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Biomedical subjects

K Holmes

Publications and source records attributed to K Holmes.

At least 19 recordsLinked to original sources
PubMed2002

Quantitative and qualitative analysis of gastroesophageal reflux after percutaneous endoscopic gastrostomy.

BACKGROUND/PURPOSE: Percutaneous endoscopic gastrostomy (PEG) is of great benefit to a defined population of children, but gastrostomy has been implicated in causation or exacerbation of gastroesophageal reflux (GER). The aim of this study was to quantitatively and qualitatively analyze the effect of PEG on GER. METHODS AND MATERIAL: Sixty-four children mean age 6.7 +/- 4.2 years, most of whom were impaired neurologically were evaluated for GER after PEG between 1998 and 2000. Twenty-four-hour pH monitoring was used for quantitative assessment. Qualitative analysis was by interview to record the following: vomiting, choking, chest infection, and weight gain. RESULTS: Twenty-four hour pH monitoring was performed 9.4 +/- 1.2 weeks after PEG. Patients underwent follow-up for 18 +/- 6 months. Seventy-two percent who did not have reflux before PEG remained reflux free. Fourteen percent who had GER before PEG continued to have reflux (P <.05). Only 5% of patients without GER before PEG had reflux afterward, and 3% of patients with preexisting GER deteriorated (P >.05). Six percent of patients with preexisting GER improved post-PEG. Of the 14 patients (22%) who had or continued to have reflux after PEG, 11 of 14 (79%) underwent antireflux surgery, and 21% were managed successfully by intensive medical treatment and change of feeding regimen. Only 6% experienced difficulties and complications with the device. Forty-eight percent of patients did not vomit pre- or postoperation. In 16%, vomiting improved post-PEG, whereas 14% experienced minor deterioration (1 to 2 vomits per month). Major deterioration was experienced by 22%. Weight gain occurred in 77%, and in 23% there was no loss of weight. There was an overall improvement in quality of life in 88% after PEG. Overall improvement in quality of life post-PEG, post-antireflux surgery and post-intensive medical management for pathologic GER was 94%. CONCLUSIONS: (1) PEG did not precipitate or exacerbate GER quantitatively or qualitatively in the majority of children. (2) A normal 24-hour pH study predicted a favourable outcome after PEG. (3) An abnormal preoperation pH study predicted persistence or worsening reflux after PEG, but not all of these patients required an antireflux procedure. (4) GER is not a contraindication to PEG, the overall benefits of which outweigh the risks.

Acute Disease↗
PubMed2001

Combinatorial synthesis of CCR5 antagonists.

Herein we report the preparation of a combinatorial library of compounds with potent CCR5 binding affinity. The library design was aided by SAR generated in a traditional medicinal chemistry effort. Compounds with novel combinations of subunits were discovered that have high binding affinity for the CCR5 receptor. A potent CCR5 antagonist from the library, compound 11 was found to have moderate anti-HIV-1 activity.

CCR5 Receptor Antagonists↗
PubMed2001

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes.

(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.

Animals↗
PubMed2001

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1: discovery and initial structure-activity relationships for 1 -amino-2-phenyl-4-(piperidin-1-yl)butanes.

Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.

Animals↗
PubMed2001

Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure-activity relationships for substituted 2-Aryl-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes.

(2S)-2-(3,4-Dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (3) has been identified as a potent CCR5 antagonist lead structure having an IC50 = 35 nM. Herein, we describe the structure-activity relationship studies directed toward the requirement for and optimization of the C-2 phenyl fragment. The phenyl was found to be important for CCR5 antagonism and substitution was limited to small moieties at the 3-position (13 and 16: X= H, 3-F, 3-Cl, 3-Me).

Animals↗
PubMed2001

Pyridoxine improves endothelial function in cardiac transplant recipients.

BACKGROUND: Endothelial dysfunction is common in cardiac transplant recipients and predicts the development of transplant coronary artery disease. Hyperhomocysteinemia is associated with endothelial dysfunction in the general population, is common in transplant recipients, and has been associated with transplant coronary artery disease. Thus therapy that decreases homocysteine concentrations might also improve endothelial function and decrease the risk of transplant coronary artery disease. Folate and pyridoxine are important cofactors in distinct aspects of homocysteine metabolism. The purpose of this study was to determine whether folate or pyridoxine supplementation improves endothelial function in cardiac transplant recipients. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled trial. We assigned 31 transplant recipients to either pyridoxine (n = 11:100 mg/day), folate (n = 12:5 mg/day), or placebo (n = 8) for 10 weeks. Fasting and post-methionine-load (methionine 100 mg/kg orally) homocysteine concentrations were determined. Brachial artery flow-mediated dilatation was used as a measure of endothelial function. At follow-up, we noted no significant changes in homocysteine concentrations in any of the groups. However, pyridoxine supplementation was associated with a significant improvement in endothelial function (2.8 +/- 6.7 to 6.9 +/- 6.3, p = 0.05). No significant changes were seen in patients treated with folate or placebo. CONCLUSIONS: Pyridoxine, but not folate supplementation, significantly improves endothelial function in cardiac transplant recipients.

Double-Blind Method↗
PubMed2000

Currarino triad--diagnostic dilemma and a combined surgical approach.

PURPOSE: The authors present 2 families with 3 cases of Currarino triad, diagnostic difficulties, their familial occurrence, and genetic mapping, with emphasis on a combined pediatric surgical and pediatric neurosurgical approach in managing these children. RESULTS: The main presentation was intractable constipation. In the first family there was a 4-generation pedigree with recurrence of Currarino triad. The mother and the child have the condition. Family 2 screening showed a 3-generation pedigree with presence of Currarino triad in 3 members. Patients 2 and 3 are cousins whose fathers are affected by spina bifida occulta and Currarino triad, respectively. In patient 1, the diagnosis was made after inadvertent rupture of an anterior meningocele during posterior myectomy. In patient 2, the presacral mass was found on examination under anesthesia, and the planned anorectal myectomy for intractable constipation was abandoned. Patient 3 was a cousin of patient 2, and the diagnosis was considered when she presented with intractable constipation at the age of 7 months. Magnetic resonance scan was useful in showing the presence of presacral mass, spinal abnormalities, and tethered cord. A combined pediatric and neurosurgical approach optimized the extirpation of the presacral mass with minimal complications. Surgical treatment was individualized according to the estimation of the operative risk factors. All patients have a normal bladder function. Patient 1 has required laxatives and enemas for intermittent constipation. She has associated learning difficulties but is otherwise well. Patient 2 and 3, aged 10 and 2 years, respectively, are awaiting closure of colostomy. They are thriving and well. CONCLUSIONS: The authors recommend a combined pediatric and neurosurgical assessment and management for all cases of Currarino triad. Family screening is obligatory. The authors suggest the use of a magnetic resonance scan or computerized axial tomography myelogram to define the presence of anosacral and spinal cord anomalies in patients with intractable constipation.

Anal Canal↗
PubMed1997

Minimally invasive direct coronary artery bypass surgery.

Traditional coronary artery bypass surgery involves a median sternotomy and the use of a heart-lung machine to stabilize the heart during suturing. Minimally invasive coronary artery surgery employs small incisions directly over the target vessels and avoids the use of a heart-lung machine, which can cause postoperative complications. The target coronary vessels are stabilized in alternative ways, potentially hazardous manipulation of the ascending aorta is avoided, and the subclavian and axillary arteries provide alternative inflow sources. Other new techniques used in minimally invasive procedures include a coronary artery cannula to avoid intraoperative ischemia and wound irrigation catheters to administer postoperative bupivacaine hydrochloride. Perioperative nurses need to become familiar with these new techniques to be able to plan and implement effective patient care.

Coronary Artery Bypass↗
PubMed1997

Right thoracotomy approach to mitral valve surgical procedures.

The right thoracotomy approach to mitral valve surgical procedures allows surgeons to achieve excellent, rapid exposures of mitral annuli; facilitates the excision of diseased mitral valves; avoids injury to previously placed coronary artery bypass grafts; and aids surgeons with the insertion of valve prostheses. This approach is especially appropriate for patients with anatomic deviations (e.g., deep chest cavities, counterclockwise rotations of the heart) and hostile mediastina (i.e., previously opened mediastina with severe adhesions around the heart and posterior side of the sternum). This article discusses mitral valve disease, compares the right thoracotomy approach to median sternotomy, describes perioperative nursing care of patients undergoing mitral valve surgical procedures, and presents a case study.

Female↗
PubMed1995

Agonist action of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) in the amygdala.

Glutamatergic excitatory postsynaptic potentials (EPSPs) in the basolateral amygdala (BLA) are reduced in amplitude following agonist activation of presynaptic metabotropic glutamate receptors (mGluR). In this study, the effect of a presumed mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), was investigated on the EPSP recorded intracellularly in BLA neurons. Superfusion of MCPG (500 microM) significantly reduced the amplitude of evoked EPSPs. In the presence of MCPG, postsynaptic responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA, 1 microM) were unaltered while responses to N-methyl-D-aspartate (NMDA, 3-5 microM) were potentiated. These data suggest that the MCPG-induced reduction of EPSP amplitude is due to a mGluR agonist action at a presynaptic mGluR 'autoreceptor'.

Amygdala↗
PubMed1995

Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency.

Breast milk samples from human immunodeficiency virus type 1 (HIV-1)-seropositive women were analyzed by polymerase chain reaction to determine the prevalence and determinants of HIV-1-infected cells in breast milk. Breast milk samples (212) were collected from 107 women, and 58% of the samples had detectable HIV-1 DNA. The proportion of HIV-1-infected cells in the milk samples ranged from 1 to 3255/10(4) cells. Breast milk samples with detectable HIV-1 DNA were more likely to be from women with absolute CD4 cell counts of < 400 (odds ratio, 3.1; 95% confidence interval [CI], 1.5-7.0). Severe vitamin A deficiency (< 20 micrograms/dL) was associated with a 20-fold increased risk of having HIV-1 DNA in breast milk among women with < 400 CD4 cells/mm3 (95% CI, 2.1-188.5). Women with CD4 cell depletion, especially those with vitamin A deficiency, may be at increased risk of transmitting HIV-1 to their infants through breast milk.

Adolescent↗
PubMed1994

B cells from M167 mu kappa transgenic mice fail to proliferate after stimulation with soluble anti-Ig antibodies. A model for antigen-induced B cell anergy.

The transgenic (TG) mouse strain 207-4, carries mu a + kappa transgenes ligated to the anti-phosphocholine (PC) VH1 and V kappa 24 V region genes from the MOPC-167 myeloma. Although B cells from mice carrying these transgenes respond both in vivo and in vitro to thymus-dependent Ags, they failed to proliferate in response to soluble goat anti-mu Ab or other soluble anti-Ig reagents. On the other hand, B cells from the Sp6 mu kappa anti-trinitrophenyl TG mouse line proliferated normally after stimulation with soluble anti-mu. However, the 207-4 anti-PC transgene positive (TG+) splenic B cells proliferated when stimulated with anti-mu, anti-idiotype, anti-allotype, or PC-conjugated to Sepharose beads. TG+ B cells were also induced to proliferate when stimulated with anti-Lyb-2; thus, their defect may be restricted to signaling through sigM. The lack of response to soluble anti-mu could not be reversed by addition of IL-4, by removal of T cells, by addition of anti-FcR Ab, or by stimulation with F(ab')2 anti-mu. Thus, the failure to proliferate was not caused by active T cell suppression or FcR-mediated inhibition. In mixed cultures of TG+ and transgene negative (TG-) spleen cells, the TG- cells were able to proliferate normally to soluble anti-mu, indicating that suppressive factors were not involved in the unresponsiveness of the TG+ anti-PC-specific B cells. These studies suggest that B cells in the 207-4 anti-PC TG mice exhibit a defect in activation through their sIgM receptors, and this unresponsiveness may reflect a form of Ag-induced tolerance.

Animals↗
PubMed1994

Peptidoglycan isolated from nontypeable Haemophilus influenzae induces experimental otitis media in the chinchilla.

Bacterial cell wall components induce a number of biologic effects and promote inflammatory changes in a variety of hosts. Peptidoglycan isolated from Streptococcus pneumoniae can induce inflammation in the middle ear; however, an analogous role for peptidoglycan derived from gram-negative otitis media pathogens has not been described. Peptidoglycan isolated from nontypeable Haemophilus influenzae (NTHi), a major cause of otitis media, was evaluated in a chinchilla model. The direct injection of the middle ear with 3-300 micrograms of peptidoglycan resulted in tympanic membrane inflammation, abnormal pressure in the middle ear, leukocytosis, and histopathologic changes in the middle ear mucosa that included marked edema, osteoneogenesis, focal hemorrhage, and a mononuclear infiltration into the subepithelial space. These data indicate that NTHi peptidoglycan induced inflammation and histopathologic changes in the tympanic membrane and middle ear mucosal epithelium and may contribute to the pathogenesis of otitis media.

Animals↗
PubMed1994

Preparation for AIDS vaccine evaluation in Mombasa, Kenya: establishment of seronegative cohorts of commercial sex workers and trucking company employees.

In preparation for human immunodeficiency virus (HIV) prophylactic vaccine trials, prospective cohorts of HIV seronegative female commercial sex workers and male trucking company employees were established in Mombasa, Kenya, with the aims of defining HIV seroincidence and correlates of HIV seroconversion. Female and male cohorts were followed at 1- and 3-month intervals, respectively, with questionnaires, physical examinations, evaluation for sexually transmitted diseases, and HIV serologic testing. Between February and September, 1993, 1,277 women and 748 men were tested for antibodies to HIV-1. Seroprevalence was 55.4% among commercial sex workers and 17.7% among trucking company employees. Three hundred fifty-two HIV-seronegative women and 507 seronegative men were enrolled in the cohort studies. Annualized seroincidence rates of HIV infection were 16.4% (95% CI 8.8-27.0) among commercial sex workers and 6.6% (95% CI 2.5-13.8) among trucking company employees. These cohorts may be valuable resource for evaluating HIV vaccines and other potential preventive interventions.

AIDS Vaccines↗