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1.
BJS Open ; 5(5)2021 09 06.
Article in English | MEDLINE | ID: mdl-34518869

ABSTRACT

BACKGROUND: In patients with active Crohn's disease (CD), treatment of intra-abdominal abscess usually comprises antibiotics and radiologically guided percutaneous drainage (PD) preceding surgery. The aim of this study was to investigate the risk of postoperative complications and identify the optimal time interval for surgical intervention after PD. METHODS: A multicentre, international, retrospective cohort study was carried out. Details of patients with diagnosis of CD who underwent ultrasonography- or CT-guided PD were retrieved from hospital records using international classification of disease (ICD-10) diagnosis code for CD combined with procedure code for PD. Clinical variables were retrieved and the following outcomes were measured: 30-day postoperative overall complications, intra-abdominal septic complications, unplanned intraoperative adverse events, surgical-site infections, sepsis and pathological postoperative ileus, in addition to abscess recurrence. Patients were categorized into three groups according to the length of the interval from PD to surgery (1-14 days, 15-30 days and more than 30 days) for comparison of outcomes. RESULTS: The cohort comprised 335 CD patients with PD followed by surgery. Median age was 33 (i.q.r. 24-44) years, 152 (45.4 per cent) were females, and median disease duration was 9 (i.q.r. 3.6-15) years. Overall, the 30-day postoperative complications rate was 32.2 per cent and the mortality rate was 1.5 per cent. After adjustment for co-variables, older age (odds ratio 1.03 (95 per cent c.i. 1.01 to 1.06), P < 0.012), residual abscess after PD (odds ratio 0.374 (95 per cent c.i. 0.19 to 0.74), P < 0.014), smoking (odds ratio 1.89 (95 per cent c.i. 1.01 to 3.53), P = 0.049) and low serum albumin concentration (odds ratio 0.921 (95 per cent c.i. 0.89 to 0.96), P < 0.001) were associated with higher rates of postoperative complications. A short waiting interval, less than 2 weeks after PD, was associated with a high incidence of abscess recurrence (odds ratio 0.59 (95 per cent c.i. 0.36 to 0.96), P = 0.042). CONCLUSION: Smoking, low serum albumin concentration and older age were significantly associated with postoperative complications. An interval of at least 2 weeks after successful PD correlated with reduced risk of abscess recurrence.


Subject(s)
Abdominal Abscess , Crohn Disease , Abdominal Abscess/diagnostic imaging , Abdominal Abscess/etiology , Abdominal Abscess/surgery , Adult , Aged , Crohn Disease/complications , Crohn Disease/surgery , Drainage , Female , Humans , Retrospective Studies , Waiting Lists
2.
Ann Surg Oncol ; 26(4): 1103-1109, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30746598

ABSTRACT

BACKGROUND: This study aimed to examine the correlation between intraoperative and pathological findings for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and to determine their prognostic significance. METHODS: Pathological reports of all colorectal cancer (CRC) patients undergoing CRS/HIPEC between 2009 and 2016 were retrospectively reviewed. Pathological specimens lacking tumor cells were defined as negative pathological specimens (NPS). The intraoperative peritoneal cancer index (PCI) and pathological PCI (excluding NPS) were calculated separately. Receiver operating characteristic (ROC) curves were applied to compare the prognostic value of intraoperative and pathological scoring systems. RESULTS: For 108 CRC patients, 113 CRS/HIPEC procedures were performed. Of 959 pathological specimens examined, 178 (18.6%) were NPS. Overall, 78 procedures (69%) showed NPS. In 52 procedures (46%), the pathological PCI differed from the intraoperative PCI (∆PCI > 0). The ROC areas for intraoperative PCI and pathological PCI were similar in predicting 1-year overall survival (OS), 2-year OS, and 1-year disease-free survival (all p values not significant). However, for the patients with NPS, the number of positive specimens (containing tumor tissue) was superior to intraoperative PCI in predicting 2-year OS (ROC under the curve areas, 0.69 vs. 0.58, respectively; p = 0.012). In addition, a subgroup of 15 patients with a high ∆PCI (≥ 3) had a more favorable median OS than a matched group of 30 patients with similar intraoperative PCI and a ∆PCI of 0 (median survival not reached vs. 21.6 months, respectively; p = 0.05). CONCLUSIONS: In the majority of CRC CRS/HIPEC procedures, NPS may be found. Among patients with NPS, pathological correlation may have a prognostic significance.


Subject(s)
Chemotherapy, Cancer, Regional Perfusion/methods , Colorectal Neoplasms/pathology , Cytoreduction Surgical Procedures/methods , Hyperthermia, Induced/methods , Peritoneal Neoplasms/secondary , Colorectal Neoplasms/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Intraoperative Care , Male , Middle Aged , Peritoneal Neoplasms/therapy , Prognosis , Prospective Studies , Retrospective Studies , Survival Rate
3.
World J Surg ; 42(7): 2036-2042, 2018 07.
Article in English | MEDLINE | ID: mdl-29302727

ABSTRACT

BACKGROUND: Formation of protective stoma as part of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) may be an effective tool in reducing anastomotic leak incidence. Our aim was to evaluate the incidence and implications of stoma formation during CRS-HIPEC and to examine whether a creation of protective stoma reduces the postoperative morbidity. METHODS: A cohort retrospective analysis of all CRS-HIPEC procedures performed between 2004 and 2016 was conducted. Predicting factors for stoma formation were assessed by comparing all patients who underwent stoma formation to those who did not; both groups were then restricted to cases with ≥2 bowel anastomoses and compared in terms of perioperative outcomes in order to determine whether protective stoma confers a morbidity benefit. RESULTS: One hundred and ninety-nine CRS-HIPEC procedures were performed on 186 patients. Thirty-four patients (17%) underwent stoma formation, 24 of them as protective stoma. Formation of a stoma was correlated with higher peritoneal carcinomatosis index score (13.6 ± 8 vs. 9.5 ± 7.7, p = 0.007), larger number of organs resected (p < 0.001), greater number of anastomoses (p < 0.001), prolonged operative time (8.1 ± 2.7 vs. 6.6 ± 2.2 h, p = 0.002), and prolonged hospital stay (12 vs. 8.5 days, p = 0.001). In procedures requiring ≥2 anastomoses, formation of protective stoma reduced the anastomotic leak rate (6 vs. 37%, p = 0.025), the morbidity rate (6 vs. 41%, p = 0.017), and reoperation rate (0 vs. 28%, p = 0.03). Overall, 15 patients (44%) underwent stoma reversal, 3 of whom had a complication treated non-operatively. CONCLUSIONS: Protective stoma should be considered in extensive CRS-HIPEC procedures requiring two or more bowel anastomoses in order to reduce the postoperative morbidity rate.


Subject(s)
Anastomotic Leak/prevention & control , Carcinoma/therapy , Chemotherapy, Cancer, Regional Perfusion , Cytoreduction Surgical Procedures/methods , Hyperthermia, Induced , Peritoneal Neoplasms/therapy , Adult , Aged , Anastomotic Leak/epidemiology , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Reoperation/statistics & numerical data , Retrospective Studies , Treatment Outcome
4.
Eur Psychiatry ; 28(6): 340-3, 2013 Aug.
Article in English | MEDLINE | ID: mdl-22999435

ABSTRACT

BACKGROUND: Discontinuation of antipsychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative-subjective response to antipsychotics, which is composed of the subjective experience of negative drug effects and attitude towards the treatment. OBJECTIVE: To investigate the elements of subjective experience and subjective attitude towards specific drug-related adverse effects, leading to a generally negative-subjective attitude towards antipsychotics. METHODS: Schizophrenia inpatients (n=84) were administered a questionnaire measuring attitude and experience on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology. RESULTS: Weak correlation was found between subjective experience and attitude on most of the subscales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06-3.3, df=1, χ(2)=4.525, P<0.05). CONCLUSION: Negative attitude towards most adverse drug effects did not correlate with personal experience. Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse.


Subject(s)
Antipsychotic Agents/therapeutic use , Attitude , Schizophrenia/drug therapy , Weight Gain/drug effects , Adult , Affect/drug effects , Antipsychotic Agents/adverse effects , Female , Humans , Male , Middle Aged , Schizophrenic Psychology
6.
Science ; 293(5529): 430-3, 2001 Jul 20.
Article in English | MEDLINE | ID: mdl-11463897

ABSTRACT

Clear and quantitative discussion of uncertainties is critical for public policy making on climate change. The recently completed report of the Intergovernmental Panel on Climate Change assessed the uncertainty in its findings and forecasts. The uncertainty assessment process of the IPCC should be improved in the future by using a consistent approach to quantifying uncertainty, focusing the quantification on the few key results most important for policy making. The uncertainty quantification procedure should be fully documented, and if expert judgment is used, a specific list of the experts consulted should be included.

7.
JAMA ; 286(24): 3115-9, 2001 Dec 26.
Article in English | MEDLINE | ID: mdl-11754677

ABSTRACT

CONTEXT: Millions of assays are performed each year to monitor for substance abuse in various settings. When common medications cross-react with frequently used testing assays, false-positive results can lead to invalid conclusions. OBJECTIVE: To evaluate cross-reactivity of quinolone antimicrobials in common opiate screening assays and to assess the in vivo implications of this phenomenon. DESIGN, SETTING, AND PARTICIPANTS: The reactivity of 13 quinolones (levofloxacin, ofloxacin, pefloxacin, enoxacin, moxifloxacin, gatifloxacin, trovafloxacin, sparfloxacin, lomefloxacin, ciprofloxacin, clinafloxacin, norfloxacin, and nalidixic acid) was tested in 5 commercial opiate screening assays from September 1998 to March 1999. In 6 healthy volunteers, we confirmed the cross-reactivity of levofloxacin or ofloxacin with these opiate screening assays. MAIN OUTCOME MEASURE: Opiate assay activity (threshold for positive result, 300 ng/mL of morphine). RESULTS: Nine of the quinolones caused assay results above the threshold for a positive result in at least 1 of the assays. Four of the assay systems caused false-positive results for at least 1 quinolone. Eleven of the 13 compounds caused some opiate activity by at least 1 assay system. At least 1 compound caused opiate assay activity in all 5 assay systems. Levofloxacin, oflaxacin, and perfloxacin were most likely to lead to a false-positive opiate result. Positive results were obtained in urine from all 6 volunteers. CONCLUSION: Greater attention to the cross-reactivity of quinolones with immunoassays for opiates is needed to minimize the potential for invalid test interpretation.


Subject(s)
Anti-Infective Agents/metabolism , Opioid-Related Disorders/diagnosis , Substance Abuse Detection , 4-Quinolones , Cross Reactions , False Positive Reactions , Humans , Immunoassay , Opioid-Related Disorders/urine , Urinalysis
8.
Aliment Pharmacol Ther ; 14(6): 669-90, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10848650

ABSTRACT

Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.


Subject(s)
Alginates/pharmacology , Aluminum Hydroxide/pharmacology , Antacids/pharmacology , Gastroesophageal Reflux/drug therapy , Heartburn/drug therapy , Silicic Acid/pharmacology , Sodium Bicarbonate/pharmacology , Adult , Alginates/chemistry , Alginates/metabolism , Alginates/therapeutic use , Aluminum Hydroxide/therapeutic use , Antacids/therapeutic use , Carbon Dioxide/metabolism , Child , Cost-Benefit Analysis , Drug Combinations , Female , Gastric Acid/metabolism , Humans , Infant , Infant, Newborn , Male , Pregnancy , Pregnancy Complications/diagnosis , Proton Pumps/physiology , Silicic Acid/therapeutic use , Sodium Bicarbonate/therapeutic use
9.
AIDS Res Hum Retroviruses ; 16(4): 337-43, 2000 Mar 01.
Article in English | MEDLINE | ID: mdl-10716371

ABSTRACT

A 32-amino acid HIV-1 Gag immunogen was assessed for its ability to augment existing virus-specific CTL responses in chronically HIV-1-infected individuals. The immunogen was an HIV-1 synthetic lipopeptide conjugate composed of an N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R)-propyl-N-(R)-cysteinyl] group covalently coupled to a synthetic 32-amino acid Gag peptide containing at least 5 CTL epitopes known to be restricted by HLA-A33, -B8, -B27, -B35, and -Bw62. This potential immunotherapeutic was first determined to be safe in six HIV-1-seropositive subjects, with no adverse clinical effects noted during a 182-day period after administration of a dose of 350 microg. The immunogenicity of this lipopeptide conjugate was then assessed in a pilot study in nine HIV-1-seropositive volunteers with peripheral blood CD4+ lymphocyte counts of >500/microl. Three groups of individuals were studied: HLA-selected subjects who received 350 microg of the immunogen on days 0, 28, and 56 (four subjects); HLA-selected subjects who received a placebo according to a similar inoculation schedule (three subjects); and HLA-mismatched subjects who received the experimental immunogen (two subjects). All subjects were monitored for 26 weeks. After treatment, PBLs from two of the four HLA-selected subjects who received the experimental immunogen showed a transient increase in Gag peptide-specific bulk CTL activity. None of the placebo-vaccinated or vaccinated HLA-mismatched subjects showed any change in bulk Gag peptide-specific CTL activity. However, no consistent decrease in plasma HIV-1 RNA levels was noted in any of the subjects. The present study illustrates that this peptide formulation may not be a sufficiently potent immunogen to significantly augment HIV-1-specific CTLs and to decrease virus load in HIV-1-seropositive individuals.


Subject(s)
AIDS Vaccines/therapeutic use , Gene Products, gag/therapeutic use , HIV Infections/immunology , HIV Infections/therapy , HIV-1/immunology , Lipoproteins/therapeutic use , AIDS Vaccines/chemistry , AIDS Vaccines/immunology , Adult , Amino Acid Sequence , Cytotoxicity Tests, Immunologic , Epitopes, T-Lymphocyte , Gene Products, gag/chemistry , Gene Products, gag/immunology , HIV Infections/virology , Humans , Lipoproteins/chemistry , Lipoproteins/immunology , Male , Molecular Sequence Data , Peptides/chemistry , Peptides/immunology , Peptides/therapeutic use , Pilot Projects , T-Lymphocytes, Cytotoxic/immunology , Vaccination , Viral Load
10.
Eff Clin Pract ; 2(3): 101-7, 1999.
Article in English | MEDLINE | ID: mdl-10538257

ABSTRACT

OBJECTIVE: To determine if the length of hospital stay could be reduced for patients with AIDS by performing screening head and abdominal-pelvic computed tomography (CT) scans within 24 hours of admission, regardless of presenting signs and symptoms. DESIGN: Randomized, prospective trial. SETTING: Tertiary, academic medical center. PATIENTS: On presentation to the emergency department, 42 patients with AIDS were identified as being eligible to participate in our study. Twenty-two patients consented to participate and were assigned to screening CT or control group. INTERVENTION: Patients assigned to the screening CT group had head and abdominal-pelvic CT scans within 24 hours of admission, regardless of presenting signs or symptoms. The findings of the screening CT scans were immediately communicated to the patient's referring physician. Patients assigned to the control group had CT studies done solely at the discretion of their physician. MAIN OUTCOME MEASURE: Length of stay for patients in the screening CT and control groups. RESULTS: The average length of stay for patients in the screening CT group was 1.3 days longer than the average length of stay for patients in the control group (95% CI, 1.4 days shorter to 4 days longer). The study was terminated after 22 patients were enrolled. CONCLUSION: Screening CT scans of the head and abdomen and pelvis at the time of hospital admission do not reduce the length of stay for patients with AIDS.


Subject(s)
Acquired Immunodeficiency Syndrome/diagnostic imaging , Diagnostic Tests, Routine/statistics & numerical data , Length of Stay/statistics & numerical data , Radiology Department, Hospital/organization & administration , Tomography, X-Ray Computed/statistics & numerical data , Acquired Immunodeficiency Syndrome/complications , Adult , Female , Head/diagnostic imaging , Health Services Research , Humans , Male , Middle Aged , Outcome and Process Assessment, Health Care , Patient Admission , Patient Selection , Pelvis/diagnostic imaging , Prospective Studies , Radiography, Abdominal , Time Factors , United States
11.
J Pharmacol Exp Ther ; 280(2): 988-1000, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9023316

ABSTRACT

Mice treated p.o. with 5% dextran sodium sulfate develop a mild to moderate colitis characterized by focal areas of inflammation and crypt abscesses. Immunohistological analysis of colons from dextran sodium sulfate-treated mice revealed an increased expression of intercellular adhesion molecule 1 (ICAM-1) and infiltration of lymphocyte function antigen 1-positive cells. A murine-specific antisense oligonucleotide, ISIS 3082, was used to determine the role of ICAM-1 expression in the development of colitis. Prophylactic treatment of dextran sodium sulfate-treated mice with ISIS 3082 reduced the clinical signs of colitis in a dose-dependent manner, with maximal effects occurring at a dose of 1 mg/kg/day. Reductions in ICAM-1 immunostaining and infiltrating leukocytes were observed in colons of animals treated with 1 mg/kg ISIS 3082. Scrambled control oligonucleotides failed to modify the course of the disease. The ICAM-1 oligonucleotide also diminished the clinical severity of colitis in mice with established colitis. The toxicity of ISIS 3082 was assessed in normal CD-1 mice by administering the oligonucleotide intravenously every other day for 2 weeks. At pharmacologically relevant doses of ISIS 3082 (1 and 10 mg/kg), there were no signs of toxicity with respect to body and organ weights, clinical chemistry or hematology. At a dose of oligonucleotide 20- to 100-fold greater than maximal pharmacological doses, the oligonucleotide produced an increase in liver and spleen weights; a mild chronic inflammation in liver, lung and lymph nodes; monocytosis and an elevation of serum liver transaminases. These data suggest that an antisense oligonucleotide that reduces ICAM-1 expression could be effective in the therapy of inflammatory bowel disease in humans and that such an oligonucleotide would be safe at pharmacologically relevant doses.


Subject(s)
Colitis/drug therapy , Colitis/prevention & control , Colon/pathology , Intercellular Adhesion Molecule-1/genetics , Intestinal Mucosa/pathology , Oligonucleotides, Antisense/therapeutic use , Animals , Base Sequence , Blood Cell Count/drug effects , Body Weight/drug effects , Colitis/chemically induced , Colon/drug effects , Colon/metabolism , Dextran Sulfate , Female , Intercellular Adhesion Molecule-1/analysis , Intercellular Adhesion Molecule-1/biosynthesis , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Lymphocyte Function-Associated Antigen-1/analysis , Lymphocyte Function-Associated Antigen-1/biosynthesis , Macrophage-1 Antigen/analysis , Macrophage-1 Antigen/biosynthesis , Male , Mice , Oligonucleotides, Antisense/toxicity , Organ Size/drug effects , Sex Characteristics , Thionucleotides
12.
Clin Infect Dis ; 24(2): 226-32, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9114152

ABSTRACT

Mycobacterium xenopi is a recognized cause of smoldering pulmonary disease in patients with chronic lung disease. This organism is frequently isolated from respiratory specimens from individuals infected with human immunodeficiency virus (HIV) and is often considered nonpathogenic. Cases of pulmonary and disseminated M. xenopi disease have been described in patients with HIV infection and other immunodeficiencies. Many physicians are unaware of the clinical significance of M. xenopi isolation. Whether this organism represents a commensal or a pathogen capable of causing considerable morbidity and mortality is not fully understood. In this study, we investigated the clinical significance of M. xenopi isolation and explored the clinical spectrum of M. xenopi disease. Clinical illness occurred both in elderly people with chronic lung disease and in young individuals with HIV infection. The repeated isolation of M. xenopi in association with pulmonary lesions suggests significant infection and mandates further workup and therapy.


Subject(s)
Nontuberculous Mycobacteria/isolation & purification , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , HIV Infections/microbiology , Humans , Male , Middle Aged , Mycobacterium Infections/drug therapy , Mycobacterium Infections/etiology , Radiography, Thoracic
13.
Infect Immun ; 65(1): 242-7, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8975918

ABSTRACT

Conjugation of carbohydrate antigens to protein carriers significantly improves the immune response to many carbohydrates. In order to evaluate the potential for this approach to improve the performance of pneumococcal vaccine in the elderly, we evaluated pneumococcal polysaccharide-derived oligosaccharides conjugated to cross-reacting material 197 (CRM197) (CRM-OS) in 49 older adults over 60 years of age (median age, 66 years) and compared the results to those from 50 younger adults under age 45 (median age, 27 years). Subjects were randomly assigned to receive licensed 23-valent polysaccharide vaccine (PS) which contain 25 micrograms of polysaccharide per serotype, or 5-valent CRM-OS, which contains 10 micrograms of oligosaccharide per serotype, in double-blind fashion. Both vaccines were associated with moderate local pain on administration. Antibody responses to type 14 were seen in the majority of both younger and older subjects following administration of both CRM-OS and PS, and there was no significant improvement of responses with CRM-OS in either age group. Antibody responses in young adults to the less immunogenic type 6B were seen in only 36% of subjects receiving PS and in 56% of subjects receiving CRM-OS (P = 0.15), and the geometric mean 6B titer 1 month after vaccination was higher in CRM-OS recipients (10.9 versus 3.7 micrograms/ml; P = 0.04). However, 6B responses were poor following the administration of either vaccine to elderly adults and there was no difference between results with CRM-OS and those with PS in this age group. Relatively few subjects developed measurable mucosal immunoglobulin A responses in nasal secretions following administration of either vaccine. Revaccination of CRM-OS recipients with PS at 2 months did not result in significant additional responses to 6B or 14. Though CRM-OS is possibly more immunogenic in young adults, the formulation of the pneumococcal glycoconjugate vaccine used in this study does not appear to offer an advantage to the elderly for types 6B or 14.


Subject(s)
Bacterial Vaccines/therapeutic use , Oligosaccharides/therapeutic use , Pneumococcal Infections/prevention & control , Polysaccharides, Bacterial/therapeutic use , Adjuvants, Immunologic , Adult , Age Factors , Aged , Antibodies, Bacterial/blood , Bacterial Vaccines/adverse effects , Humans , Immunization, Secondary , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Middle Aged , Nose/immunology , Oligosaccharides/adverse effects , Polysaccharides, Bacterial/adverse effects , Serotyping , Species Specificity
14.
J Pharmacol Exp Ther ; 278(1): 1-7, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8764328

ABSTRACT

The behavioral response elicited in mice by an i.p. injection of endothelin-1 (ET-1) (0.1 mg/kg) was differentiated from that elicited by standard agents such as acetylcholine (ACh) (5.5 mg/kg) or phenyl-p-quinone (PpQ) (1.25 mg/kg). First, there was lack of two-way "cross-tolerance' between test paradigms. That is, at equieffective doses, a 60-min prior i.p. injection of ET-1 blocked the behavioral response to a subsequent i.p. injection of ET-1 or PpQ, but not of ACh, whereas a 60-min prior injection of ACh or of PpQ had no effect on a subsequent i.p. injection of ACh, PpQ or ET-1. Second, differential antagonism of ET-1-, ACh- or PpQ-induced responses was observed in an examination of 36 test compounds. For example, cyclo-oxygenase inhibitors such as indomethacin and ibuprofen did not block the ET-1-induced response at > 10 times the doses that blocked ACh- or PpQ-induced responses, whereas other compounds (such as certain benzodiazepines) inhibited ET-1-induced, but not ACh- or PpQ-induced, responses. These findings suggest that ET-1 produces a novel nociceptive stimulus, mechanistically distinct from ACh and PpQ. Hence, the ET-1-induced behavioral response in mice serves as a rapid and convenient measure of in vivo endothelin activity. In addition, this test might be a model for clinical pains not adequately treated by present analgesic agents or adequately tested by preclinical antinociceptive screens using ACh or PpQ. As such, it is a potentially valuable model for the identification of novel analgesic and other agents.


Subject(s)
Analgesia , Endothelins/pharmacology , Models, Neurological , Pain Measurement , Acetylcholine/pharmacology , Animals , Dose-Response Relationship, Drug , Indomethacin/pharmacology , Male , Mice , Mice, Inbred ICR , Morphine/pharmacology
15.
J Pharmacol Exp Ther ; 276(2): 647-51, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8632332

ABSTRACT

Endothelins (ET-1, ET-2 or ET-3) or endothelin precursors (big-ET-1[1-38], big-ET-2[1-37] or big-ET-3[1-41]) injected i.p. in mice have previously been shown to elicit a characteristic nociceptive behavioral response. In this study, we investigated the endothelin receptor type (ETA or ETB) that mediates this behavioral response. Mice were injected i.p. with ET-1, ET-2, ET-3, big-ET-1[1-38], big-ET-2[1-37], big-ET-3[1-41], sarafotoxin S6a, sarafotoxin S6b, sarafotoxin S6c, ET-1 with Ala substitutions for Cys3 and Cys11 or His-Leu-Asp-Ile-Ile-Trp, and quantal dose-response curves were obtained for each of the compounds (except the latter). Co-administration of enzyme inhibitors with the big-endothelins was used to establish the requisite conversion to endothelins and big-ET-1[22-38], big-ET-2[22-37] and ET-3[22-41] amide, and the ETA-selective antagonist cyclo[-D-Asp-Pro-D-Val-Leu-D-Trp-] was used to determine receptor specificity. The ED50 values were 2.9, 3.3 and 23.9 micrograms/kg i.p. for ET-1, ET-2 and ET-3, respectively, 0.6, 0.6 and 13.1 micrograms/kg i.p. for sarafotoxin S6a, sarafotoxin S6b and sarafotoxin S6c, respectively, and 5.3 micrograms/kg i.p. for ET-1 with Ala substitutions for Cys3 and Cys11. Big-ET-1[22-38], big-ET-2[22-37], big-ET-3[22-41] amide and ET-C produced less than 25% effect up to 2000 micrograms/kg. The big-ET-1-induced effects were blocked by the enzyme inhibitors phosphoramidon and thiorphan (ID50 = 0.9 mg/kg) but not by ubenimex (bestatin), captopril or perindopril. Cyclo[-D-Asp-Pro-D-Val-Leu-D-Trp-] blocked ET-1- and ET-2-induced effects but not ET-3-, ACh- or phenyl-p-quinone-induced effects. These results suggest that endothelin-induced nociceptive behavioral response in mice can be mediated via both ET receptor types, ETA and ETB. Further, the ET-1 carboxy-terminal hexapeptide is insufficient to produce the effect, and the Cys3-Cys11 disulfide bridge of ET-1 is not required.


Subject(s)
Endothelins/pharmacology , Pain/chemically induced , Receptors, Endothelin/physiology , Animals , Male , Mice , Mice, Inbred ICR , Peptide Fragments/pharmacology , Peptides, Cyclic/pharmacology , Receptor, Endothelin A , Receptor, Endothelin B , Viper Venoms/pharmacology
16.
Life Sci ; 58(5): PL 73-6, 1996.
Article in English | MEDLINE | ID: mdl-8594299

ABSTRACT

In the same mice in which the intracerebroventricular (i.c.v.) administration of antisense oligodeoxyribonucleotide (oligo) directed against the Gi2alpha (but not Gi1alpha, Gi3alpha or G(s)alpha) G-protein subunits attenuated i.c.v. morphine-induced antinociception in the tail-flick test, none of the oligos altered naloxone-precipitated jumping (acute dependence). Likewise, none of the oligos significantly altered morphine-induced constipation. Hence, i.c.v. morphine-induced antinociception might be preferentially mediated via transduction pathway(s) different from constipation or acute dependence, offering novel opportunities for drug discovery.


Subject(s)
Analgesics, Opioid/pharmacology , Cerebral Ventricles/physiology , Constipation/physiopathology , GTP-Binding Proteins/genetics , Morphine Dependence/physiopathology , Morphine/pharmacology , Oligonucleotides, Antisense/pharmacology , Pain , Analgesics, Opioid/administration & dosage , Animals , Base Sequence , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiopathology , Constipation/chemically induced , Injections, Intraventricular , Kinetics , Male , Mice , Mice, Inbred Strains , Molecular Sequence Data , Morphine/administration & dosage , Naloxone/pharmacology , Oligonucleotides, Antisense/administration & dosage , Reaction Time/drug effects
17.
Sex Transm Dis ; 22(6): 380-2, 1995.
Article in English | MEDLINE | ID: mdl-8578412

ABSTRACT

This is a case report of a 35-year-old woman infected with the human immunodeficiency virus who presented with acute bacterial sepsis that proved to be secondary to Neisseria gonorrhoeae. Typical skin and joint findings developed only after the acute sepsis had resolved. Patients with disseminated gonococcal infection rarely have signs of acute bacterial sepsis. This case raises the question of whether HIV-infected patients are at an increased risk of contracting severe gonococcal disease.


Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Bacteremia/microbiology , Gonorrhea/microbiology , AIDS-Related Opportunistic Infections/immunology , Acute Disease , Adult , Bacteremia/immunology , CD4 Lymphocyte Count , Female , Gonorrhea/immunology , Humans
18.
Clin Infect Dis ; 20(5): 1399-401, 1995 May.
Article in English | MEDLINE | ID: mdl-7620033

ABSTRACT

Mycobacterium xenopi infections have rarely been reported among patients infected with the human immunodeficiency virus (HIV). We recently treated two HIV-infected men, neither of whom had a history of pulmonary disease or AIDS-defining conditions, and who had M. xenopi lung infections. Both patients presented with night sweats, cough, and pleuritic chest pain. Chest radiographs showed an upper-lobe nodule in the first patient and a perihilar cavitary infiltrate in the second patient. Both patients were initially believed to have pulmonary tuberculosis and were treated accordingly; however, only M. xenopi grew on cultures of multiple respiratory specimens. This diagnosis was confirmed by cultures of biopsied lung tissue from the first patient and of fluid from a peritracheal abscess in the second patient. Both patients' clinical conditions improved after multidrug therapy (isoniazid, rifampin, pyrazinamide, ethambutol, and ciprofloxacin in the first case; isoniazid, rifampin, and pyrazinamide in the second case). The second patient's condition improved despite in vitro resistance of his isolate to isoniazid and rifampin.


Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Mycobacterium Infections, Nontuberculous/diagnosis , Tuberculosis, Pulmonary/diagnosis , Adult , Humans , Male , Nontuberculous Mycobacteria/isolation & purification
19.
Eur J Clin Pharmacol ; 49(1-2): 57-60, 1995.
Article in English | MEDLINE | ID: mdl-8751022

ABSTRACT

In a double-blind randomised study, 14 volunteers applied 4% erythromycin plus 1.2% zinc (Zineryt lotion) and 4% erythromycin lotions, each on half of the forehead twice daily for 3 months. The sebum output was evaluated at 3-week intervals using the photometric and the lipid-sensitive film methods. Evaluations of casual level (CL) and sebum excretion rate (SER) were made with a Sebumeter, and total area of lipid spots (TAS) was measured on Sebutapes. Compared to baseline values, the formulation of the erythromycin-zinc complex induced significant reductions in SER after 6 and 9 weeks, and in CL and TAS at 3, 6, 9 and 12 weeks. The mean reduction in TAS was over 20% for four successive 1-h samplings on completion of the study. Significant reductions in CL, SER and TAS were observed for the erythromycin-zinc formulation compared to the control lotion at 6 and 9 weeks, and also at 3 weeks for SER and TAS, and at 12 weeks for CL and TAS. This study indicates that sebum output is significantly reduced by the erythromycin-zinc complex. This reduction is theoretically beneficial for the acneic patient.


Subject(s)
Acetates/therapeutic use , Anti-Bacterial Agents/therapeutic use , Erythromycin/therapeutic use , Sebum/drug effects , Acetic Acid , Acne Vulgaris/drug therapy , Administration, Topical , Adult , Double-Blind Method , Drug Therapy, Combination , Humans , Male , Sebum/metabolism
20.
J Pharmacol Exp Ther ; 267(1): 331-40, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8229760

ABSTRACT

The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.


Subject(s)
Analgesics/chemistry , Tramadol/administration & dosage , Acetylcholine/pharmacology , Animals , Arthritis/drug therapy , Drug Synergism , Male , Mice , Mice, Inbred Strains , Neurotransmitter Uptake Inhibitors , Norepinephrine/metabolism , Pain Threshold/drug effects , Receptors, Opioid/metabolism , Serotonin/metabolism , Stereoisomerism , Structure-Activity Relationship , Tramadol/chemistry , Tramadol/metabolism
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