Biomedical subjects
Publications and source records attributed to K Lewis.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The carrier rates of a genetic marker for arylsulphatase A pseudodeficiency (ASA-PD) were determined in three series of patients with vascular dementia (VaD) or Alzheimer's disease (AD). In the first community-based sample, the 1524 + 95A-->G mutation, which is known to be associated with ASA-PD, was present in 35% of VaD cases and none of the AD cases. In a second sample of cases drawn from a Dementia Register, the mutation rates were 18% (VaD) and 16% (AD). Brain DNA from a post-mortem sample revealed the ASA-PD mutation in 60% of VaD cases and 34% of AD cases. These rates are higher than previous studies of culturally similar populations and suggest that ASA-PD may be a risk factor for dementia.
Two new antimicrobial peptides related to the gamma-thionine family have been isolated by acid extraction from the broad bean Vicia faba. The extract was separated by ion exchange chromatography, and a fraction showing antibacterial activity was further purified by reverse-phase HPLC. Material from a single HPLC peak was sequenced and revealed the presence of two peptides differing by one amino acid. The peptides were named fabatins. They are 47 amino acids long, have an overall positive charge and contain 8 cysteines that probably form 4 disulfide bridges characteristic of the gamma-thionins. Fabatins were active against both Gram-negative and Gram-positive bacteria, but were inactive against the yeasts Saccharomyces cerevisiae and Candida albicans.
The Notch gene encodes a receptor protein that is involved in many processes during development. Its best understood role is during neurogenesis in a process called "lateral inhibition." However, it has been proposed that Notch also has a role in defining the proneural clusters in the first place. This raises the possibility that the Notch protein is acting as a multifunctional receptor. To test this hypothesis, we have carried out a genetic analysis of molecularly characterized Notch alleles to identify alleles that affect only one of the two proposed functions. Here we present evidence that Notch alleles can be identified that appear to affect the function of Notch during either lateral inhibition or the definition of proneural clusters. In addition our results indicate that there may be discrete regions of the Notch protein required for each function.
SUBJECTS AND METHODS: In an anonymous study of HIV-I sero-reactivity in dental patients in a Government clinic in Namibia, 29 (7%) out of 405 patients (10 female and 19 male) were confirmed as HIV-infected. HIV-antibody testing was done cheaply and conveniently by collecting and storing finger-prick blood on absorbent paper, and eluting the samples 7 weeks later. Testing was done by GACPAT, a simple, inexpensive temperature independent assay which requires no specialised equipment. RESULTS AND CONCLUSIONS: Six patients had orofacial lesions, including Kaposi's sarcoma, leukoplakia (bilateral on buccal mucosa), cervical lymphadenopathy, hairy leukoplakia, circum-oral herpes simplex, HIV-gingivitis and necrotising ulcerative gingivitis. This sampling and testing system is well suited for use in epidemiological surveys in developing countries.