Assessing potential risk of drugs: the elusive target.
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Aged↗
Biomedical subjects
J K Jones
Publications and source records attributed to J K Jones.
High resolution proton magnetic resonance spectroscopy of cyst fluids from patients with polycystic kidney disease.
High field 1H-NMR spectra of fluid collected from the cysts of six renal transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) have been measured and the major metabolite signals assigned. Quantitative NMR measurements have revealed a combination of unusual biochemical features of the cystic fluids that shows them to be distinct from both blood plasma and urine. Isoleucine, lysine, threonine and valine were present at mM concentrations, in cyst fluid and in some cases levels up to 2 orders of magnitude higher than normal plasma or urine were recorded. Mean glucose concentrations in the cyst fluids ranged from 3.4-9.6 mM and a number of organic acids and bases, including acetate, lactate, succinate, creatinine and dimethylamine were also present at high concentration and in different ratios to those found in either plasma or urine. The majority of cyst fluids examined also contained significant quantities of glycoproteins with characteristic 1H-NMR signals from N-acetyl groups of amino-sugar and sialic acid side chains which had a high degree of molecular mobility (as indicated by their relatively long T2 relaxation times, greater than 120 ms). High levels of ethanol (0.5-12.6 mM/l) were found in all fluid samples from the six transplanted patients (confirmed by conventional analysis). In general there was little variation in the 1H-NMR spectral patterns of either the intra- or interpatient cyst fluids, although the contribution of the protein macromolecules to individual spectra was lower in a few cysts. This constancy of biochemical composition probably reflects the chronic nature of the accumulation of cyst fluid and a long turnover of the cystic fluid components which has the effect of averaging composition. These findings suggest that the dynamic composition of cyst fluid from ADPKD patients is unique among the other body fluids and that the unusual composition may be related to epithelial polarity reversal of the cystic epithelium which could also contribute to the growth of the cysts.
Amino Acids↗
Severe laryngotracheobronchitis complicating measles.
OBJECTIVE: To determine the incidence of severe measles-related laryngotracheobronchitis in patients hospitalized during a recent measles epidemic and to evaluate factors associated with severity of airway injury and its management. DESIGN: Clinical description of patient series. SETTING: Children's hospital and county general hospital, Houston, Tex. PATIENTS: One hundred twenty-four children (aged 1 month to 19 years) admitted with a diagnosis of measles. INTERVENTIONS: None. MEASUREMENTS/RESULTS: Twenty-seven patients had significant laryngotracheobronchitis, including 10 who had not received appropriate immunization. Six patients required endotracheal intubation for relief of upper airway obstruction. The median age of patients requiring intubation was 12 months (range, 4 to 24 months). Two patients died of complications of superinfection. Two patients survived but required prolonged intubation. Two patients underwent early diagnostic laryngoscopy and bronchoscopy and required shorter artificial airway maintenance. CONCLUSIONS: Severe laryngotracheobronchitis frequently occurs in patients younger than 2 years hospitalized with measles and may be related to bacterial or viral super-infection. Early diagnostic laryngoscopy and bronchoscopy for injury assessment and possible endotracheal tube exchange are recommended and, in some severe cases, tracheostomy should be considered to shorten artificial airway maintenance and decrease the incidence of airway complications.
Adolescent↗
The relationship of cigarette smoking to impaired intraoral wound healing: a review of evidence and implications for patient care.
Cigarette smoking has long been suspected to adversely effect wound healing. Review of our experiences with impaired wound healing in patients undergoing intraoral bone grafting and simultaneous implant placement implicated smoking as a potentially significant risk factor. Fifteen consecutive adult patients (5 smokers and 10 nonsmokers) who underwent intraoral bone grafting with simultaneous implant placement were retrospectively reviewed. Five of 15 patients experienced impaired wound healing defined as loss of bone and/or implants. Four of these five (80%) admitted to smoking in the perioperative period. One of 10 nonsmokers experienced problematic healing (10%). Although other factors may have played a role, cigarette smoking is a potentially controllable risk factor strongly associated with problem wounds in this series of patients. Evidence implicating smoking as a risk factor is presented and discussed.
Adult↗
Systemic lupus erythematosus complicated by tricuspid stenosis and regurgitation: successful treatment by valve transplantation.
Clinical tricuspid stenosis has not previously been reported in patients with systemic lupus erythematosus (SLE). A 25 year old woman with active SLE presented with signs of severe right ventricular failure. Cardiac catheterisation confirmed the diagnosis of tricuspid stenosis and regurgitation together with mitral regurgitation. This patient underwent successful tricuspid and mitral valve replacement.
Adult↗
Clinical pharmacology and pharmacoepidemiology: synergistic interactions.
There are many opportunities for synergistic interactions between clinical pharmacology and pharmacoepidemiology. They range from the applications of molecular biology and pharmacogenetics to population studies, and vice versa, to population pharmacokinetics, to the evolution of well-designed, large scale clinical trials in less contrived settings. Ultimately, the synergy can contribute to intelligent and hopefully more efficient drug development, and when a drug goes to market, a better understanding of what will happen.
Epidemiology↗
Progestins and breast cancer: an epidemiologic review.
OBJECTIVE: To provide a worldwide review of all studies that have examined the relationship between progestins, as contained in both contraceptive and postmenopausal replacement therapies, and breast cancer risk. An overview of utilization patterns for progestins, as well as a review of possible biological mechanisms for progestins' action on breast tissue, are also presented. DATA IDENTIFICATION: All major epidemiologic studies conducted since 1980 have been identified through MEDLINE searches through the published literature and personal communications with prominent researchers in the area. STUDY SELECTION: Only studies that specifically examined the effects of progestin use are discussed here; these include investigations of progestins, in combination or singularly, as the main hypothesis or a subgroup analysis. RESULTS: The majority of studies have examined combination estrogen and progestin products (oral contraceptives), and subgroup analyses of progestins have been impeded by low statistical power and the fact that each progestin possesses different types of pharmacological activity. Only a few studies of long-acting injectable progestins exist, confirming a general lack of specific information on the progesterone-breast cancer relationship. Investigations of the effect on breast cancer of the addition of progestins to postmenopausal replacement therapy have also produced inconsistent results. CONCLUSIONS: To date, there is no consistent evidence of an association between progestins and breast cancer. There is need for further study, particularly of patients in potentially high-risk groups, including those with (1) extended hormone exposure before age 25 and/or first full term pregnancy and (2) exposure in the postmenopausal period.
Breast Neoplasms↗
Comparison of proteoglycans synthesized by porcine normal and polycystic renal tubular epithelial cells in vitro.
Newly synthesized porcine tubular epithelial cell proteoglycans were labeled in vitro with Na2[35S]SO4. At the beginning of the labeling period (24 h) [35S] sulfate incorporated into macromolecules was measured following PD-10 chromatography. There was a significant reduction in the amount of 35S-labeled macromolecules isolated from polycystic cells compared to that from normal cells. The distribution of recovered radiolabeled material among the medium, cell surface, and intracellular fractions was similar for both normal and polycystic cells. Analysis of the proteoglycans in polycystic cells demonstrated that 86 and 73% of 35S-labeled macromolecules were of the heparan sulfate type in polycystic and normal cells, respectively. The remainder was chondroitin sulfate. Proteoglycans were characterized using DEAE-Sephacel ion-exchange chromatography, chondroitinase ABC, heparitinase, and nitrous acid digestion followed by Sepharose CL-4B gel permeation chromatography. The majority of radiolabeled material in the medium, cell surface, and intracellular fractions eluted between 0.35 and 0.39 M NaCl. However, a second peak (peak II) that eluted at 0.25 M NaCl was found in the medium from polycystic cells. This peak accounted for 27% of the total macromolecules secreted into the medium. Proteoglycans in the major peak were susceptible to nitrous acid and chondroitinase ABC digestion. A similar proportion of peak II was degraded by chondroitinase ABC. However, the remainder was only slightly susceptible to treatment with nitrous acid or heparitase. In normal cells a small amount of material eluted at a similar low charge; the proteoglycans were the same as those found in the major peak and appeared as a shoulder on this peak.
Animals↗
A preliminary report of arthroscopic findings following acute condylar trauma.
Standard therapy in orthopedics dictates that joints with suspected hemarthrosis be considered for irrigation or exploration, especially when immobilization is part of the treatment plan. In this preliminary report, 14 patients who had condylar/subcondylar fractures underwent superior joint space arthroscopy as part of the evaluation and treatment of their fractures. In all but two patients, blood was found in the superior joint space. Length of time from injury to time of examination correlated with the quantities of blood found. The severity and direction of the blow seemed to influence the findings in the joints. Synovial ecchymosis was a consistent finding. The disc appeared to be grossly intact and within the glenoid fossa in all cases, even when the condyle was grossly displaced. These findings raise questions about the role of direct disc injury as a source of postoperative temporomandibular joint (TMJ) symptoms, as well as about the practice of immobilization of fractures immediately after trauma. Further studies will be necessary to compare the treatment results in patients who have had arthroscopy versus those who have not.
Arthroscopy↗
Facial nerve injuries associated with orthognathic surgery: a review of incidence and management.
While facial nerve injuries associated with both extraoral and intraoral orthognathic surgery are rare, the results of such an injury can be devastating to the patient. A review of the literature shows that the majority of such injuries fall into the first-, second-, and third-degree injury categories. Prevention cannot be stressed enough; however, early recognition of an injury with prompt electrodiagnostic testing can assist with determining prognosis and treatment planning. When close observation is indicated, a variety of medical therapies have been suggested. For more severe injuries, nerve repair and facial reanimation have been reported.
Anastomosis, Surgical↗
A view from the drug utilization review management organization sector.
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Data Collection↗
Bulimia: determining prevalence and examining intervention.
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Adolescent↗
Rigid fixation: a review of concepts and treatment of fractures.
Rigid fixation has been given considerable attention in the current literature. The concepts of treatment and the philosophies of the different systems vary, as do the results reported by different authors. This article reviews the basic tenets of rigid fixation and points out where systems are similar or diverge. Advantages and disadvantages of each system are covered.
Bone Screws↗
The role of bacterial-laden biofilms in infections of maxillofacial biomaterials.
Biomaterials from 11 consecutive patients with persistent infections refractory to antimicrobial therapy and local wound care were surgically removed and studied by scanning electron microscopy for the presence of bacterial-laden biofilms. Unlike previously reported biomaterial infections involving other regions of the body, infections in this study were not associated with a conspicuous bacterial-laden biofilm. Instead, adherent light bacterial colonization without a biofilm layer was noted. The only specimen that was suggestive of a bacterial-laden biofilm was in a patient who suffered from a chronic infection. Consistent with previous reports, bacterial colonization was frequently polymicrobial. Observations made in this study suggest that bacterial adherence may not require an obvious biofilm layer.
Adolescent↗
Definition of events associated with drugs: regulatory perspectives.
Drug regulations in the United States require that all clinical events reported associated with a marketed drug be collected by the manufacturer and provided to the regulatory agency. In the clinical setting, many factors determine (a) the likelihood of an event being detected, (b) the attribution of the event to the drug, and (c) the actual spontaneous reporting of the drug event association to the manufacturer, regulator or to the literature. In formal postmarketing trials to collect information on events occurring in drug exposed patients, the events detected are greatly determined by characteristics of the trial design. The further analysis of events suspected to be adverse drug effects is described. Once an adverse effect is hypothesized, a number of factors will determine whether it can be further studied in a meaningful, cost effective way.
Algorithms↗
A new colon carcinoma cell line (LIM1863) that grows as organoids with spontaneous differentiation into crypt-like structures in vitro.
A new colon carcinoma cell line (LIM1863) has been characterized. This cell line is unique in that the culture consists of organoids which are morphologically and functionally organized. Histological studies of the organoids show that the cells are arranged around a central lumen and the nuclei are polarized to the periphery. Two major morphological types are present: a columnar cell with a polarized, structurally normal brush border and goblet cells. The cells are also functionally mature and express the brush border enzymes aminopeptidase N, dipeptidyl peptidase IV, alkaline phosphatase, and sucrase-isomaltase. These enzymes are localized to the luminal membrane and the apical cytoplasm (of some cells). The goblet cells contain mucus and this mucus is secreted into the lumen. This functional differentiation suggests that the organoids contain precursor cells capable of differentiating along both the columnar and goblet cell pathways. At present no endocrine cells have been detected by morphological or histochemical analysis. The organoids have been in continuous culture with regular passaging for 21 months and also grow and differentiate normally in serum-free medium.
Aged↗
A Bayesian approach to causality assessment.
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Bayes Theorem↗
The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.
To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.
Anti-Inflammatory Agents, Non-Steroidal↗