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Biomedical subjects

B Winther

Publications and source records attributed to B Winther.

At least 19 recordsLinked to original sources
PubMed2001

Computed tomography imaging of the maxillary and ethmoid sinuses in children with short-duration purulent rhinorrhea.

INTRODUCTION: Adults with a common cold often have paranasal sinus effusions detected by computed tomographic (CT) scans. There are no comparable data for children. The purpose of this study was to document the sinus CT findings in children with short-duration purulent rhinorrhea. DESIGN: Thirty children, 3 to 12 years of age (median age, 7 years), with purulent rhinorrhea for a mean duration of 5 days (and always less than 9 days) were enrolled in the study. The children were otherwise well. Institutional Review Board (IRB)-approval was obtained before enrollment of the first patient. Informed written consent was obtained from each child's parent. CT imaging of the maxillary and ethmoid sinuses was obtained on the day of the initial visit (occasionally, the following day). Follow-up CT scans were obtained from cooperative children/parents, 3 to 4 weeks later. RESULTS: Opacification or an air/fluid level in the maxillary sinuses was seen in 27 (90%) of 30 study children at study entry. Ethmoid sinuses were not opacified without opacification of a maxillary sinus. Three weeks later, 24 of 27 study children, who had positive CT scans on study entry, improved clinically. Of 17 follow-up CT scans, 10 (58%) normalized, 4 had improvement of bilateral disease, and 3 improved with unilateral disease. None appeared worse than baseline. CONCLUSIONS: Pansinus opacification (ethmoid and maxillary sinuses), on CT scans in children with short-duration purulent nasal drainage was seen in 70% of children. An additional 20% had isolated maxillary sinus effusions (10% had no effusion). Three-week follow-up CT scans on 17 children were normal in 60% and improved (partial clearance) in 40%. In this patient population, the decision to treat with antibiotics should be made on clinical grounds alone.

Cefuroxime↗
PubMed2001

Bacterial pathogens of otitis media and sinusitis: detection in the nasopharynx with selective agar media.

Carriage rates for the bacterial pathogens associated with otitis media (Streptococcus pneumoniae [SP], Hemophilus influenzae [HI], and Moraxella catarrhalis [MC]) are of interest. Culture on three selective agars was compared with culture on two standard agars to determine the more accurate method for detection of these species in the nasopharynx of healthy children. Weekly samples were obtained in winter from 18 healthy children (ages 1 through 9 years) as part of a longitudinal study. A 0.1-mL sample of 116 nasopharyngeal aspirate/washes was inoculated onto each of five agars. Two were standard (sheep blood and chocolate), and three were selective (blood with gentamicin for SP; chocolate with vancomycin, bacitracin, and clindamycin for HI; blood with amphotericin B, vancomycin, trimethoprim, and acetazolamide for MC). One technician read the standard plates and another the selective; both were blinded to the results of the other. SP was found in 44% of samples with selective agar versus 25% with standard agar; HI was found in 31% with selective versus 9% with standard; MC was found in 56% with selective versus 37% with standard. Overall, 80% of samples had one or more pathogens detected with selective agars as compared with 58% with standard agars (P =.0004). Selective agars were more accurate than standard agars for detecting otitis pathogens in the nasopharynx, where they are a common part of normal flora in healthy children.

Agar↗
PubMed2000

Nose blowing propels nasal fluid into the paranasal sinuses.

Intranasal pressures were measured in adults during nose blowing, sneezing, and coughing and were used for fluid dynamic modeling. Sinus CT scans were performed after instillation of radiopaque contrast medium into the nasopharynx followed by nose blowing, sneezing, and coughing. The mean (+/-SD) maximal intranasal pressure was 66 (+/-14) mm Hg during 35 nose blows, 4.6 (+/-3.8) mm Hg during 13 sneezes, and 6.6 (+/-3.8) mm Hg during 18 coughing bouts. A single nose blow can propel up to 1 mL of viscous fluid in the middle meatus into the maxillary sinus. Sneezing and coughing do not generate sufficient pressure to propel viscous fluid into the sinus. Contrast medium from the nasopharynx appeared in >/=1 sinuses in 4 of 4 subjects after a nose blow but not after sneezing or coughing.

Adult↗
PubMed1999

Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial.

CONTEXT: Attachment of most rhinovirus subtypes to cells depends on a cellular receptor, the intercellular adhesion molecule 1 (ICAM-1). A recombinant soluble ICAM-1 (tremacamra, formerly BIRR 4) has shown possible efficacy in early studies. OBJECTIVE: To determine the efficacy and safety of intranasal administration of tremacamra in experimental rhinovirus colds in humans. DESIGN: Four randomized, double-blind, placebo-controlled trials conducted in January to March 1996. SETTING AND SUBJECTS: Volunteers between the ages of 18 and 60 years who had an antibody titer of 1:4 or less to the challenge virus. Subjects were isolated in a hotel room during study days 0 to 8; symptoms were recorded through day 14. A total of 198 subjects were randomized, of whom 196 received drug or placebo and were included in the safety analysis. A total of 177 subjects were included in the efficacy analysis. INTERVENTIONS: Tremacamra or placebo was given beginning 7 hours before inoculation with rhinovirus type 39 (preinoculation studies) or 12 hours after (postinoculation studies). Tremacamra as an inhaled solution or as a powder (each given preinoculation and postinoculation for a total of 4 studies) and placebo were given in 6 doses at 3-hour intervals daily during days 1 through 7. Recipients of active treatment received 367 microg of tremacamra per nostril per dose for a total of 4.4 mg/d. MAIN OUTCOME MEASURES: Effect of tremacamra on infection, as determined by virus isolation and seroconversion, and on illness, as determined by symptom scores, clinical colds, and nasal mucus weights. Treatment-by-study interaction was not significant, so results were pooled for the main analysis. RESULTS: A total of 88 (92%) of the 96 subjects in the placebo groups and 69 (85%) of the 81 subjects in the active treatment groups were infected (P=.19). For placebo vs tremacamra, respectively, the total symptom score (+/- 95% confidence interval [CI]) was 17.6 (+/- 2.7) vs 9.6 (+/- 2.9), the proportion of clinical colds was 64/96 (67% +/- 9%) vs 36/81 (44% +/- 11%), and the nasal mucus weight was 32.9 (+/- 8.8) g vs 14.5 (+/- 9.4) g (P<.001 for all comparisons). Tremacamra was not associated with adverse effects or evidence of absorption through the nasal mucosa and did not interfere with development of neutralizing antibody. CONCLUSION: Tremacamra reduced the severity of experimental rhinovirus colds. Whether tremacamra will be useful clinically will require further study.

Administration, Intranasal↗
PubMed1998

High-efficiency retrovirus-mediated gene transfer into the livers of mice.

Recombinant retroviral vectors represent an attractive means of transferring genes into the liver because they integrate in the host cell genome and result in permanent gene expression. However, efficient gene transfer is limited by the requirement of active cell division for integration. Surgical partial hepatectomy has been the traditional method of inducing hepatocellular proliferation, but this invasive approach would be difficult to justify in clinical gene therapy. As an alternative, we used a recombinant adenovirus expressing a nonsecreted form of urokinase plaminogen activator (Ad.PGKmuPA), which results in liver regeneration over a period of 8 days. When a high-titer retroviral vector was continuously infused into the portal vein of mice during this period of hepatocyte proliferation, 33.5% of hepatocytes were stably transduced. In addition, high-level expression of a secreted transgene reporter was sustained for at least 48 weeks (length of experiment). We investigated the influence of vector titer on the in vivo transduction efficiency in our system, and found that the total number of infectious retroviral particles delivered per target cell is a critical factor. The results presented here demonstrate the ability to obtain a high gene transfer efficiency and long-term gene expression in hepatocytes in vivo without the need for surgical hepatectomy. The two-vector system described here may be of clinical relevance, as the level of hepatic gene transfer achieved has potential to be curative for a large number of genetic liver diseases.

Adenoviridae↗
PubMed1997

Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors.

Haemophilia B, or factor IX deficiency, is a X-linked recessive disorder that occurs in about one in 25,000 males, and severely affected people are at risk for spontaneous bleeding into numerous organs. Bleeding can be life-threatening or lead to chronic disabilities with haemophilic arthropathy. The severity of the bleeding tendency varies among patients and is related to the concentration of functional plasma factor IX. Patients with 5-30% of the normal factor IX have mild haemophilia that may not be recognized until adulthood or after heavy trauma or surgery. Therapy for acute bleeding consists of the transfusion of clotting-factor concentrates prepared from human blood and recombinant clotting factors that are currently in clinical trials. Both recombinant retroviral and adenoviral vectors have successfully transferred factor IX cDNA into the livers of dogs with haemophilia B. Recombinant retroviral-mediated gene transfer results in persistent yet subtherapeutic concentrations of factor IX and requires the stimulation of hepatocyte replication before vector administration. Recombinant adenoviral vectors can temporarily cure the coagulation defect in the canine haemophilia B model; however, an immune response directed against viral gene products made by the vector results in toxicity and limited gene expression. The use of recombinant adeno-associated virus (rAAV) vectors is promising because the vector contains no viral genes and can transduce non-dividing cells. The efficacy of in vivo transduction of non-dividing cells has been demonstrated in a wide variety of tissues. In this report, we describe the successful transduction of the liver in vivo using r-AAV vectors delivered as a single administration to mice and demonstrate that persistent, curative concentrations of functional human factor IX can be achieved using wild-type-free and adenovirus-free rAAV vectors. This demonstrates the potential of treating haemophilia B by gene therapy at the natural site of factor IX production.

Alanine Transaminase↗
PubMed1997

Surface expression of intercellular adhesion molecule 1 on epithelial cells in the human adenoid.

Human rhinoviruses enter the host by way of the nose and conjunctiva. Intercellular adhesion molecule 1 (ICAM-1) is the cellular receptor for the majority of rhinoviruses. ICAM-1 expression on the luminal surface of epithelial cells in the upper airway may be an important determinant of virus localization in the airway. Eighteen adenoids and 5 nasopharyngeal biopsies were evaluated by immunohistochemistry for surface expression of ICAM-1. Heavy immunoreactivity of ICAM-1 was found on the surface of a small number of single nonciliated cells in the lymphoepithelium. Squamous epithelial cells showed minimal to no staining, and ciliated epithelium had positive ICAM-1 staining of the basal cells but not on the ciliated border. The localization of ICAM-1 expression to specific, limited areas of the surface epithelium of the nasopharynx may have important implications in the pathogenesis of rhinovirus infections, especially initiation of the host response to rhinovirus.

Adenoids↗
PubMed1997

The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors.

Systemic application of first-generation adenovirus induces pathogenic effects in the liver. To begin unraveling the mechanisms underlying early liver toxicity after adenovirus infusion, particularly the role of macrophage activation and expression of viral genes in transduced target cells, first-generation adenovirus or adenovirus vectors that lacked most early and late gene expression were administered to C3H/HeJ mice after transient depletion of Kupffer cells by gadolinium chloride treatment. Activation of NF-kappaB, and the serum levels of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) were studied in correlation with liver damage, apoptosis, and hepatocellular DNA synthesis. While Kupffer cell depletion nearly eliminated adenovirus-induced TNF release, it resulted in a more robust IL-6 release. These responses were greatly reduced in animals receiving the deleted adenovirus. Although there were quantitative differences, NF-kappaB activation was observed within minutes of first-generation or deleted adenovirus vector administration regardless of the status of the Kupffer cells, suggesting that the induction is related to a direct effect of the virus particle on the hepatocyte. Early liver toxicity as determined by serum glutamic-pyruvic transaminase elevation and inflammatory cell infiltrates appeared to be dependent on adenovirus-mediated early gene expression and intact Kupffer cell function. Kupffer cell depletion had little effect on adenovirus-mediated hepatocyte apoptosis but did increase hepatocellular DNA synthesis. Finally, Kupffer cell depletion decreased the persistence of transgene (human alpha1-antitrypsin [hAAT]) expression that was associated with a more pronounced humoral immune response against hAAT. The elucidation of these events occurring after intravenous adenovirus injection will be important in developing new vectors and transfer techniques with reduced toxicity.

Adenoviridae↗
PubMed1997

Common cold and high-dose ipratropium bromide: use of anticholinergic medication as an indicator of reflex-mediated hypersecretion.

UNLABELLED: It was our aim to study the role played by parasympathetic reflexes for the amount and physical characteristics of nasal discharge during a common cold, and to define the maximum anti-rhinorrhoea effect obtainable with anticholinergic medication. Fifty adults with naturally acquired colds were treated with a very high dose of the topically active cholinoceptor-antagonists ipratropium bromide in a randomized, double-blind, placebo-controlled study of parallel groups. A dosage of 400 micrograms was given 4 times daily for 3 days, using a specially manufactured high-dosed pressurized aerosol. This treatment resulted in a 56% reduction in the number of nose blowings (p < 0.01) and a 58% reduction in the weight of blown secretions (p < 0.01). Assessment of the "pourability" of the nasal discharge indicated that ipratropium bromide mainly reduces the watery secretions but not the mucopurulent secretions. The high dose of ipratropium bromide caused nose- and mouth-dryness in a considerable number of the patients. IN CONCLUSION: (1) during the first days of a common cold about 60% of the nasal discharge is a reflex-mediated product from nasal glands; (2) this type of secretion is predominantly watery; and (3) ipratropium bromide can reduce watery rhinorrhoea in the common cold, but a lower dose is required in order to avoid side effects.

Administration, Inhalation↗
PubMed1995

Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization.

To localize the sites and determine the extent of human rhinovirus (HRV) replication in the upper respiratory tract, biopsies of nasal and nasopharyngeal epithelia were collected from 26 HRV- or 7 sham-inoculated volunteers on days 1, 3, and 5 and on days 12, 20, or 33 after inoculation and analyzed by in situ hybridization. HRV-infected cells were detected on at least 1 day in 22 of the 23 HRV-infected subjects and in 1 of the 7 sham-inoculated subjects who developed a cold and had nasal secretions positive for a picornavirus by polymerase chain reaction. Low numbers of in situ hybridization-positive ciliated cells were present in nasal biopsies. In the nasopharynx, most HRV-infected cells were ciliated, but infected nonciliated epithelial cells were also detected. Our results indicate that HRV replicates in a very small proportion of cells in the nasal epithelium and in both ciliated and nonciliated cells in the nasopharynx of experimentally infected humans.

Adult↗
PubMed1994

The human adenoid. A morphologic study.

OBJECTIVE: We examined the route by which antigen on the surface of the adenoid may be brought into contact with the lymphoid follicles in the submucosa of the adenoid. DESIGN: We studied under light and electron microscopy 13 adenoids from children undergoing elective surgery. Portions of all of the specimens were fixed in formalin and embedded in paraffin and plastic for hematoxylin-eosin and periodic acid-Schiff staining. Portions of four adenoids were fixed in glutaraldehyde for electron microscopy. RESULTS: Two major types of epithelium were evident by light microscopy: a ciliated or squamous epithelium containing few lymphocytes and a nonciliated-flat epithelium with a heavy infiltration of lymphocytes ("lymphoepithelium"). Scanning microscopy showed the surface of this lymphoepithelium to be composed largely of cells with multiple microfolds known as M-cells. Freeze-fracture technique showed many lymphocytes under the M-cells. Transmission electron microscopy showed the lymphocytes to be located in compartments formed by the epithelial cells. Light microscopy study of 50 serial sections embedded in plastic suggested that the compartments communicated to form intraepithelial channels for the lymphocytes. CONCLUSION: The epithelium of the adenoid has areas with ciliated epithelium adjacent to areas with epithelium containing M-cells and intraepithelial lymphatic channels. HYPOTHESIS: The lymphoepithelium of the adenoid is a mechanism for transporting antigen via the M-cells to the underlying lymphoid follicles.

Adenoids↗
PubMed1994

Effects on the nasal mucosa of upper respiratory viruses (common cold).

Delineation of the pathogenesis of symptoms during common colds is the overall aim of this work. The studies included in this thesis have focused on the histopathologic changes in the nasal mucosa produced by infection with respiratory viruses. The accepted concept when these studies were undertaken was that cold symptoms were caused by destruction of nasal epithelium by virus and that epithelial damage sometimes led to secondary bacterial infection evidenced by purulent nasal secretions. The pathogenesis of cold symptoms has been reviewed in this thesis based on investigations by others and my own research. Chapter 1 described the clinical design of a naturally acquired cold model and an experimental rhinovirus cold model which were used. The advantages of the experimental model over the natural cold model are that the viral etiology is known and that volunteers can be studied beginning at viral inoculation rather than onset of symptoms. Unfortunately, the experimental model is very expensive. Chapter 2 reviewed the histopathology of the nasal mucosa during colds. The degree of destruction of the mucosa during naturally acquired colds reported in the literature has varied. We did not detect any discernible damage of the epithelium by light and scanning electron microscopy in naturally acquired colds. We repeated the study in volunteers with rhinovirus colds and again did not find any damage to the surface epithelium (light microscopy). Although different viruses may cause epithelial damage in naturally acquired colds, in rhinovirus colds the epithelium of the anterior part of the inferior turbinate is not destroyed. There was an early influx of neutrophils into the nasal mucosa in patients both with naturally acquired colds (day 2 after onset) and with experimental rhinovirus colds. This discovery in combination with the minimal damage of the nasal epithelium led to formulation of a new hypothesis of how cold symptoms may be produced. The influx of neutrophils might be a direct response to viral infection and/or may reflect the release of a cascade of inflammatory mediators which are responsible in part for the symptoms. Naclerio et al (1988) has since shown that the number of neutrophils in nasal secretions increases early in rhinovirus colds. This increase correlated nicely with the symptoms. In addition, Turner (1988) demonstrated the elaboration of a chemoattractant factor for neutrophils by cell cultures infected with rhinovirus type 39. Chapter 3 focused on the location of rhinovirus replication in the nose and nasopharynx. The entire mucosal lining of the nasal cavities was not infected during the first week of a rhinovirus colds.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical Trials as Topic↗
PubMed1992

Fireside conference 11. Common cold.

The accepted concept that cold symptoms are usually caused by destruction of the nasal epithelium by virus and that epithelial damage may led to secondary bacterial infection is not supported by this work. Although influenza and adenovirus may destroy the epithelium, no destruction of the nasal epithelium was detected either in vivo during natural or rhinovirus cold on in-vitro in nasal epithelial organ cultures. Infiltration of the nasal mucosa with neutrophils early in the cold does not indicate bacterial infection but may be a direct result of the viral infection. Purulent nasal secretions, which are common in uncomplicated colds, were not accompanied by discernible changes in the aerobic bacterial flora. The nasopharynx may be an important area for further exploration in the study of the pathogenesis of rhinovirus infection since it is a site to which mucus containing virus from the entire nasal mucosa is brought. A prominent feature of the posterior nasopharyngeal wall in both children and adults is a mass of mucosa-associated lymphoid tissue (adenoid or nasopharyngeal tonsils). Preliminary data has suggested that the epithelium overlying the lymphoid tissue expresses ICAM-1 receptors in the normal state, whereas the nasal epithelium does not. This is interesting since the majority of rhinovirus serotypes gain entrance to human cells by this receptor. Symptoms in a rhinovirus cold could result from release of inflammatory and/or neuromediators from the adenoid. Recently, Naclerio et al (8) have demonstrated that kinins and an increased number of neutrophils in nasal secretions correlate with occurrence of symptoms in volunteers with rhinovirus colds.

Biopsy↗
PubMed1991

Localization of rhinovirus replication in vitro with in situ hybridization.

To facilitate understanding of human rhinovirus (HRV) pathogenesis, methods were developed for detection of HRV infection in vitro using in situ hybridization (ISH). HRV-14 RNA probes and oligonucleotide probes representing conserved sequences in the 5'-non-translated region were labeled with 35S and used to detect infected HeLa or WI-38 strain human embryonic lung cells in cytological preparations. ISH was shown to be specific for detection of HRV on a single-cell basis. Subsequently, in human nasal polyps infected in vitro, both oligonucleotide- and ribo-probes produced a strong signal in association with ciliated epithelial cells. In human adenoids infected in vitro, a signal was observed in non-ciliated epithelial cells. This study shows that HRV replicates in ciliated cells in the epithelium of human nasal polyps infected in vitro, and the presence of viral RNA in non-ciliated cells of the human adenoid infected in vitro suggests that other cell types may also support rhinovirus replication.

Adenoids↗
PubMed1990

Respiratory virus infection of monolayer cultures of human nasal epithelial cells.

The effect on nasal epithelial cells in monolayer cultures of infection with rhinovirus, coronavirus 229E, influenza type A, and adenovirus was studied. Fragments (1 x 2 mm) of epithelium with adherent submucosa from nasal polyps, adenoids, or nasal turbinates were cultured in plastic dishes with media containing a serum supplement. Within a week a monolayer of epithelial cells with interspersed ciliated cells surrounded each fragment. Epithelial monolayers were exposed to 10(3) to 10(4) TCID50/ml of each virus; unattached virus was removed after 3 h. Replication of virus was examined by doing viral titrations of the media daily, and ciliated and nonciliated epithelial cells in the monolayer were examined morphologically with an inverted microscope. The peak titer of rhinovirus and coronavirus occurred 24 to 48 h after inoculation, indicating that viral replication was occurring. However, no detectable damage or cytopathic effect (CPE) developed in the monolayer of epithelial cells when compared with that in uninfected control cells. In contrast, infection of epithelial monolayers with influenza or adenovirus resulted in CPE and destruction of the monolayer. The marked difference in the effect of these respiratory viruses on nasal epithelial cells may reflect similar differences in their effect on respiratory tract mucosa in the intact host. If so, the pathogenesis of symptom production during rhinovirus and coronavirus infections must be by mechanisms other than destruction of the nasal lining.

Adenoids↗
PubMed1990

Therapeutic approach to sinusitis: antiinfectious therapy as the baseline of management.

Although acute sinusitis is an infectious disease in which several bacterial species play a major etiologic role, there is an important interaction between the respiratory viruses (common cold viruses) and the bacteria in the pathogenesis of acute community-acquired sinusitis. The relative inaccessibility of the sinus cavities makes special techniques of sampling necessary to acquire specimens that accurately reflect disease conditions in the sinuses. Bacterial etiology of sinus infection has therefore been determined by sinus puncture studies, chiefly of the maxillary sinus, several of which are reviewed here. Because the bacteria causing acute sinusitis have not changed in many years, puncture is not often necessary for clinical diagnosis. Patients with acute, community-acquired sinusitis can usually be treated empirically, on the basis of previous studies, unless complications are suspected. In that case, and in other patients with hospital-acquired sinusitis, puncture of the involved sinus and aspiration of sinus fluid for Gram's staining and quantitative microbial cultures and sensitivities are required for appropriate antimicrobial management.

Acute Disease↗