Biomedical subjects

K Lewis

Publications and source records attributed to K Lewis.

At least 19 recordsLinked to original sources

PubMed2000

Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor.

Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The RAFFT as a screening tool for adolescent substance use disorders.

The objective of this study was to measure the sensitivity and specificity of the RAFFT, a screening instrument for problematic adolescent substance use. Two hundred and twenty-six adolescent patients, aged 13 to 18, who were referred to an emergency room or an ambulatory evaluation clinic were included. Patients answered the five questions of the RAFFT before a comprehensive psychiatric assessment was completed. Diagnoses were made according to DSM-IV. The best results were obtained with two positive answers on the RAFFT: a sensitivity of 89% and a specificity of 69% in the screening for substance abuse or dependence. The RAFFT performed well in this highly selected patient population.

Adolescent↗

PubMed2000

A dose-response study of antibiotic resistance in Pseudomonas aeruginosa biofilms.

Bacterial biofilms show enormous levels of antibiotic resistance, but little is known about the underlying molecular mechanisms. Multidrug resistance pumps (MDRs) are responsible for the extrusion of chemically unrelated antimicrobials from the bacterial cell. Contribution of the MDR-mediated efflux to antibiotic resistance of Pseudomonas aeruginosa biofilms was examined by using strains overexpressing and lacking the MexAB-OprM pump. Resistance of P. aeruginosa biofilms to ofloxacin was dependent on the expression of MexAB-OprM but only in the low concentration range. Unexpectedly, biofilm resistance to ciprofloxacin, another substrate of MexAB-OprM, did not depend on the presence of this pump. Dose-dependent killing indicated the presence of a small "superresistant" cell fraction. This fraction was primarily responsible for very high resistance of P. aeruginosa biofilms to quinolones. Bacterial cells recovered from a biofilm and tested under nongrowing conditions with tobramycin exhibited higher resistance levels than planktonic cells but lower levels than cells of an intact biofilm.

Anti-Bacterial Agents↗

PubMed2000

Programmed death in bacteria.

Programmed cell death (PCD) in bacteria plays an important role in developmental processes, such as lysis of the mother cell during sporulation of Bacillus subtilis and lysis of vegetative cells in fruiting body formation of Myxococcus xanthus. The signal transduction pathway leading to autolysis of the mother cell includes the terminal sporulation sigma factor Esigma(K), which induces the synthesis of autolysins CwlC and CwlH. An activator of autolysin in this and other PCD processes is yet to be identified. Autolysis plays a role in genetic exchange in Streptococcus pneumoniae, and the gene for the major autolysin, lytA, is located in the same operon with recA. DNA from lysed cells is picked up by their neighbors and recombined into the chromosome by RecA. LytA requires an unknown activator controlled by a sensory kinase, VncS. Deletion of vncS inhibits autolysis and also decreases killing by unrelated antibiotics. This observation suggests that PCD in bacteria serves to eliminate damaged cells, similar to apoptosis of defective cells in metazoa. The presence of genes affecting survival without changing growth sensitivity to antibiotics (vncS, lytA, hipAB, sulA, and mar) indicates that bacteria are able to control their fate. Elimination of defective cells could limit the spread of a viral infection and donate nutrients to healthy kin cells. An altruistic suicide would be challenged by the appearance of asocial mutants without PCD and by the possibility of maladaptive total suicide in response to a uniformly present lethal factor or nutrient depletion. It is proposed that a low rate of mutation serves to decrease the probability that asocial mutants without PCD will take over the population. It is suggested that PCD is disabled in persistors, rare cells that are resistant to killing, to ensure population survival. It is suggested that lack of nutrients leads to the stringent response that suppresses PCD, producing a state of tolerance to antibiotics, allowing cells to discriminate between nutrient deprivation and unrepairable damage. High levels of persistors are apparently responsible for the extraordinary survival properties of bacterial biofilms, and genes affecting persistence appear to be promising targets for development of drugs aimed at eradicating recalcitrant infections. PCD in unicellular eukaryotes is also considered, including aging in Saccharomyces cerevisiae. Apoptosis-like elimination of defective cells in S. cerevisiae and protozoa suggests that all unicellular life forms evolved altruistic programmed death that serves a variety of useful functions.

Apoptosis↗

PubMed1999

Multidrug resistance: Versatile drug sensors of bacterial cells.

One way that bacteria resist antimicrobial agents involves 'drug sensors', proteins that bind a range of structurally unrelated antimicrobial drugs and induce expression of multidrug resistance pumps. The basis for drug recognition is now becoming clear from the recently determined crystal structure of a drug sensor.

Anti-Bacterial Agents↗

PubMed1999

Human longevity: an evolutionary approach.

Humans are unique in having a considerably longer life span post female reproductive age as compared to other primates. It is proposed that transmission of knowledge from grandparents to progeny served as a driving force for extending human longevity. It is suggested that grandparents and grandchildren have evolved adaptive complementary behaviors that fit the educator/pupil roles. Older individuals specifically retain the ability to preserve their knowledge base that allows them to focus on transmitting to children knowledge accumulated over generations. A repair management model of aging is proposed, according to which inhibition of repair in older individuals at times of stress allows to focus resources on the task at hand. Such an adaptation will inevitably accelerate the rate of aging in animals and in humans and will appear as 'programmed aging'. It is further suggested that in humans, older individuals in early societies who are no longer useful could increase their reproductive success by activating this programmed aging mechanism, which would result in channeling resources to progeny. Decreased emotional support and mastery are mortality risk factors in the elderly, supporting this hypothesis of programmed death in humans, and providing a rationale for increasing longevity.

Aged↗

PubMed1999

Nitric oxide limits the eicosanoid-dependent bronchoconstriction and hypotension induced by endothelin-1 in the guinea-pig.

1. This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid-releasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3. In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4. The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5. Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Purification and ligand binding of EmrR, a regulator of a multidrug transporter.

EmrR, the repressor of the emrRAB operon of Escherichia coli, was purified to 95% homogeneity. EmrR was found to bind putative ligands of the EmrAB pump-2,4-dinitrophenol, carbonyl cyanide m-chlorophenylhydrazone, and carbonyl cyanide p-(trifluoro-methoxy)phenylhydrazone-with affinities in the micromolar range. Equilibrium dialysis experiments suggested one bound ligand per monomer of the dimeric EmrR.

2,4-Dinitrophenol↗

PubMed1999

Digital teledermatology for skin tumours: a preliminary assessment using a receiver operating characteristics (ROC) analysis.

A low-cost store-and-forward teledermatology system using digital images for the remote diagnosis and management of skin tumours was evaluated. Two hospitals participated in the trial. Patients were seen face to face at one hospital, and had their images and clinical history viewed remotely by a different dermatologist at a second hospital. A preliminary receiver operating characteristics (ROC) analysis revealed clinical agreement between the teledermatologist and face-to-face dermatologist in 93% of cases in terms of their assessment of the benign/malignant nature of the lesions. Sensitivity of the judgements was 88% and specificity was 80%. These preliminary findings indicate the potential for remote management of skin tumours using a low-cost system in the National Health Service.

Diagnosis, Differential↗

PubMed1999

Managing chronic fatigue syndrome: overview and case study.

1. The basic principles of envelope theory are explained. By not overexerting themselves, people with CFS can avoid the setbacks and relapses that commonly occur in response to overexertion while increasing their tolerance to activity. 2. By collecting time series data on fluctuations in energy levels, important clinical observations can be made in respect to a client's unique condition and experience with CFS.

Fatigue Syndrome, Chronic↗

PubMed1999

The nocebo effect: do no harm.

The nocebo effect creates negative expectations about symptoms and can have devastating influence on patient recovery. Just as the placebo effect works by making patients believe they will get better, the nocebo effect can serve to make patients worse. Two case histories are presented in which patients were assigned diagnoses without objective physical findings. This resulted in poor outcomes. Physicians should avoid assigning a diagnosis without objective physical evidence and thus avoid creating the nocebo effect in patients.

Adult↗

PubMed1998

Pathogen resistance as the origin of kin altruism.

It is suggested that pathogen and parasite avoidance act as a driving force for kin selection. Preferential association with relatives decreases the probability of infection with unfamiliar pathogens. Altruistic behavior towards kin will further decrease the danger of infection by increasing the representation of relatives in a group. Such a behavioral strategy could evolve if pathogen resistance were heritable. Highly polymorphic major histocompatibility (MHC) genes largely determine heritable resistance to particular pathogens. The degree of relatedness within a group correlates with the degree of similarity in MHCs. It has been shown that detection of MHC type by mice guides preferential kin association. Pathogen avoidance appears to be the simplest explanation for the existence of a direct link between detecting the heritable component of the immune system and kin altruism. Detection of MHC also serves kin avoidance in mating. Periodic introduction of new genes including MHCs through mating provides resistance to the unavoidable appearance of foreign virulent pathogens (Hamilton et al., 1990, Proc. Natl Acad. Sci. U.S.A. 87, 3566-3573). It is suggested that kin preference favoring homogeneity punctuated by introduction of new genes through mating provides an optimal strategy for pathogen avoidance. Aggression might also serve to decrease infection by isolating or eliminating individuals with unrelated MHCs.

Altruism↗

PubMed1998

Bacteria lacking a multidrug pump: a sensitive tool for drug discovery.

Microorganisms express multidrug resistance pumps (MDRs) that can confound antibiotic discovery. We propose the use of mutants deficient in MDRs to overcome this problem. Sensitivity to quinolones and to amphipathic cations (norfloxacin, benzalkonium chloride, cetrimide, pentamidine, etc.) was increased 5- to 30-fold in a Staphylococcus aureus mutant with a disrupted chromosomal copy of the NorA MDR. NorA was required both for increased sensitivity to drugs in the presence of an MDR inhibitor and for increased rate of cation efflux. This requirement suggests that NorA is the major MDR protecting S. aureus from the antimicrobials studied. A 15- to 60-fold increase in sensitivity to antimicrobials also was observed in wild-type cells at an alkaline pH that favors accumulation of cations and weak bases. This effect was synergistic with a norA mutation, resulting in an increase up to 1,000-fold in sensitivity to antimicrobials. The usefulness of applying MDR mutants for natural product screening was demonstrated further by increased sensitivity of the norA- strain to plant alkaloid antimicrobials, which might be natural MDR substrates.

Anti-Bacterial Agents↗

PubMed1998

Stretch-induced membrane type matrix metalloproteinase and tissue plasminogen activator in cardiac fibroblast cells.

In the normal heart, cardiomyocytes are surrounded by extracellular matrix (ECM) and latent matrix metalloproteinases (MMPs), which are produced primarily by cardiac fibroblasts. An activator of latent MMPs might be induced by ischemic conditions or pressure-induced stretching. To test the hypothesis that an activator of latent MMP is induced in the ischemic heart during transformation of a compensatory hypertrophic response to a decompensatory failing response in cardiac fibroblast cells, we stretched the human cardiac fibroblasts at 25 cycles/min in serum-free or 5% serum culture condition. The membrane type (MT)-MMP activity in stretched cells was measured by zymography and immuno-blot analyses using MT-MMP-2 antibody. The MT-MMP activity was further characterized by transverse-urea gradient (TUG)-zymography. The results suggested that stretch induced a membrane MMP in the fibroblasts that was similar to the MT-MMP induced in ischemic heart. Furthermore, we observed that membrane MMP has distinct mobility in TUG-zymography. To localize the MT-MMP and tissue plasminogen activator (tPA) of latent MMPs, the membrane and cytosol were separated by a method employing a detergent and sedimentation. The MT-MMP and tPA activities of cytosol and membrane fractions were measured by gelatin- and plasminogen-zymography, respectively. Differential-display mRNA analysis was performed on control and stretched cells. In situ immuno-labelling was performed to localize the MT-MMP. The results indicate that induction of MT-MMP occurred in the membrane fractions. The secretion of tPA was elevated in the stretched cells. The MT-MMP activity was inhibited by prior incubation with an antibody generated to membrane MMP. The tPA activity was inhibited by using tPA antibody. These results suggest that, under stretched conditions, neutral transmembrane matrix proteinases are induced in the cardiac fibroblasts. This may lead to activation of adverse ECM remodeling, cardiac dilatation, and failure.

Blotting, Northern↗

PubMed1998

Expanded profile of the SHAFT syndrome.

The SHAFT syndrome is a factitious disorder in which a patient manipulates the surgeon to perform operations to fulfill his or her psychological needs. The acronym describes patients who are sad, hostile, anxious, frustrating, and tenacious. A chart review from January 1990 to June 1996 was undertaken to provide a profile to aid in the recognition and diagnosis of the SHAFT syndrome. An analysis of 28 patients revealed characteristics supporting a definitive SHAFT profile. Patients with SHAFT syndrome seek physicians to perform invasive procedures. Their typical complaint is pain, usually without objective physical findings that would support a more definitive diagnosis. Such patients tend to be women, cry with pain, describe symptoms out of proportion to objective findings, and have a history of psychiatric care.

Adult↗

PubMed1998

Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase.

Several phosphonate and bisphosphonate analogues of farnesyl pyrophosphate have been prepared for an examination of their ability to inhibit farnesyl protein transferase (FPTase). A Horner-Wadsworth-Emmons condensation of farnesal or geranial with tetraethyl methylenediphosphonate gave the desired vinyl phosphonates, while alkylation of the dimethyl methylphosphonate anion with a terpenoid bromide gave the corresponding saturated phosphonates. Alkylation of tetraethyl methylenediphosphonate with farnesyl bromide gave the expected alkyl bisphosphonate, which was converted to its alpha, beta-unsaturated derivative by preparation of the phenyl selenide, oxidation to the selenoxide, and elimination. In a similar fashion, triethyl phosphonoacetate was converted to a farnesyl pyrophosphate analogue by reaction with farnesyl bromide. After preparation of the respective acids, each compound was tested for inhibition of FPTase at concentrations ranging up to 10 microM. The effect of these compounds on FPTase activity varied substantially, ranging from depressed to surprisingly enhanced enzymatic activity.

Alkyl and Aryl Transferases↗

PubMed1998

L-NAME potentiates endothelin-stimulated thromboxane release from guinea pig lung.

The bronchoconstrictor response after systemic administration of endothelins (ETs) in the guinea pig is indirectly mediated by thromboxane A2 (TxA2) release through ETB receptor activation. ETs also trigger the release of nitric oxide (NO) in endothelial cells by activation of ETB receptors. A growing body of evidence indicates that endogenous NO plays a key role in the regulation of pulmonary function. In this study we investigated the effect of an NO synthase inhibitor, L-NAME, on the release of TxA2 from the isolated, perfused guinea pig lung induced either by ET-1, the selective ETB receptor agonist IRL-1620, bradykinin (BK), or a TxA2-mimetic, U 46619. A 30 min intra-arterial (intra-arterial) infusion of L-NAME (300 microM) potentiated the TxA2 release with ET-1, IRL 1620, and BK (5, 50, and 50 nM, respectively) infused for 3 min (i.a.). U 46619 (10 nM) was ineffective as a stimulant of pulmonary eicosanoid release. Interestingly, L-NAME did not potentiate the release of prostacyclin (PGI2) triggered by ET-1, IRL 1620, or BK. Our results suggest a predominant role of ETB receptor activation in the release of TxA2. Furthermore, we suggest that NO in the guinea pig lung is a potent modulator of the TxA2 releasing activity of ET-1, IRL 1620, and BK, three agonists known to stimulate the release of NO.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1998

Audit of timing of antibiotic prophylaxis in hip and knee arthroplasty.

Infection following arthroplasty can have devastating consequences. Antibiotic prophylaxis is routinely given in modern orthopaedic practice in an attempt to reduce infection rates. The aim is to achieve clinically useful tissue concentrations of antibiotic peri-operatively, and this is accomplished with antibiotic administration at induction of anaesthesia and at 6 and 12 h post-operatively. The case notes of 16 consecutive patients undergoing elective joint replacement surgery were reviewed. All received antibiotic prophylaxis, but the time intervals between doses were longer than the current standard in 50% of patients for the second dose and 81% of patients for the third dose. Our practice has been reviewed to ensure that all patients receive antibiotics at the appropriate times.

Antibiotic Prophylaxis↗