Retrospective Analysis of the Association of a Small Vestibular Aqueduct with Cochleovestibular Symptoms in a Large, Single-Center Cohort Undergoing CT.

BACKGROUND AND PURPOSE: Temporal bones in some patients with Ménière disease have demonstrated small vestibular aqueducts; however, the prevalence and clinical importance of small vestibular aqueducts remain unclear in patients without Ménière disease. This study correlates the presence of a small vestibular aqueduct with cochleovestibular symptoms. MATERIALS AND METHODS: Consecutive temporal bone CTs in adults from January to December 2020 were reviewed. The midpoint vestibular aqueduct size in the 45°-oblique Pöschl view was measured by 2 reviewers independently in 684 patients (1346 ears). Retrospective chart review for the clinical diagnosis of Ménière disease, the presence of cochleovestibular symptoms, and indications for CT was performed. RESULTS: Fifty-two of 684 patients (7.6% of patients, 62/1346 ears) had small vestibular aqueducts. Twelve patients (15/1346 ears) had Ménière disease. Five of 12 patients with Ménière disease (5 ears) had a small vestibular aqueduct. There was a significant correlation between a small vestibular aqueduct and Ménière disease (P < .001). There was no statistical difference between the small vestibular aqueduct cohort and the cohort with normal vestibular aqueducts (0.3-0.7 mm) regarding tinnitus (P = .06), hearing loss (P = .88), vertigo (P = .26), dizziness (P = .83), and aural fullness (P = .61). CONCLUSIONS: While patients with Ménière disease were proportionately more likely to have a small vestibular aqueduct than patients without Ménière disease, the small vestibular aqueduct was more frequently seen in patients without Ménière disease and had no correlation with hearing loss, vertigo, dizziness, or aural fullness. We suggest that the finding of a small vestibular aqueduct on CT could be reported by radiologists as a possible finding in Ménière disease, but it remains of uncertain, and potentially unlikely, clinical importance in the absence of symptoms of Ménière disease.

On the dynamic behaviour of the "click" mechanism in dipteran flight.

In this paper, the dynamic behaviour of the "click" mechanism is analysed. A more accurate model is used than in the past, in which the limits of movement due to the geometry of the flight mechanism are imposed. Moreover, the effects of different damping models are investigated. In previous work, the damping model was assumed to be of the linear viscous type for simplicity, but it is likely that the damping due to drag forces is nonlinear. Accordingly, a model of damping in which the damping force is proportional to the square of the velocity is used, and the results are compared with the simpler model of linear viscous damping. Because of the complexity of the model an analytical approach is not possible so the problem has been cast in terms of non-dimensional variables and solved numerically. The peak kinetic energy of the wing root per energy input in one cycle is chosen to study the effectiveness of the "click" mechanism compared with a linear resonant mechanism. It is shown that, the "click" mechanism has distinct advantages when it is driven below its resonant frequency. When the damping is quadratic, there are some further advantages compared to when the damping is linear and viscous, provided that the amplitude of the excitation force is large enough to avoid the erratic behaviour of the mechanism that occurs for small forces.

A new approach to modelling the ground reaction force from a runner.

The impact force experienced by a runner when his/her foot makes contact with the ground has been the subject of much research. This force is called the ground reaction force (GRF), and has been measured by several groups. In parallel with this, mathematical models have been developed to simulate GRFs in order to investigate various effects on this, such as the parameters of the human body and types of running shoe soles. Lumped parameter models have been developed by several researchers with limited success, because they are either constrained to model translational motion, or become complicated if they include rotational motion. This paper proposes a new approach based on modes of vibration, which encompasses the simplicity of the lumped parameter approach, without the motion constraints. The GRF is decomposed into contributions due to the various vibration modes of the system. To achieve this, a linear system is required, so a Zener model, which is used to model viscoelastic materials, is employed as the ground reaction model. The modal modelling approach is described in detail using established lumped parameter models used to predict the GRF. It is then applied to four experimental data sets from the literature, where it is shown that at most three modes are required to model GRF data accurately. Two of these modes are oscillatory modes and one is a non-oscillatory exponentially decaying mode. In general, it is shown that the modal model can capture the dynamics of each measured GRF independently of speed and running style.

Characterization of the protective capacity and immunogenicity of the 69-kD outer membrane protein of Bordetella pertussis.

Immunization with the 69-kD outer membrane protein (OMP) of Bordetella pertussis protected neonatal mice against lethal respiratory challenge with B. pertussis 18323. Active immunization elicited a serum IgG anti-69-kD OMP response at the time of challenge, with IgG anti-69-kD OMP antibodies detected in bronchoalveolar lavage fluid after challenge. Intravenous administration of BPE8, a monoclonal IgG1 anti-69-kD OMP, also protected young mice against B. pertussis challenge. Intravenously injected BPE8 was detected in the lungs of mice at the time of aerosol challenge, suggesting that the presence of specific antibody in the lungs may mediate protection. Thus the 69-kD OMP of B. pertussis is a protective antigen in mice that elicits specific serum antibody that can transude to the lung. The 69-kD OMP was detected in a preparation of a Takeda acellular vaccine by immunoblot analysis and a serum antibody response to the 69-kD OMP was observed in 18-mo-old children boosted with this preparation of Japanese acellular vaccine. Our results demonstrate that the B. pertussis 69-kD OMP is a protective antigen in animals, is immunogenic in humans, and is present in a preparation of acellular pertussis vaccine that is widely used in Japan. These findings indicate that the 69-kD OMP should be seriously considered as a candidate for inclusion in new formulations of antigenically defined acellular pertussis vaccines.

Identification of a heparin-binding hemagglutinin present in mycobacteria.

Adherence to mammalian host tissues is an important virulence trait in microbial pathogenesis, yet little is known about the adherence mechanisms of mycobacteria. Here, we show that binding of mycobacteria to epithelial cells but not to macrophages can be specifically inhibited by sulfated carbohydrates. Using heparin-Sepharose chromatography, a 28-kD heparin-binding protein was purified from culture supernatants and cell extracts of Mycobacterium bovis and Mycobacterium tuberculosis. This protein, designated heparin-binding hemagglutinin (HBHA), promotes the agglutination of rabbit erythrocytes, which is specifically inhibited by sulfated carbohydrates. HBHA also induce mycobacterial aggregation, suggesting that it can mediate bacteria-bacteria interactions as well. Hemagglutination, mycobacterial aggregation, as well as attachment to epithelial cells are specifically inhibited in the presence of anti-HBHA antibodies. Immunoelectron microscopy using anti-HBHA monoclonal antibodies revealed that the protein is surface exposed, consistent with a role in adherence. Immunoblot analyses using antigen-specific antibodies indicated that HBHA is different from the fibronectin-binding proteins of the antigen 85 complex and p55, and comparison of the NH2-terminal amino acid sequence of purified HBHA with the protein sequence data bases did not reveal any significant similarity with other known proteins. Sera from tuberculosis patients but not from healthy individuals were found to recognize HBHA, indicating its immunogenicity in humans during mycobacterial infections. Identification of putative mycobacterial adhesins, such as the one described in this report, may provide the basis for the development of new therapeutic and prophylactic strategies against mycobacterial diseases.

Polychlorinated biphenyl dechlorination in aquatic sediments.

The polychlorinated biphenyl (PCB) residues in the aquatic sediments from six PCB spill sites showed changes in PCB isomer and homolog (congener) distribution that indicated the occurrence of reductive dechlorination. The PCB dechlorinations exhibited several distinct congener selection patterns that indicated mediation by several different localized populations of anaerobic microorganisms. The higher (more heavily chlorinated) PCB congeners that were preferentially attacked by the observed dechlorination processes included all those that are either pharmacologically active or persistent in higher animals. All the lower (less heavily chlorinated) PCB congeners formed by the dechlorinations were species that are known to be oxidatively biodegradable by the bacteria of aerobic environments.

DNA polymerase activities of human milk.

DNA polymerases have been partially purified from human milk. A DNA polymerase detected by phosphocellulose chromatography is similar to the enzymes of RNA tumor viruses in that a hybrid of polyriboadenylate and oligodeoxythymidylate is a better template than is DNA. However, this polymerase differed from that of the RNA tumor viruses in its chromatographic behavior. Three different methods of detecting "reverse transcriptase" activity failed to correlate with the donor's family history of cancer.

Racial differences in breast cancer patients.

One thousand seventy-eight patients diagnosed with primary breast cancer were examined for racial differences in histopathologic and clinical parameters. There were no observed differences in tumor histopathologic type or tumor endocrine status between races. There were no differences with respect to time to breast tumor recurrence observed between black and white patients. However, differences were observed in factors that contributed to tumor stage at diagnosis and to tumor grade. Survival differences observed in univariant analysis of blacks vs. whites were explainable by the presence of more severe skin involvement, tumor grade, and tumor size at diagnosis in the black patients.

Murine and rat mammary tumors as models for the immunological study of human breast cancer.

The human breast cancer process and some aspects of experimental mammary cancer are compared in the light of Huxley's hypothesis that each neoplastic cell line may be viewed as a new obligate parasitic species derived from metazoan cells. Sufficient correlations are found to justify the hope that the viral-induced mouse mammary oncogenic process and the carcinogen-induced rat mammary system may serve as reasonable models of the human disease for immunological studies.

Effect of a proteoglycan produced by rat tumor cells on their adhesion to fibronectin-collagen substrata.

In this paper, we demonstrate that a chondroitin sulfate proteoglycan purified from a rat yolk sac tumor alters the adhesion of the tumor cells to substrata containing fibronectin or type I collagen. In the presence of the proteoglycan, these substrata were much less adhesive and did not promote cell spreading. The inhibitory effect of the proteoglycan was reversible and more pronounced during the early stages of cell attachment in vitro. The effect of the proteoglycan was selective in that it depended on the ability of the adhesive substratum to bind the proteoglycan. The proteoglycan did not inhibit the attachment of the cells to type IV collagen, which bound 12 times less proteoglycan than did type I collagen. Similarly, attachment of the cells to fibronectin fragments which did not bind the proteoglycan was not affected by it. The selective effects of the proteoglycan on the adhesion of cells to extracellular matrices suggest that such proteoglycans may promote tumor invasion by reducing interaction of cells with interstitial extracellular matrices while permitting attachment to basement membranes.

Node-negative breast cancer treated by modified radical mastectomy without adjuvant therapies: variables associated with disease recurrence and survivorship.

The present study attempts to identify poor prognosis subgroups of women with node-negative breast cancer that might benefit from systemic adjuvant therapy. The cases were collected through a cooperative effort of 57 surgeons at eight hospitals in the Detroit area and coordinated by the Michigan Cancer Foundation where data collection and analyses were completed. The primary treatment of all patients was a modified radical mastectomy. Of the 1,078 cases accessioned between October 1975 and April 1983, 537 were found to have no microscopic lymph node involvement and 462 of these cases received no adjuvant antineoplastic therapy. The period of follow-up of these cases (alive, n = 358) has been 78.75 +/- 24.6 months (mean +/- SD). Overall, the cumulative 6-year recurrence rate as calculated by life table analysis was 26%, with 16.8% dying of their disease. Tumor size was an important prognostic factor; the recurrence rate was 16.2% for those with primaries measuring less than or equal to 1 cm, with only a 6.3% mortality. Patients with tumors measuring greater than 5 cm also did well: 13.7% recurrence and 13.7% mortality rates at 6 years. The premenopausal women did slightly, but not statistically significantly, better than those who were postmenopausal. The presence or absence of quantifiable estrogen receptor protein (ER) was of little predictive value as far as rates of recurrence were concerned, but patients with an ER-positive tumor survived significantly longer. In postmenopausal women, those whose tumor lacked ER (n = 112) fared poorly: 30.4% experienced a recurrence by 6 years and 28% died of their disease. Recurrence rates and death rates were also high in a small group (n = 35) of postmenopausal women with ER+ tumors exhibiting nuclear pleomorphism (nuclear grade [NG]3) (38% and 24.3%, respectively). No poor prognosis group of premenopausal women was identified.

Naturally crystalline porin in the outer membrane of Bordetella pertussis.

The Gram-negative bacterium Bordetella pertussis is the agent responsible for whooping-cough, and much interest has focused on the functions, structures and immunological properties of the molecules exposed at its outer surface. We have found by electron microscopy that cells of two strains of B. pertussis are covered with a crystalline surface lattice. This lattice is not an extrinsic layer of high molecular weight glycoproteins, such as occur on many other bacteria, but is a natural crystal of an intrinsic membrane protein of 40,000 Mr. This molecule has been shown to be an anion-selective member of an extensive family of proteins ("porins") that render Gram-negative outer membranes permeable to solutes of up to approximately 650 Mr. Computer image processing reveals a trimeric channel-like structure that closely resembles other porins visualized in artificial arrays after treatment with detergents, but in a novel (p2) crystal form. This correlation provides a "missing link" between earlier structural studies based on artificial arrays of porins (of undefined physiological status), and membrane-permeabilization experiments with solubilized porins (in undefined structural states). For the strains characterized so far, crystallinity of the porin surface lattice shows an intriguing correlation with nonpathogenicity.

Filamentous hemagglutinin of Bordetella pertussis. A bacterial adhesin formed as a 50-nm monomeric rigid rod based on a 19-residue repeat motif rich in beta strands and turns.

The filamentous hemagglutinin (FHA) of Bordetella pertussis is an adhesin that binds the bacteria to cells of the respiratory epithelium in whooping-cough infections. Mature FHA is a 220 kDa secretory protein that is highly immunogenic and has been included in acellular vaccines. We have investigated its structure by combining electron microscopy and circular dichroism spectroscopy (CD) with computational analysis of its amino acid sequence. The FHA molecule is 50 nm in length and has the shape of a horseshoe nail: it has a globular head that appears to consist of two domains; a 35 nm-long shaft that averages 4 nm in width, but tapers slightly from the head end; and a small, flexible, tail. Mass measurements by scanning transmission electron microscopy establish that FHA is a monomer. Its sequence contains two regions of tandem 19-residue pseudo-repeats: the first, of 38 cycles, starts at residue 344; the second, of 13 cycles, starts at residue 1440. The repeat motifs are predicted to consist of short beta-strands separated by beta-turns, and secondary structure measurements by CD support this prediction. We propose a hairpin model for FHA in which the head is composed of the terminal domains; the shaft consists mainly of the repeat regions conformed as amphipathic, hyper-elongated beta-sheets, with their hydrophobic faces apposed; and the tail is composed of the intervening sequence. Further support for the model was obtained by immuno-labeling electron microscopy. The 19-residue repeats of FHA have features in common with the leucine-rich repeats (LRRs) that are present in many eukaryotic proteins, including some adhesion factors. The model is also compared with the two other classes of filamentous proteins that are rich in beta-structure, i.e. viral adhesins and two beta-helical secretory proteins. Our proposed structure implies how the functionally important adhesion sites and epitopes of FHA are distributed: its tripeptide (RGD) integrin-binding site is assigned to the tail; the putative hemagglutination site forms part of the head; and two classes of immunodominant epitopes are assigned to opposite ends of the molecule. Possible mechanisms are discussed for two modes of FHA-mediated adhesion.

Involvement of hippocampal serotonergic activity in age-related changes in exploratory behavior.

The effect of aging on exploratory behavior was investigated in adult (5 month) and aged (28 month) CB6F1 mice. During the first 10 minutes of the test session, aged mice made fewer head dip responses and spent less time exploring the novel stimuli. Because the aged mice were observed to subsequently increase their duration of exploration, it was suggested that the initial differences in exploration reflected a suppression of exploratory behavior by the aged mice. Immediately after behavioral testing, mice were sacrificed and hippocampal serotonin (5HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined. While 5HT concentrations were not found to be significantly altered with age, significant increases in 5-HIAA concentrations and in the ratio of 5-HIAA/5HT were observed in the aged mice. Further, the elevation in the 5-HIAA/5HT ratio was found to be significantly correlated with age-related differences in the duration, but not the frequency, of head dip responses. In view of this finding, it was suggested that alterations in serotonergic function with age may selectively affect specific aspects of an animal's response to novel stimuli.

Isolated ocular myopathy and celiac disease in childhood.

Neurologic deficits complicating celiac disease are well-described in adults. Here we report a 12-year-old girl in whom isolated ocular myopathy was the presenting feature of biopsy-proven celiac disease; the process was apparently reversed by a gluten-free diet and vitamin supplementation.

Global Forum on TB Vaccine Research and Development. World Health Organization, June 7-8 2001, Geneva.

The TB community now envisions a turning point in the development of improved TB vaccines for both high and low incidence countries. With a number of viable TB vaccine candidates now available for testing, the investigation of safety and immunogenicity in human clinical trials is seen as the driving force for the future development of effective vaccines for the prevention of tuberculosis.

Peptide nucleic acid probe detection of mutations in Mycobacterium tuberculosis genes associated with drug resistance.

The emergence of drug-resistant strains of Mycobacterium tuberculosis is a serious public health problem. Many of the specific gene mutations that cause drug resistance in M. tuberculosis are point mutations. We are developing a PCR-peptide nucleic acid (PNA)-based ELISA as a diagnostic method to recognize point mutations in genes associated with isoniazid and rifampin resistance in M. tuberculosis. Specific point mutation-containing sequences and wild-type sequences of cloned mycobacterial genes were PCR-amplified, denatured, and hybridized with PNA probes bound to microplate wells. Using 15-base PNA probes, we established the hybridization temperatures (50 degrees C-55 degrees C) and other experimental conditions suitable for detecting clinically relevant point mutations in the katG and rpoB genes. Hybridization of PCR-amplified sequences that contained these point mutations with complementary mutation-specific PNAs resulted in significant increases in ELISA response compared with hybridization using wild-type-specific PNAs. Conversely, PCR-amplified wild-type sequences hybridized much more efficiently with wild-type PNAs than with the mutation-specific PNAs. Using the M. tuberculosis cloned genes and PCR-PNA-ELISA format developed here, M. tuberculosis sequences containing point mutations associated with drug resistance can be identified in less than 24 h.

Genotypic variation in age-related changes in peripheral catecholamines.

The effects of aging on catecholamine concentrations in heart ventricle, aorta, and adrenal gland were evaluated in two inbred mouse strains (C57BL/6J and DBA/2J) and an F1 hybrid (B6D2F1). The effects of aging on ventricular norepinephrine (NE) levels were found to be strain specific; only the C57BL/6J strain showed a significant decline in ventricular NE levels with age. Though all strains showed a decline in ventricular epinephrine (EPI) levels with age, the magnitude of the decrease varied between strains. An age-related increase in ventricular dopamine (DA) levels was observed in each of the strains. Although strain differences in catecholamine levels were also observed in aorta and adrenal gland, no age-related changes in catecholamine concentrations were noted in any of the strains. The findings indicate strain and organ specific changes in the effects of aging on catecholamine concentrations in peripheral organs.

Endocrinology in cancer of the breast. Status and prospects.

Breast cancer is the result of a multistage carcinogenic process. Initiation, promotion, dependency and autonomy make up a sequence of experimentally distinguishable phases of this process. Progression--the transition from dependency on hormonal support to autonomy--is demonstrable clinically. High-affinity saturatable estrogen binding by breast cancer cytosols distinguishes endocrine-responsive mammary neoplasms from autonomous breast cancers. Approximately 70% of neoplasms containing estrogen-recepor protein at a level of 2.5 femtomoles per mg. protein or higher regress after endocrine ablation (ovariectomy in premenopausal women; adrenalectomy or hypophysectomy in postmenopausal women). Only about 5% of neoplasms lacking the receptor will respond to these maneuvers. Estrogen-receptor content also predicts clinically for estrogen and androgen responsiveness, and experimentally for prolactin dependency. Fifty per cent of primary breast cancers in women are receptor-positive. Normal breast tissue and benign breast lesions characteristically lack receptor protein. The receptor proteins appear to be induced in neoplastic cells during mammary carcinogenesis in endocrinologic settings where non-cancerous breast cells do not contain free receptor in large amounts and fail to manifest endocrinologic growth stimulation. Implications of these findings for endocrinologic management of disseminated mammary cancer, adjuvant therapy, and breast cancer prevention are discussed.

Adult development of the hippocampal-serotonin system of C57BL/6N mice; analysis of high-affinity uptake of (3)H-5HT in slices and synaptosomes.

The saturable and specific high-affinity uptake of [(3)H]serotonin ([(3)H]5HT) (5 x 10(?8) M) was studied in slices from the hippocampus, parietal cortex, septum-preoptic area, and hypothalamus of male 2, 6, 12 and 24-32 month old C57BL/6N mice. Hippocampal [(3)H]5-HT uptake showed a significant biphasic relationship to age, with lower values in the 2 and 24-32 month old mice compared to 6 month old mice. No significant age effects were seen in the other regions, or in [(3)H]norepinephrine high-affinity uptake in the hippocampus. Studies of the high-affinity uptake mechanism in synaptosomal preparations were made in a subgroup of 12 and 24 month old mice. A micro-assay using a tissue-harvester measured high-affinity uptake on 8-30 ?l of the P(2) suspension (crude-synaptosomal preparation). The high-affinity uptake was linear for 4 min at 37 degrees C and inhibited in both the adult and aged tissue by 10(?5) M cold 5-HT (83 and 78% respectively), 10(?5) M fluoxetine (85 and 82% respectively) and 10(?3) M NaCN (57 and 57% respectively). Kinetic analysis of the [(3)H]5HT high-affinity uptake in the hippocampus (3 min, 37 degrees C) revealed the same apparent K(m) for serotonin at both ages (6.7 x 10(?8) M), but a 44% decrease in V(max) in the aged hippocampal synaptosomal high-affinity uptake compared to adults (120 vs 215 pmol of 5-HT/g-tissue/3 min). These results are discussed in relationship to the reported age effects on the intrinsic neurons of the hippocampus.