Various causes and clinical characteristics in vertigo in children with normal eardrums

OBJECTIVE: The differential diagnosis of vertigo in children is extensive. Otitis media and middle ear effusion could be the most common causes of vertigo in children, but there are some problems in detecting the other causes for vertigo because they are one of most frequent diseases of childhood. The purpose of this study is to review the clinical characteristics and both the audiological and vestibular findings of vertigo in children with normal eardrums, who do not show otitis media or middle ear effusion, and to assist in making a differential diagnosis of vertigo. METHODS: The fifty five children (< 16 years old) with vertigo, who visited the Department of Otolaryngology, Ajou University Hospital, Suwon, South Korea between January 1995 and December 2001 were selected for this study. These excluded the patients with abnormal eardrums/tympanograms or those that did not perform questionnaires, audiological, or vestibular evaluations. They were retrospectively analyzed for clinical symptoms, vestibular functions, and differential diagnosis. RESULTS: The most common causes for vertigo in children were migraine in 17 (30.9%) and benign paroxysmal vertigo of childhood (BPVC) in 14 (25.5%). Other less frequent causes included four cases of trauma, two cases each of Meniere's disease, delayed endolymphatic hydrops, benign positional vertigo, and one case only for cerebellopontine angle tumor, seizure, acute vestibular neuritis, juvenile rheumatoid arthritis, leaving ten cases (18.2%) as unclassified. Abnormal findings were noted in 13 (23.6%) in pure tone audiogram, 3 (5.5%) in positioning test, 6 (10.9%) in bithermal caloric test, and 36 (65.5%) in rotation chair test. CONCLUSIONS: The vertigo in children with normal eardrums, who did not show otitis media or middle ear effusion, was most commonly caused by migraine and BPVC. These findings have shown to be very different from those with adult vertigo. The evaluation of vertigo in children requires a questionnaire for extensive and complete history taking, audiograms and vestibular function tests. And in selected cases, electroencephalography, hematological evaluation, imaging of the brain or temporal bone should be performed.     

Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071

An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidase was isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.Influenza virus infections remain a serious seasonal health concern and the potential of severe pandemics due to the emergence of new influenza strains, such as the H5N1 “bird flu” recently identified in Hong Kong (39), provides additional impetus to develop potent and effective antiviral agents (24). At present, only amantadine and, in some countries, rimantadine are approved for the treatment and prophylaxis of influenza A infections. However, the usefulness of these two compounds is limited by their lack of activity against influenza B viruses and their rapid selection of drug-resistant mutants which remain transmissible and pathogenic (10, 25).The influenza neuraminidase, which is expressed on the virus surface, has long been considered a valid target for antiviral therapy. This enzyme, which cleaves terminal sialic acid residue from glycoconjugates, is essential for virus proliferation and infectivity (3, 17, 19, 27, 28). The observation that the structural and catalytic amino acids which line the enzyme active site are highly conserved among different influenza neuraminidase types and subtypes (reviewed in reference 6) suggests that inhibitors of this enzyme would be active against a broad range of influenza viruses.Based on information gained from crystallographic studies of influenza neuraminidases complexed with sialic acid or the transition state analog Neu5Ac2en (2, 41, 43), several potent and selective inhibitors of the influenza neuraminidases have been synthesized (15, 16, 43). Two of these, GS 4071 ([3R,4R,5S]-4-acetamido-5-amino-3-[1-ethylpropoxy]1-cyclohexene-1-carboxylic acid), in the form of its oral prodrug GS 4104, and zanamivir (GG167, 4-guanidino-Neu5Ac2en) are currently under clinical development for the prophylaxis and treatment of influenza virus infections. Both compounds have demonstrated efficacy against influenza A and B viruses in vitro (13, 23, 40, 43, 45), in animal models of influenza virus infection (23, 31, 32, 34), and in experimental influenza virus infection in humans (11, 12, 14) when GS 4104 is taken orally and zanamivir is delivered topically to the respiratory tract as an inhalant.Although the development of resistance to zanamivir in animals or people treated with the drug has not been reported, influenza variants resistant to zanamivir due to mutations within their hemagglutinin or neuraminidase genes have been selected in vitro (1, 7, 8, 20, 38). In general, zanamivir-resistant hemagglutinin mutants have been easier to generate than neuraminidase mutations. These hemagglutinin mutants commonly contain amino acid substitutions in or near the sialic acid binding site and are believed to make the virus replication less dependent on neuraminidase activity (7, 20, 33). However, these mutations likely only affect the in vitro, not the in vivo, susceptibility to zanamivir (29).The most common neuraminidase mutation which arises in vitro under selective pressure of zanamivir has been that of the conserved Glu119 residue in the neuraminidase active site (1, 7, 38). Mutations of Glu119, which interacts with the guanidino side chain of zanamivir but not with the natural substrate (43), cause a 100-fold reduction in the sensitivity of the enzyme to zanamivir (1, 7, 38). Viruses containing mutations at this position remain infectious (8) and capable of inducing a febrile response in ferrets (5). Recently, a Lys substitution for the conserved Arg at position 292 has also been reported for a variant selected in the presence of zanamivir (8). The neuraminidase containing this mutation exhibited only a 10-fold reduction in sensitivity to zanamivir. A reassortant virus containing the mutant neuraminidase was 500-fold less infectious than wild-type virus in mice (8).In this report, we describe the first in vitro isolation and characterization of variants of a human influenza virus, A/Victoria/3/75 (H3N2), selected in the presence of GS 4071. In contrast with the experience with amantadine and rimantadine, with which drug-resistant variants can be selected after one or two passages in culture (26), variants with decreased susceptibility to GS 4071 did not readily occur. In the eighth passage, a variant containing two mutations in the stalk region of the hemagglutinin was isolated. This variant exhibited a minor decrease in susceptibility to neuraminidase inhibitors in general. A second variant, containing a conservative substitution of a Lys for an Arg at amino acid 292 of the neuraminidase enzyme active site, was isolated later in the selection process. This mutation caused a marked decrease in the susceptibility of the virus and the sensitivity of the enzyme to GS 4071. However, this mutation also adversely affected neuraminidase enzyme activity, compromised the ability of the virus to replicate in tissue culture, and reduced the infectivity of the virus 10,000-fold in mice.     

Anti-Human Immunodeficiency Virus Activity and Cellular Metabolism of a Potential Prodrug of the Acyclic Nucleoside Phosphonate 9-R-(2-Phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA

Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.     

Comparison of percentage fall in FVC at the provocative concentration of methacholine causing a 20% fall in FEV(1) between patients with asymptomatic bronchial hyperresponsiveness and mild asthma

BACKGROUND: A significant proportion of individuals who have no symptoms of asthma or other respiratory diseases show bronchial hyperresponsiveness (BHR). BHR is usually assessed by measuring the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)). The percentage fall in FVC at the PC(20) (DeltaFVC) has been suggested to reflect maximal airway response and to be a more useful index of disease severity in asthma than PC(20). The aim of this study was to investigate whether asymptomatic BHR would differ from symptomatic BHR with regard to DeltaFVC. METHODS: Methacholine bronchial challenge tests were conducted in children with no past or current symptoms of asthma, allergic rhinitis, or other respiratory diseases, who were identified among siblings of children with asthma. Forty-three children with asymptomatic BHR (PC(20) < 16 mg/mL) were recruited, and 43 children with mild asthma who were matched for age, sex, and PC(20) were selected (mild asthma group). The DeltaFVC on methacholine concentration-response curves was retrospectively analyzed in the two groups. RESULTS: There were no differences in the frequency of atopy, blood eosinophil counts, serum IgE levels, and spirometric values between the asymptomatic BHR and mild asthma groups. Mean (+/- SD) DeltaFVC was significantly (p = 0.005) lower in the asymptomatic BHR group (14.5 +/- 3.6%) than in the mild asthma group (16.9 +/- 4.3%). CONCLUSIONS: Our results suggest that children with asymptomatic BHR have a lower level of maximal airway response than mild asthmatics with a similar degree of BHR. This may be a possible explanation for the lack of symptoms in subjects with asymptomatic BHR.     

Do distinct dyspepsia subgroups exist in the community? A population-based study

BACKGROUND: The heterogeneity of the dyspepsia symptom complex is well known. Several attempts to classify dyspepsia into subgroups have been proposed as a basis for diagnosis and therapy, but data are conflicting. We postulated that dyspepsia comprises three distinct subsets, characterized by pain, early satiety, or nausea/vomiting. We aimed to identify these subsets of dyspepsia: "frequent upper abdominal pain (UAP),"early satiety (ES)," and "nausea/vomiting (NV)." METHODS: A population-based, cross-sectional survey study was conducted by mailing a valid questionnaire to an age- and gender-stratified random sample of residents of Olmsted County, MN, aged 20-94 yr (response rate 55%). Dyspepsia and irritable bowel syndrome (IBS) prevalence were estimated by Rome II criteria; gastroesophageal reflux (GERD) by weekly or more frequent heartburn or acid regurgitation. Dyspepsia subgroups were categorized based on a priori defined symptoms. RESULTS: The prevalence (95% CI) of dyspepsia was 15% (14, 17). Of 351 dyspeptic subjects, 51% (46, 56) reported UAP, 21% (16, 25) NV, and 47% (42, 52) ES. The overlap of the subgroups was significantly less than expected by chance. Among the three groups, the subjects were similar in age, educational level, IBS status, and overall symptom severity. A high somatic symptom checklist score and those with GERD were associated with greater odds for reporting combination symptoms compared with the upper abdominal pain subgroup of dyspepsia or the early satiety subgroup of dyspepsia, respectively. CONCLUSION: Distinct subgroups of uninvestigated dyspepsia do exist in the general population, suggesting that separate evaluation and treatment strategies are needed.     

Foreign-body reaction to the Artelon CMC joint spacer: case report

The Artelon CMC spacer (Small Bone Innovations, Inc., Morrisville, PA) is a relatively new device that was developed for the treatment of basal joint arthritis. It is composed of a biodegradable polycaprolactone-based polyurethane urea that acts to resurface the distal part of the trapezium and stabilize the trapeziometacarpal joint by augmenting the joint capsule. This is a case report of a foreign-body tissue reaction to the Artelon CMC spacer.