed on BPTI complexed to serine proteases, where the hydrophobic surface of APPI faces a complementary group of nonpolar side chains on kallikrein A versus polar side chains on trypsin.

Alzheimer Disease↗
PubMed1988

Mouse placental receptor for basic somatomedin following maternal ethanol administration.

We have previously reported a reduction in the basic somatomedin (B-SM) binding activity of day-15 mouse placental membranes following 3 days of acute maternal ethanol administration. In the present experiments, we have investigated the effects of acute maternal ethanol administration early in gestation on the subsequent development of the placental B-SM receptor, and its relationship to alcohol-related embryofetal growth deficits. Following administration of aqueous ethanol (0.0, 3.6, 5.5 or 7.1 ml/kg) by gavage on days 7, 8 and 9 of gestation, there was no evidence of reproductive impairment in alcohol-treated dams, but there was a significant reduction in day-15 embryonic body weight. Crown-rump length was unaffected. There was no treatment-related difference in the percentage specific binding of [125I]-B-SM by day-15 placental membranes, or in maternal serum B-SM concentrations. These observations suggest that embryofetal growth restriction following maternal ethanol administration is not mediated directly by peripheral unresponsiveness of the B-SM receptor, at least when the exposure occurs early in or prior to placental receptor ontogeny.

Animals↗
PubMed1986

Multimodal liquid chromatography columns for the separation of proteins in either the anion-exchange or hydrophobic-interaction mode.

Several high-performance stationary phases suitable for protein chromatography were synthesized. Columns packed with these materials could be operated independently in either the anion-exchange or hydrophobic-interaction mode. Two approaches were used to prepare these materials. In the first method, a polyamine was adsorbed on the surface of macroporous silica and then crosslinked with a multifunctional oxirane. The hydrophobicity of the crosslinking agent and the extent of interconnection were used to modulate the electrostatic and solvophobic interactions. The second approach also utilized a crosslinked polyamine stationary phase; however, the forces of interaction were attenuated through controlled acylation of surface amines with a small anhydride molecule. The resolving ability of these columns, functioning in either mode, was comparable to commercial high-performance liquid chromatographic columns, designed to operate by a single retention mechanism. Column selectivity for proteins was completely different in each mode. Protein fractions collected from a multimodal column, operated in the anion-exchange mode, could be further purified by rechromatographing them on the same column in the hydrophobic-interaction mode. Utility of the multimodal column was demonstrated with the fractionation of several cytochromes and ferredoxins from the cyanobacterium Microcystis aeruginosa.

Chemical Phenomena↗
PubMed1986

Ocular changes in the mouse embryo following acute maternal ethanol intoxication.

The development of the eye was investigated in the mouse embryo following a single administration of ethanol plus [3H]thymidine to the dam on day 13 of gestation. After 1 hr there was no difference in the number of labelled cells/100 micron 2 in the neural layer of the retina compared to controls, but there was an alcohol-related reduction in labelling density. After 24 hr there was an increase in the numbers of both pyknotic cells and mitotic figures, breaks occurred in the inner surface of the retina and cell debris was being extruded into the posterior chamber. At 48 hr the increase in pyknotic cells persisted, but there was less evidence of cell debris and the borders had been repaired. The estimated cell cycle time in the neural progenitor cells following maternal alcohol administration was increased 7-fold compared to controls. Morphometric analysis revealed that after 48 hr there were significant alcohol-related reductions in the width and depth of the eye, in the thickness of the neural layer and in the interocular distance. It appears that many of the ophthalmic abnormalities reported in human fetal alcohol syndrome can be produced in the mouse embryo following a single episode of acute maternal intoxication during a critical period of ocular ontogeny, and that they evolve primarily from disturbances in the normal patterns of recruitment and loss of neural progenitor cells in the developing retina.

Animals↗
PubMed1986

The ontogeny of placental Na+-K+ ATPase in the mouse and its impairment by ethanol.

We have investigated the normal ontogeny of Na+-K+ ATPase in the mouse placenta and the possibility that impairment in placental transport capacity, as reflected in reductions in NA+-K+ ATPase activity, is associated with alcohol-related embryonic growth restriction. We have demonstrated that over the normal course of pregnancy there is a dramatic increase in placental NA+-K+ ATPase activity which occurs in concert with the embryofetal body growth spurt. Maternal ethanol administration during the early period of placental enzymogenesis (days 7-9) resulted in a significant reduction (up to 40%) of placental Na+-K+ ATPase activity on day 15. Both the severity and the frequency of the reduction were dose dependent. The effect was associated with significant reductions in embryonic body and brain weight but no change in body length or prenatal mortality. Incubation of term placental fragments for 2 h in increasing concentrations of ethanol resulted in a comparable reduction in enzyme activity. Our studies demonstrate that direct ethanol exposure produces a reduction of placental Na+-K+ ATPase activity, that exposure during the early stages of enzymogenesis results in persistent reductions in Na+-K+ ATPase activity in the mature placenta, and that this effect is associated with deficits of embryonic body and brain growth. A direct causal relationship has not been proven; however, it is conceivable that the correlation between reduced placental Na+-K+ ATPase activity and impaired embryofetal growth reflects a common causal pathway.

Animals↗
PubMed1986

Reduced binding of basic somatomedin by mouse placental membranes following maternal alcohol administration.

The effects of 3 days of maternal ethanol administration on the placenta and on basic somatomedin (B-SM) were investigated in the mouse. Following administration of aqueous ethanol by gavage on days 13, 14 and 15 of gestation, there was no treatment-related difference in embyonic growth or placental weight as seen on day 15. There was a significant reduction in the specific binding of [125I]B-SM by day 15 placental membranes, but no difference in serum B-SM concentrations or in the frequency or severity of degenerative changes in the placenta. We have shown that changing levels of serum B-SM over the normal course of pregnancy correspond closely to patterns of cellular proliferation and aging in the placenta. It is possible that impairment in the binding activity of B-SM receptors contributes to the premature aging observed in term placentas exposed to alcohol during pregnancy in the rodent.

Animals↗
PubMed1984

Comparison of hydrophobic-interaction and reversed-phase chromatography of proteins.

The variable hydrophobic nature of proteins allows their separation through differential hydrophobic surface interactions. From these observations two modes of protein chromatography have been developed, hydrophobic-interaction chromatography (HIC) and reversed-phase chromatography (RPC). Selectivity of the HIC column can be easily manipulated by changing mobile phase variables. Protein retention was increased by decreasing the pH from neutrality or by using a salt with a greater "salting-out" ability. In addition, selectivity can be altered through chemical modification of the matrix surface. Protein retention and resolution decreased concomitantly with matrix ligand density. There were several major differences in HIC and RPC selectivity. Hydrophilic proteins such as cytochrome c and myoglobin were weakly retained on the HIC column but strongly retained on the RPC column. In contrast, a hydrophobic protein such as beta-glucosidase was strongly retained on the HIC column and only weakly retained on the RPC column. Other proteins were retained equally by RPC and HIC columns. Load capacity on the HIC column was determined by plotting resolution as a function of protein load. Resolution decreased significantly after 7.5 mg of total protein had been loaded onto the column per cm3 of column material. Samples of lactic dehydrogenase and alpha-chymotrypsin ranging in size from 10-200 micrograms were recovered from an HIC column with greater than 86% enzymatic activity in all cases. The recovery of enzymatic activity of alpha-chymotrypsin ranged from 55-91%, while none of the activity of beta-glucosidase was recovered from the RPC column.

Animals↗
PubMed1984

Changes in the term mouse placenta associated with maternal alcohol consumption and fetal growth deficits.

Primiparous mice were fed alcohol in their drinking water as 0%, 10%, 15%, 20% (v/v) solutions on days 11 through 18 of gestation. Based on blood alcohol levels and on locomotor and health impairments, these treatment groups represent situations of mild, moderate, and severe alcohol abuse. There were significant alcohol-related fetal growth deficits but no increase in fetal mortality or malformation. Placental weight was reduced with increasing alcohol intake. Histologic examination of the placenta revealed an increase in the frequency and severity of intravascular coagulation of maternal erythrocytes in the labyrinth and advanced degenerative changes in the basal zone of alcohol-exposed placentas. These observations suggest that both the vascular and the endocrine functions of the placenta are compromised in alcohol-consuming dams.

Alcohol Drinking↗
PubMed1984

Renal transplantation after removal and prevention of resynthesis of HLA antibodies.

Plasma exchange and immunosuppression with prednisolone and cyclophosphamide were used to remove HLA antibodies and prevent their resynthesis in five patients awaiting renal transplantation. After treatment HLA antibody titres and reactivities against a panel of donor lymphocytes were considerably reduced and, as a result, these patients received transplants. Four of these patients have successfully functioning transplants; the other patient died as a result of septicaemia with a poorly functioning allograft.

Adolescent↗
PubMed1984

The pathogenesis of brain abnormalities in the fetal alcohol syndrome: an integrating hypothesis.

The most obvious characteristics of the fetal alcohol syndrome are a cluster of minor, physical malformations that are rather nonspecific and that vary greatly in the frequency and severity of expression. The most common characteristics are general body and organ growth deficits, including microcephaly. The most debilitating characteristics, however, are central nervous system (CNS) dysfunctions, such as behavioral and intellectual impairments, which appear to be closely related to the growth deficits. The mechanisms whereby alcohol exerts its deleterious effects on intrauterine growth and development are being intensively investigated. Because of its pharmacological properties, maternal consumption of alcohol is associated with widespread effects throughout the maternal-placental-fetal organism, many of which can secondarily alter the in utero environment. Both direct and indirect mechanisms are discussed with respect to their contribution to alcohol-related effects on embryofetal growth and development. It is suggested that impairment in the protein synthetic machinery, resulting in cellular growth restriction at critical periods of development is the common mechanism underlying alcohol's teratogenicity. Because the development of the CNS is so prolonged and complex compared to other organ systems, it is exquisitely vulnerable to derangement throughout pregnancy.

Brain↗