Search PubMed⌕ Search

Biomedical subjects

K May

Publications and source records attributed to K May.

At least 19 recordsLinked to original sources
PubMed2007

Prevalence of antimicrobial resistance among Salmonella on midwest and northeast USA dairy farms.

The objective of this study was to determine the prevalence of antimicrobial resistance among Salmonella isolated from dairy herds in New York, Minnesota, Michigan, and Wisconsin, USA. Serogroup and antimicrobial susceptibility characteristics were determined for Salmonella from cattle and environmental samples collected during August 2000-October 2001 as part of a longitudinal study where 129 herds were visited at 2-month intervals. Salmonella isolates were tested (using a broth microdilution method) for susceptibility to amoxicillin/clavulanic acid, ampicillin, ceftiofur, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim/sulfamethoxazole. Of the 1506 isolates tested for minimum inhibitory concentrations to these 14 antimicrobial agents, 81.2% were pan-susceptible and for most herds (81.6%) the predominant antimicrobial resistance pattern was pan-susceptible. At least 1 Salmonella isolate resistant to 5 or more antimicrobial agents was found on 23.6% of herds. This resistance phenotype was most common among serogroups B and E1 and among samples from calves and farmer-designated sick cows. Resistant samples most frequently exhibited resistance to tetracycline, streptomycin, and/or ampicillin. No samples were resistant to ceftriaxone (though 13 were in the intermediate range), and very few samples were resistant to ciprofloxacin (n=1), nalidixic acid (n=5), or trimethoprim/sulfamethoxazole (n=7).

Animals↗
PubMed2006

Antimicrobial susceptibility of Salmonella from organic and conventional dairy farms.

The objective of this study was to compare antimicrobial susceptibility of Salmonella isolated from conventional and organic dairy farms in the Midwest and Northeast United States. Environmental and fecal samples were collected from organic (n = 26) and conventional (n = 69) farms in Michigan, Minnesota, New York, and Wisconsin every 2 mo from August 2000 to October 2001. Salmonella isolates (n = 1,243) were tested using a broth microdilution method for susceptibility to amoxicillin-clavulanic acid, ampicillin, ceftiofur, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim-sulfamethoxazole. Herd-level logistic regression and logistic proportional hazards multivariable models were used to examine the association between farm management type and susceptibility to antimicrobial agents. For most antimicrobial agents tested, susceptibility of Salmonella isolates was similar on organic and conventional herds when controlling for herd size and state. Conventional farms were more likely to have at least one Salmonella isolate resistant to streptomycin using logistic regression (odds ratio = 7.5; 95% confidence interval = 1.7-5.4). Conventional farms were more likely to have Salmonella isolates with greater resistance to streptomycin (odds ratio = 5.4; 95% confidence interval = 1.5-19.0) and sulfamethoxazole (odds ratio = 4.2; 95% confidence interval = 1.2-14.1) using logistic proportional hazards models. Although not statistically significant, conventional farms tended to be more likely to have at least one Salmonella isolate resistant to 5 or more antimicrobial agents when compared with organic farms.

Animals↗
PubMed2005

The mutagenicity testing of tertiary-butyl alcohol, tertiary-butyl acetate and methyl tertiary-butyl ether in Salmonella typhimurium.

Tertiary-Butyl alcohol (TBA), tertiary-butyl acetate (TBAc) and methyl tertiary-butyl ether (MTBE) are chemicals to which the general public may be exposed either directly or as a result of their metabolism. There is little evidence that they are genotoxic; however, an earlier publication reported that significant results were obtained in Salmonella typhimurium TA102 mutagenicity tests with both TBA and MTBE. We now present results of testing these chemicals and TBAc against S. typhimurium strains in two laboratories. The emphasis was placed on testing with S. typhimurium TA102 and the use of both dimethyl sulphoxide and water as vehicles. Dose levels up to 5000 microg/plate were used and incubations were conducted in both the presence and absence of liver S9 prepared from male rats treated with either Arochlor 1254 or phenobarbital-beta-naphthoflavone. The experiments were replicated, but in none of them was a significant mutagenic response observed, thus the current evidence indicates the TBA, TBAc and MTBE are not mutagenic in bacteria.

Acetates↗
PubMed2005

The anticholinergic drug propiverine inhibits the protein kinase C activity in the rat urinary bladder.

UNLABELLED: There is ample evidence that non-cholinergic protein kinase C (PKC) mediated signal transduction pathways are involved into regulation of bladder smooth muscle contractions. To evaluate whether the anticholinergic and calcium modulating drug propiverine exerts intracellular effects by inhibition of the PKC, male inbred LEW 1A rats were pretreated with 0.6, 2, 6 and 60 mg/kg body weight for 5 days. Furthermore, competition assays with partially purified PKC were performed with propiverine in vitro. The activities of the membrane-bound and soluble PKC were assessed by 32P enrichment of lysine-rich histone. RESULTS: The active, membrane-bound PKC decreased by about 60% accompanied by increase of the soluble form after propiverine in doses above 0.6 mg/kg. 100 nM of the drug inhibited the PKC also in vitro whereas the propiverine metabolites M5 and M6 and atropine were without any effect. CONCLUSIONS: Propiverine was identified to be an inhibitor of the protein kinase C. Its contribution to the noncholinergic control of hyperactive detrusor smooth muscle cells needs further investigation.

Animals↗
PubMed2002

Seizure induced dentate neurogenesis does not diminish with age in rats.

Neurogenesis in the mammalian dentate gyrus occurs throughout life, is believed to be important for the laying down of episodic memory and diminishes significantly with increasing age. Pathological insults such as seizures, hypoxia and traumatic brain injury increase dentate neurogenesis compared to age matched controls. Using unilateral intracerebroventricular kainate we show that although baseline neurogenesis is significantly lower in 3 month old rats compared to 1 month old rats, kainate increases neurogenesis to reach similar levels in both age groups. Additionally, this effect is bilateral after a unilateral intracerebroventricular kainate injection. We conclude that the potential for dentate neurogenesis is maintained despite diminishing baseline levels with increasing age and that injury signals override the age related suppression of neurogenesis.

Aging↗
PubMed2001

CCR1-specific non-peptide antagonist: efficacy in a rabbit allograft rejection model.

The classic signs of acute cellular rejection during organ transplantation include the infiltration of mononuclear cells into the interstitium. This recruitment of leukocytes into the transplanted tissue is promoted by chemokines like RANTES. Since RANTES is a potent agonist for the CC chemokine receptor CCR1, we examined whether the CCR1 antagonist BX 471 was efficacious in a rabbit kidney transplant rejection model. BX 471 was able to compete with high affinity with the CCR1 ligands MIP-1alpha and RANTES for binding to HEK 293 cells expressing rabbit CCR1. BX 471 was a competitive antagonist of rabbit CCR1 in Ca(2+) flux studies. Two separate studies in which animals were subcutaneously implanted with slow release pellets of BX 471 demonstrated that animals implanted with BX 471 had increased survival compared with untreated controls or animals implanted with placebo. The mean survival time for the placebo group was 12.33+/-1.7 days. The animals in the BX 471 treated group had mean survival times of 16.9+/-2.1 and 16.0+/-1.7 days, respectively, for the two studies. Analysis of the combined data by Student t-test gave a P value of 0.03 that is significant at the 0.05 level. In addition, there was a marked reduction in the urea and creatinine levels in the BX 471 treated animals compared with the control and placebo groups in both studies. Finally, pathologic analysis of the kidneys in the rabbit renal transplantation model from animals in the different groups showed that BX 471 was similar to cyclosporin in its ability to prevent extensive infarction of transplanted kidneys. Based on the data from these studies, BX 471 shows clear efficacy at the single dose tested compared with animals treated with placebo.

Animals↗
PubMed2001

The biopsychosocial model and spinal cord injury.

OBJECTIVE: To highlight the importance of taking the psychological, social and biological aspects into consideration when dealing with somatic complaints of spinal cord injured patients. SETTING: Supra-regional Spinal Injury Unit in the UK. STUDY DESIGN: Case study series. MATERIAL AND METHODS: The somatic complaints of four patients with spinal cord injury were assessed and their relationship to psychological and social issues were correlated. Two patients suffered unexplained pain, another excessive spasm uncontrolled with intrathecal Baclofen pump and the fourth with several pressure sores, constipation and other physical problems. The impact of psychosocial issues on the somatic complaints were analysed. RESULTS: In all four patients the resolution of their psychosocial issues resulted in significant gains vis-à-vis their somatic complaints. CONCLUSION: Psychological and social issues of spinal injury patients could have a serious impact on the resolution of somatic complaints. It is important to take these into consideration in their treatment.

Adaptation, Physiological↗
PubMed2001

Home monitoring with the ClearPlan Easy Fertility Monitor for fertility awareness.

Many couples planning a pregnancy have had to gauge the best time for sexual intercourse from subjective indications, e.g. cervical mucus changes, or retrospective information, e.g. temperature and calendar methods. Between women, and within a woman, there are considerable variations in menstrual cycle length and underlying hormonal patterns. Although fertility test kits are available, most still rely on visual interpretation by the user. A new combination of immunochemical testing and computing technology is now available in the ClearPlan Easy Fertility Monitor. This paper describes the features of this accurate, simple-to-use, home-based fertility monitor, which gathers data on hormonal patterns and takes account of the individuality of menstrual cycles in women. These data and information about other events, such as sexual intercourse, can be stored in the monitor and accessed by the couple and their medical professional for retrospective review. The monitor is useful for couples who have just started trying to conceive, or those who have been planning a pregnancy for some time.

Estrone↗
PubMed2000

A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection.

Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.

Animals↗
PubMed2000

Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

Administration, Oral↗
PubMed2000

Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor.

The species specificity of a small molecule antagonist for the human CCR1 chemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitrile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and human CCR1, and was able to block the functional activation of these receptors. However, it failed to significantly displace radiolabeled macrophage inflammatory protein-1alpha (MIP-1alpha) binding to mouse CCR1 at concentrations up to 10 microM. These data suggested that the antagonist binding site is well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 were further characterized. CCR1 antagonist 1 blocked the increase in intracellular Ca(2+) stimulated by CCR1 agonists, but had no effect on N-formyl-Met-Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1alpha (SDF1alpha)-induced Ca(2+) mobilization, demonstrating functional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagonist of marmoset and rabbit CCR1 receptors, it should be possible to test its efficacy in animal models of disease.

Amino Acid Sequence↗
PubMed2000

Ophthalmic complications of childhood medulloblastoma.

BACKGROUND: To study the ophthalmic complications and sequelae in children surviving medulloblastoma in order to assess the need for therapeutic intervention by the ophthalmologist. PROCEDURE: We identified all children attending the Leeds General Infirmary and St. James' University Hospital for treatment of medulloblastoma in the period January 1990 to March 1997, and the notes of all surviving patients were reviewed. Those patients who had not had an ophthalmic assessment within the last 6 months were recalled for examination. RESULTS: Twenty-four surviving patients underwent full ophthalmic assessment. The follow-up period ranged between 6 months and 7 years (range 3.6 yr): 66% had ocular symptoms at presentation; 25% developed ocular complications following treatment; 50% were left with ocular sequelae; 41% percent required ophthalmic intervention (25% medical/orthoptic intervention; 16% surgical intervention). CONCLUSIONS: Early (preferably preoperative) referral to the ophthalmology department is important in order to ensure appropriate management of diplopia, preservation of binocular single vision, and prevention of amblyopia in younger children.

Abducens Nerve Diseases↗
PubMed2000

Pediatric orbital floor fracture : direct extraocular muscle involvement.

OBJECTIVE: To study the clinical presentation, operative findings, and postoperative results of a surgical series of isolated orbital floor fractures in children. DESIGN: Noncomparative, retrospective, consecutive case series. PARTICIPANTS: Thirty-four patients (34 orbits) less than 18 years of age with isolated orbital floor fractures. Indications for surgery were severe limitation of extraocular ductions, 22 of 34; enophthalmos, 8 of 34: or both, 4 of 34. INTERVENTION: Surgical repair. MAIN OUTCOME MEASURES: Cause of fracture, symptoms, clinical signs, radiographic data, operative findings, postoperative results, and complications. RESULTS: Children older than 12 years of age were more likely to sustain an orbital floor fracture as a result of interpersonal violence than were children less than 12 years of age (P: = 0.020). Sixty-two percent of patients (21 of 34) exhibited pain with eye movements and/or nausea and vomiting. Most had a trapdoor type fracture (21 of 34). The inferior rectus muscle was entrapped in the orbital floor fracture in 69% (18 of 26) of patients with a severe limitation of ocular ductions. Preoperative nausea and vomiting were immediately relieved after surgery. The median time for improvement of preoperative duction deficits and diplopia was 4 days for patients receiving surgery within 7 days and 10.5 days for those undergoing surgery after 14 days (P: = 0.030). Resolution of duction deficits or diplopia was not dependent on time of surgery if performed within 1 month of injury. Loss of vision, worsening of motility, or implant complications did not occur. CONCLUSIONS: Pediatric patients with isolated orbital floor fractures who had pain, nausea, vomiting, and severe limitation of extraocular motility often have direct entrapment of the inferior rectus muscle into the fracture site. Surgical repair rapidly relieved preoperative pain, nausea, and vomiting. For patients with severe limitation of ductions, early surgical repair within 7 days of injury resulted in more rapid improvement of ductions and diplopia than surgery performed later.

Accidental Falls↗
PubMed1999

Discovery of novel non-peptide CCR1 receptor antagonists.

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.

Anti-Inflammatory Agents↗
PubMed1999

Nitric oxide-dependent ethanol stimulation of ciliary motility is linked to cAMP-dependent protein kinase (PKA) activation in bovine bronchial epithelium.

BACKGROUND: The first line of protection in the lung from the outside environment is provided by the mucociliary apparatus, which continually clears the airways of inhaled microorganisms, dust, and debris. Because alcohol is known to impair airway host defenses, we have examined the effects of ethanol on mucociliary function. In earlier studies, we found that ethanol rapidly and transiently stimulates ciliary motility through a nitric oxide-dependent mechanism. Because many agonists stimulate ciliary motility through activation of cyclic nucleotide-dependent protein kinases, we hypothesized that ethanol stimulates ciliary motility by activating protein kinases. METHODS: Protein kinase activity and ciliary beat frequency (CBF) were assayed in primary cultures of bovine bronchial epithelial cells after exposure to ethanol. RESULTS: Ethanol markedly activated cyclic adenosine monophosphate (cAMP)-dependent protein kinase [protein kinase A (PKA)] at biologically relevant concentrations (20-100 mM), with activation detectable after 15 min and persisting up to 4 hr. Ethanol's PKA activation was blocked by nitric oxide synthase inhibitors, indicating a nitric oxide-dependent pathway, and was also specifically blocked by PKA inhibitors. Ethanol did not directly activate cyclic guanosine monophosphate (cGMP)-dependent protein kinase [protein kinase G (PKG)] in bovine bronchial epithelial cells, but inhibitors of PKG attenuated PKA activation, suggesting a link between PKA activation and PKG activation during ethanol exposure. CBF increased in parallel to PKA activation, suggesting tight coupling between stimulated CBF and PKA activation. CONCLUSION: We conclude that ethanol stimulates CBF through activating PKA in bovine bronchial epithelial cells and we suggest a cooperative mechanism involving PKA and nitric oxide.

Animals↗
PubMed1998

Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor.

The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitri te), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 microM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha, RANTES, and CCR1.

Arthritis, Rheumatoid↗