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Biomedical subjects

P A Kenny

Publications and source records attributed to P A Kenny.

At least 19 recordsLinked to original sources
PubMed2005

Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes.

It is now widely accepted that elements of the cellular and tissue microenvironment are crucial regulators of cell behavior in culture and homeostasis in vivo, and that many of the same factors influence the course of tumor progression. Less well established is the extent to which extracellular factors actually cause cancer, and the circumstances under which this may occur. Using physiologically relevant three-dimensional culture assays and transgenic animals, we have explored how the environmental and architectural context of cells, tissues, and organs controls mammary-specific gene expression, growth regulation, apoptosis, and drug resistance and have found that loss of tissue structure is a prerequisite for cancer progression. Here we summarize this evidence and highlight two of our recent studies. Using mouse mammary epithelial cells, we show that exposure to matrix metalloproteinase-3 (MMP-3) stimulates production of reactive oxygen species (ROS) that destabilize the genome and induce epithelial-mesenchymal transition, causing malignant transformation. Using a human breast cancer progression series, we find that ADAM-dependent growth factor shedding plays a crucial role in acquisition of the malignant phenotype. These findings illustrate how normal tissue structure controls the response to extracellular signals so as to preserve tissue specificity and growth status.

Animals↗
PubMed1999

Molecular evolution of immunoglobulin and fibronectin domains in titin and related muscle proteins.

The family of regulatory and structural muscle proteins, which includes the giant kinases titin, twitchin and projectin, has sequences composed predominantly of serially linked immunoglobulin I set (Ig) and fibronectin type III (FN3) domains. This paper explores the evolutionary relationships between 16 members of this family. In titin, groups of Ig and FN3 domains are arranged in a regularly repeating pattern of seven and 11 domains. The 11-domain super-repeat has its origins in the seven-domain super-repeat and a model for the duplications which gave rise to this super-repeat is proposed. A super-repeat composed solely of immunoglobulin domains is found in the skeletal muscle isoform of titin. Twitchin and projectin, which are presumed to be orthologs, have undergone significant insertion/deletion of domains since their divergence. The common ancestry of myomesin, skelemin and M-protein is shown. The relationship between myosin binding proteins (MyBPs) C and H is confirmed, and MyBP-H is proposed to have given rise to MyBP-C by the acquisition of some titin domains.

Amino Acid Sequence↗
PubMed1999

Inflammatory processes in a murine model of intra-abdominal abscess formation.

Abscess formation has been viewed as a host defense strategy to contain the spread of infection. However, abscesses are also serious and life-threatening manifestations of persisting microbial infection. The initiation of abscess formation, both clinically and experimentally, involves the release of bacteria and an abscess-potentiating agent (e.g., fecal fiber or an analog) into a sterile site, with host defense mechanisms being unable to eliminate the infecting organisms. Abscess formation is aided by a combination of factors that share a common feature: impairment of phagocytic killing and hence clearance of microorganisms. These include bacterial virulence factors (e.g., capsule formation, succinic acid production); complement activation by the abscess potentiating agent; fibrin deposition; and microbial sequestration within abscess neutrophils. Recruitment of cells into the peritoneal cavity follows mast cell activation in the pathogenesis of infection: histamine and tumor necrosis factor alpha can be detected in the peritoneal cavity within minutes of challenge with an abscess-inducing mixture. However, the role of mast cells in host defense is made less clear by the finding of diminished abscess formation (but no mortality or increased morbidity) in mast-cell-depleted mice. This may indicate that mast cell products have a role in not only the initiation of an inflammatory response but also the promotion of fibrin deposition and abscess formation.

Abdominal Abscess↗
PubMed1997

The effect of the bacterial product, succinic acid, on neutrophil bactericidal activity.

We investigated the effect of succinic acid on neutrophil bactericidal activity in a model of intra-abdominal abscess induced in mice by the peritoneal inoculation of 5 x 10(6) cfu ml-1 E. coli and 5 x 10(8) cfu ml-1 B. fragilis plus 1 mg of bran as faecal fibre analogue. The mean pH of the induced abscesses at week 1 was 6.7, higher than the pH associated with succinic acid inhibitory activity. We therefore determined the effect of succinic acid (0-100 mM) at pH 6.7 on the bactericidal activity of mouse bone marrow-derived neutrophils. Phagocytic killing of Proteus mirabilis by neutrophils was significantly inhibited by 30-100 mM succinic acid at pH 6.7 but there was no significant effect of succinic acid on engulfment of bacteria at this pH. However, significant inhibition of intracellular killing (assayed by adding succinic acid to suspensions of neutrophils which had engulfed bacteria in low serum concentrations but in the absence of succinic acid) was noted at 70 and 100 mM. These results indicate that succinic acid inhibits neutrophil bactericidal activity at a physiological pH, principally through inhibition of intracellular killing mechanisms and therefore contributing to bacterial persistence in this model of abscess formation.

Abdominal Abscess↗
PubMed1996

Functional chemotactic factor CP-10 and MRP-14 are abundant in murine abscesses.

Murine abscesses induced by intraperitoneal injection of a mixture of Escherichia coli, Bacteroides fragilis, and bran are established models for the study of localized infectious and inflammatory lesions. Chemotactic factors are though to mediate the directed migration of large numbers of leukocytes into the abscess. Microorganisms located within the encapsulated lesion are not readily eliminated by the leukocytes, but their numbers are controlled over many weeks. We report the presence of large amounts of two murine S100 proteins, CP-10 and migration inhibition factor-related protein 14 (MRP-14), in abscesses as demonstrated by immunohistochemistry and measured by enzyme-linked immunosorbent assay and Western blotting (immunoblotting). High levels of CP-10 (7.7 +/- 1 mg/ml) and MRP-14 (5.5 +/- 1 mg/ml) were found throughout the time course of abscess development from early acute-phase lesions, which are predominantly neutrophilic, to late chronic-phase lesions, which contained more mononuclear cells. Approximately one-third of these amounts occurred as monomers (2.0 mg/ml for MRP 14 and 2.2 mg/ml for CP-10). Abscess fluid was strongly chemotactic, and a portion of the activity was due to CP-10, indicating its important role in leukocyte recruitment. CP-10-MRP-14 complexes were present in abscess fluid, and the proteins were immunoabsorbed together. In analogy with the related human MRP-8-MRP-14 complex, these proteins could be involved in the inhibition of microbial growth. No growth inhibition occurred with 20 microgram of CP-10 or MRP-14 per ml or with mixtures of both, but these concentrations may have been insufficient and were not representative of the high concentrations found within abscesses. CP-10 may contribute indirectly to the antimicrobial response in abscesses by virtue of its strong chemotactic properties and its capacity to modulate the activation state of recruited leukocytes.

Abscess↗
PubMed1994

Rapid diagnosis of cutaneous herpes simplex infections using specific monoclonal antibodies.

One hundred children with suspected herpes simplex virus (HSV) infection and 20 controls were studied to compare a rapid immunofluorescence (RIF) test for detection and typing of HSV from smears of lesions with standard viral culture. The RIF test was evaluated for ease of use and speed of diagnosis. RIF and/or culture were positive in 64% of patients. All infections diagnosed by RIF and culture were HSV type 1. In 92% of patients RIF and culture results were in concordance. In 57 cases, RIF and cultures were positive for HSV infection and in 35 cases RIF and cultures were negative for HSV infection. Three patients had inadequate samples for RIF and five children had positive RIF but were culture negative. All controls had negative results both by RIF test and culture. The RIF test demonstrated 100% sensitivity and 95% specificity. The RIF test was type specific, easy to perform and gave diagnosis of HSV infections within an hour of taking the clinical specimen. This study suggests the RIF test is as good, if not more sensitive, in the diagnosis of HSV infections as standard viral culture and has the advantage of speed of diagnosis.

Adolescent↗
PubMed1993

Skin microflora of atopic eczema in first time hospital attenders.

The bacterial flora of the skin was assessed quantitatively in 50 children with eczema, aged 6 months to 14 years, referred to the hospital for the first time. Twenty nonatopic controls with an unrelated non-infective disorder were also studied. Cotton-tipped swabs and contact agar discs were taken from the worst affected area of eczema and from an uninvolved site in patients and from the forearm in controls. Swabs were also taken from the nose, axilla and groin in all children. Bacterial colonization of the skin was consistently more common and greater in amount from patients compared with controls. Staphylococcus aureus was the most common pathogen isolated from patients only; from the worst affected area of eczema in 74% of patients and from an uninvolved skin site in 30% of patients. Quantitative assessment showed that the density of colonization was proportional to the severity of eczema. The most common S. aureus phage group was group II accounting for 32% of strains. Resistance to penicillin was present in 88% of strains and to two or more antibiotics in 38% of strains. No relationship was noted between the pattern of resistance and phage group.

Adolescent↗
PubMed1993

The effect of cytokines on bactericidal activity of murine neutrophils.

A range of recombinant cytokines have now been shown to modify aspects of the phenotype and function of human and murine neutrophils. However, few reports describe modification of the bactericidal activity of neutrophils. We therefore examined the recombinant murine cytokines tumor necrosis factor-alpha (TNF-alpha, 10-1000 ng ml-1) and granulocyte macrophage-colony stimulating factor (GM-CSF, 10-1000 U ml-1) for their ability to increase the bacterial killing capacity of murine neutrophils. Neutrophils from either bone marrow (fresh or cultured), or peritoneal exudates, or abscesses, were pre-incubated with either cytokine for 30-60 min and the killing of Proteus mirabilis, Escherichia coli, or Bacteroides fragilis was examined in the presence or absence of serum over a 90 min period. Only for one combination was a small but significantly enhanced level of bacterial killing observed, the phagocytic killing of P. mirabilis by peritoneal exudate neutrophils in the presence of GM-CSF and serum. With this exception there was no enhancement of bacterial killing for the range of combinations of neutrophils and bacterial species tested. In contrast, at the concentrations tested for effect on bactericidal activity, TNF-alpha and GM-CSF were able to significantly upregulate CR3 (but not Fc gamma RII) expression on mouse neutrophils. These results indicate that upregulation of CR3 as an index of neutrophil activation does not necessarily correlate with increased bactericidal activity.

Animals↗
PubMed1992

Use of an east end children's accident and emergency department for infants: a failure of primary health care?

OBJECTIVE: To ascertain why parents use an accident and emergency department for health care for their infants. DESIGN: Prospective one month study. SETTING: One accident and emergency department of a children's hospital in the east end of London. SUBJECTS: Parents of 159 infants aged < 9 months attending as self referrals (excluding infants attending previously or inpatients within one month, parents advised by the hospital to attend if concerned about their child's health, infants born abroad and arrived in Britain within the previous month). MAIN MEASURES: Details of birth, postnatal hospital stay, contact with health professionals, perceptions of roles of community midwife and health visitor, and current attendance obtained from a semistructured questionnaire administered in the department by a research health visitor; diagnosis, discharge, and follow up. RESULTS: 152(96%) parents were interviewed, 43(28%) of whom were single parent and 68(45%) first time mothers. Presenting symptoms included diarrhoea or vomiting, or both (34, 22%), crying (21, 14%), and feeding difficulties (10, 7%). Respiratory or gastrointestinal infection was diagnosed in 70(46%) infants. Only 17(11%) infants were admitted; hospital follow up was arranged for 27(20%) infants not admitted. Most (141, 94%) parents were registered with a general practitioner; 146(27%) had contact with the community midwife and 135(89%) the health visitor. CONCLUSION: Most attendances were for problems more appropriately dealt with by primary care professionals owing to patients' perceptions of hospital and primary health care services. IMPLICATIONS: Closer cooperation within the health service is needed to provide a service responsive to the real needs of patients.

Community-Institutional Relations↗
PubMed1991

Pathogenesis of intraabdominal abscess formation: abscess-potentiating agents and inhibition of complement-dependent opsonization of abscess-inducing bacteria.

Bacteroides fragilis and Escherichia coli are synergistic in the production of intraabdominal abscesses. However, these bacteria initiate abscess formation only when inoculated with an agent such as autoclaved colonic contents (ACC) or bran (a fiber analogue). The mechanism of action of the abscess-potentiating agent was studied. Opsonins in normal mouse serum were determined for phagocytic killing by murine neutrophils of B. fragilis and E. coli. Opsonization required fixation of complement by the alternative pathway. ACC (0.2 mg/ml) and bran (1.0 mg/ml) inhibited phagocytic killing of Proteus mirabilis in the presence of normal but not immune serum. Assay of the alternative pathway of complement activation indicated that both bacterial components and abscess-potentiating agents in an abscess-inducing mixture activated complement. These findings suggest that abscess-potentiating agents inhibit opsonization and therefore the subsequent phagocytic killing of bacteria in the nonimmune host.

Abscess↗
PubMed1991

Bacterial killing in vitro by abscess-derived neutrophils.

In the absence of antimicrobial therapy, bacteria such as Bacteriodes fragilis, Escherichia coli and Proteus mirabilis may persist within an intra-abdominal abscess in the presence of large numbers of neutrophils which, under optimal conditions in vitro, can readily phagocytose and kill the same bacterial strains. Neutrophils taken from abscesses induced by gram-negative bacteria such as those above contain viable organisms. On incubation in vitro in the presence of serum, these neutrophils kill the bacteria phagocytosed in the abscess poorly, if at all, yet can readily kill organisms added in vitro. To determine possible mechanisms that might explain this, we examined the bactericidal activity in vitro of neutrophils from a range of abscesses induced by one or two species of bacteria plus an abscess-potentiating agent, bran. The organisms studied were B. fragilis, E. coli, P. mirabilis and Staphylococcus aureus. The killing in vitro of E. coli and P. mirabilis, engulfed within an abscess, was significantly less than that of the same organisms when they were added to the in-vitro assay. In contrast, the killing of S. aureus was similar, whether engulfed in vivo or in vitro. However, S. aureus was less susceptible to phagocytosis and killing in vitro than P. mirabilis or E. coli, and the killing of S. aureus during in-vitro incubation of neutrophils that had engulfed the organism with in the abscess was similar to that of the gram-negative bacteria engulfed within the abscess.(ABSTRACT TRUNCATED AT 250 WORDS)

Abscess↗
PubMed1991

Acute infectious erythemas in children: a clinico-microbiological study.

One-hundred children with an acute illness comprising fever and widespread erythematous rash were prospectively studied to determine whether clinical presentations are helpful in defining the causative agent and to identify the most appropriate microbiological specimens. An infectious agent was identified in 65 children; 72% were viruses, 20% were bacteria, 5% were Mycoplasma pneumoniae and in 3% both viruses and bacteria were detected. The most common infectious agents were picornaviruses, an atypical presentation of measles and Group A beta-haemolytic Streptococcus. Different patterns of rash occurred with each of these infections. The clinical presentation of a child with an acute febrile illness and rash was unhelpful in defining the causative agent. Routine management should include a throat swab for bacterial investigation and in selected cases a blood sample for IgM viral titres.

Acute Disease↗
PubMed1990

Functional activity of individual abscess neutrophils from mice.

In the absence of antibiotic therapy, viable bacteria can persist within intra-abdominal abscesses in mice for at least 10 weeks. The mechanisms contributing to this survival are unknown, but abscess-derived neutrophils have impaired abilities to kill, in vitro, organisms engulfed in vivo. In order to determine whether subpopulations of abscess neutrophils might be discernible on the basis of phenotypic or functional criteria, cells from murine intra-abdominal abscesses were examined for phagocytic activity, CR3 expression, and H2O2 production in response to soluble and particulate stimuli. With respect to phagocytosis of Proteus mirabilis, abscess cells were no less efficient than peritoneal exudate neutrophils; no significant subpopulation of cells was incapable of phagocytosis in the presence of normal mouse serum. Using flow cytometry to examine abscess neutrophils for CR3 expression, we found that no subpopulations of cells were observed with unstimulated cells or with cells incubated with either phorbol 12-myristate 13-acetate or bacteria and serum. Intracellular H2O2 levels were measured by using the probe 2',7'-dichlorofluorescin diacetate. In general, incubation with phorbol 12-myristate 13-acetate resulted in similar increases in H2O2 production in all cells of the population. However, stimulation with bacteria and serum revealed a variable but consistent, poorly responsive subpopulation of neutrophils in abscess cell populations. Cell-sorting experiments showed that cells from the poorly responsive section of the FACS profile contained significantly higher numbers of abscess-derived bacteria, suggesting the presence of a subpopulation of viable abscess neutrophils harboring persisting viable bacteria.

Abscess↗
PubMed1987

Functional neutrophils from long-term murine bone marrow cell cultures.

Murine bone marrow cell cultures that had been established for up to 26 weeks were harvested each week and found to provide functional neutrophils. Leukocytes harvested from the cultures were enriched for neutrophils using discontinuous Percoll density gradients. These cells mounted a chemiluminescence response to Proteus mirabilis in the presence of normal mouse serum (NMS). They killed several NMS-opsonised bacterial species, an activity that was blocked by a monoclonal antibody to the C3 receptor of mouse neutrophils. Cultured bone marrow neutrophils expressed both Fc and C3 receptors. C3 receptor expression could be augmented by exposure to the chemotactic peptide f-Met-Leu-Phe. We conclude that murine bone marrow cell cultures provide a useful source of functional neutrophils, and that their productivity can be sustained in long-term culture. As their receptor expression can be augmented from the resting state by exogenous stimuli, they represent a useful cell source in studies of neutrophil activation.

Animals↗
PubMed1986

Effects of unusually early visual stimulation on the development of homing behavior in the rat pup.

Two studies examined the theory that early limitations on sensory functioning contribute to the organization of a structure for perceptual development and intersensory functioning. Rat pups' eyelids were surgically opened on Day 7, following which the development of homing to their nest site was investigated, with each animal alone in its living cage. Control pups increased homing until Day 14, and then decreased. Experimental pups showed no such decline, with the highest rate of homing evident on the last day of testing. The importance of visual cues for this altered development of homing was examined. Visual cues for the home were reduced by removing all shavings during testing, while leaving an odorous substrate in place. Under these conditions, both groups showed the characteristic increase and decline in homing, suggesting that premature eyelid opening results in a modification of the distribution of attention to visual and olfactory characteristics of the nest.

Animals↗
PubMed1985

The role of developmental limitations of sensory input on sensory/perceptual organization.

The human infant is born with limited sensory capacities. Such limitations are characteristic of early stages of development of all mammals. These limitations have been conceptualized as equivalent to sensory deprivation, and it has frequently been assumed that compensatory stimulation would therefore be advantageous. It is our contention that, during normal development, limitations provide an organizational framework which enhances perceptual development, and that providing additional stimulation to prematurely born infants may, in fact, be harmful. In addition to reviewing the literature on this issue, we present the results of several studies in which the effect of surgically opening the eyes of rat pups prior to the age of normal eye opening was examined. These studies found alterations in the patterns of homing consequent upon the early availability of visual input. Pups whose eyes were opened early failed to exhibit the transitions in behavior normally found to occur around the time of eye opening. Furthermore, the pups failed to respond differentially to olfactory stimuli which littermate controls successfully discriminated.

Animals↗
PubMed1982

Limitations on input as a basis for neural organization and perceptual development: a preliminary theoretical statement.

We propose an alternative to the conventional view that limitations on infant functioning are handicaps to be overcome. According to our view, limitations, particularly of the sensory systems, produce adaptive advantages for infants by facilitating perceptual organization. During embryogenesis, developmental rates of sensory systems are unequal so that onset of functioning is sequential. We argue that such differential onset results in relative independence among emerging systems, thereby reducing competition which helps regulate subsequent neurogenesis and functioning. In addition to prenatal effects, neonatal sensory limitations are discussed as a major source of perceptual organization. Limitations reduce the amount of information with which the infant must contend and promote temporal contiguity between multimodal attributes of a stimulus. Although we focus on human perceptual development, our view is a broadly based comparative one. Thus, other organisms have evolved means of restricting sensory input, and evidence is cited suggesting the importance of this reduced input in regulating normal perceptual development.

Adaptation, Biological↗