Increasing likelihood of advanced pulmonary tuberculosis at initial diagnosis in a low-incidence US state.

SETTING: Arkansas, USA. OBJECTIVE: To investigate the relationship between an increase in the proportion of cases with advanced disease at first diagnosis and the recently observed slowing of the decline in tuberculosis (TB) incidence in low-incidence US states. DESIGN: We conducted descriptive statistical analyses of de-identified surveillance data of 1246 culture-confirmed TB patients reported in Arkansas during 1996-2013. We then fitted stepwise, multivariate logistic regression models to identify predictors for advanced disease at diagnosis, defined as having either smear-positive sputum or lung cavitation. RESULTS: From 1996 to 2013, the proportion of new cases with positive sputum smear and cases with lung cavitation increased from 51.6% to 75% and from 37.7% to 50%, respectively. Patients diagnosed during 2006-2013 were more likely to have positive sputum smears (adjusted odds ratio [aOR] 2.55, 95%CI 1.95-3.35) or lung cavitation (aOR 1.49, 95%CI 1.14-1.95) than those diagnosed during 1996-2005. During 1996-2013, age 15-64 years and excessive alcohol use were predictive of positive sputum smear or lung cavitation. CONCLUSION: Measures to reduce the proportion of cases with advanced disease at first diagnosis may be helpful to achieve further decline in TB incidence in low-incidence settings.

Fracture union following internal fixation in the HIV population.

INTRODUCTION: HIV is thought to be associated with increased rates of fracture non-union. We report on a prospective cohort of 96 HIV positive patients with 107 fractures that required internal fixation. The CD4 count was measured and patients were reviewed until eventual clinical or radiological union or non-union was established. RESULTS: Four percent of fractures (4 out of 100) failed to unite. Three patients required one further procedure to induce union, and two developed avascular necrosis. The CD4 count was not related to fracture union. CONCLUSION: Contrary to previous assumptions, this study suggests that HIV infection does not increase rates of non-union in surgically managed fractures.

Transient oscillatory force-length behavior of activated airway smooth muscle.

Airway smooth muscle (ASM) is cyclically stretched during breathing, even in the active state, yet the factors determining its dynamic force-length behavior remain incompletely understood. We developed a model of the activated ASM strip and compared its behavior to that observed in strips of rat trachealis muscle stimulated with methacholine. The model consists of a nonlinear viscoelastic element (Kelvin body) in series with a force generator obeying the Hill force-velocity relationship. Isometric force in the model is proportional to the number of bound crossbridges, the attachment of which follows first-order kinetics. Crossbridges detach at a rate proportional to the rate of change of muscle length. The model accurately accounts for the experimentally observed transient and steady-state oscillatory force-length behavior of both passive and activated ASM. However, the model does not predict the sustained decrement in isometric force seen when activated strips of ASM are subjected briefly to large stretches. We speculate that this force decrement reflects some mechanism unrelated to the cycling of crossbridges, and which may be involved in the reversal of bronchoconstriction induced by a deep inflation of the lungs in vivo.

A further analysis of why pulmonary venous pressure rises after the onset of LV dysfunction.

Based on a dynamic computational model of the circulation, Burkhoff and Tyberg (Am J Physiol Heart Circ Physiol 265: H1819-H1828, 1993) concluded that the rise in pulmonary venous pressure (Pvp) with left ventricular (LV) dysfunction requires a decrease in vascular capacitance and transfer of unstressed volume to stressed volume (nu). We argue that the values they used for venous resistance (Rvs), venous compliance (Cvs), and nu were too low, and changing these values significantly changes the conclusion. We used a computational model of the circulation that was similar to theirs, but we made Rvs four times higher (0.06 versus 0.015 mmHg.s.ml(-1)), Cvs larger (110 versus 70 ml/mmHg), and nu larger (1,400 versus 750 ml); all other parameters, including those for the heart, were essentially the same. We simulated left ventricular dysfunction by decreasing end-systolic elastance (Eeslv) as they did and examined changes in cardiac output, arterial blood pressure, and Pvp. We then examined the effect of changes in Rvs, heart rate, and nu when Eeslv was depressed with and without pericardial constraint. In contrast to their findings, with our parameters the model predicts that decreasing Eeslv substantially increases Pvp. Furthermore, increasing systemic vascular resistance or decreasing Rvs or heart rate produces large increases in Pvp when Eeslv is reduced. Pericardial constraint limits the changes in Pvp. In conclusion, when Rvs and Cvs are increased, baseline nu must be higher to maintain normal cardiac output. This increased volume can shift between compartments under flow conditions and account for the increase in Pvp with decreased left ventricular function even without recruitment of unstressed volume.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Association between Mycobacterium tuberculosis Beijing/W lineage strain infection and extrathoracic tuberculosis: Insights from epidemiologic and clinical characterization of the three principal genetic groups of M. tuberculosis clinical isolates.

Clinical strains of Mycobacterium tuberculosis can be divided into three principal genetic groups based on the single-nucleotide polymorphisms at the katG gene codon 463 and the gyrA gene codon 95. One subgroup of genetic group 1, the Beijing/W lineage, has been widely studied because of its worldwide distribution and association with outbreaks. In order to increase our understanding of the clinical and epidemiological relevance of the genetic grouping of M. tuberculosis clinical strains and the Beijing/W lineage, we investigated the genetic grouping of 679 clinical isolates of M. tuberculosis, representing 96.3% of culture-confirmed tuberculosis cases diagnosed in Arkansas between January 1996 and December 2000 using PCR and DNA sequencing. We assessed the associations of infections by different genetic groups of M. tuberculosis strains and infection by the Beijing/W lineage strains with the clinical and epidemiological characteristics of the patients using chi-square tests and multivariate logistic regression analysis. Of the 679 study isolates, 676 fell into one of the three principal genetic groups, with 63 (9.3%) in group 1, 438 (64.8%) in group 2, and 175 (25.9%) in group 3. After adjusting for potential confounding of age, gender, race/ethnicity, human immunodeficiency virus serostatus, and plcD genotype in a multivariate logistic regression model, patients infected by the Beijing/W lineage isolates were nearly three times as likely as patients infected with the non-Beijing/W lineage isolates to have an extrathoracic involvement (odds ratio [95% confidence interval], 2.85 [1.33, 6.12]). Thus, the Beijing/W lineage strains may have some special biological features that facilitate the development of extrathoracic tuberculosis.

Population-based study of deletions in five different genomic regions of Mycobacterium tuberculosis and possible clinical relevance of the deletions.

Regions of difference (RDs) have been described in clinical isolates of Mycobacterium tuberculosis, but the potential epidemiological and clinical relevance of the genotypes of these RDs remains to be investigated. We screened a population-based sample of 648 isolates for the deletion of five RDs, designated RD105, RD181, RD142, RD150, and RD239, using microarray-based hybridization, PCR, and DNA sequencing and assessed the associations between the RD deletions and the clinical characteristics of the patients using chi-square analysis and multivariate logistic regression model. Of the 648 isolates, 18 (2.8%) had the RD239 deletion and 39 (6.0%) had the RD105 deletion. The deletions of RD142, RD150, and RD181 subdivided the isolates with the RD105 deletion into four groups comprising a group with concurrent deletions of RD105, RD181, and RD142 (n = 13); a group with concurrent deletions of RD105, RD181, and RD150 (n = 5); a group with concurrent deletions of RD105 and RD181 (n = 13); and a group with a deletion of RD105 only (n = 8). Extrathoracic tuberculosis is statistically significantly associated with infection with the isolates with concurrent deletions of RD105, RD181, and RD142 (adjusted odds ratio [OR] = 3.05; 95% confidence interval [CI] = 1.58, 5.90) and the isolates with concurrent deletions of RD105, RD181, and RD150 (adjusted OR = 11.09; 95% CI = 4.27, 28.80), after controlling for the previously identified risk factors for extrathoracic tuberculosis (human immunodeficiency virus serostatus, race, gender, and the genotype of the plcD gene). These two combinations of RD deletions have the potential for predicting the clinical presentation of M. tuberculosis infection in the human host.

Distribution of insertion- and deletion-associated genetic polymorphisms among four Mycobacterium tuberculosis phospholipase C genes and associations with extrathoracic tuberculosis: a population-based study.

The Mycobacterium tuberculosis genome contains four phospholipase C (PLC)-encoding genes, designated plcA, plcB, plcC, and plcD, respectively. Each of the four genes contributes to the overall PLC activity of M. tuberculosis. PLC is hypothesized to contribute to M. tuberculosis virulence. Infection of M. tuberculosis strains carrying a truncated plcD gene is associated with the occurrence of extrathoracic tuberculosis. However, whether the other three plc genes are also associated with extrathoracic tuberculosis remains to be assessed. We investigated the insertion- and deletion-associated genetic diversity in all four plc genes among 682 epidemiologically and clinically well-characterized M. tuberculosis clinical isolates using PCR, DNA sequencing, and Southern hybridization. Two hundred sixty-six (39%) of the 682 isolates had an interruption in at least one of the four plc genes, most often associated with an IS6110 insertion. The plcD gene interruption was the most common: it was observed in 233 (34%) of the isolates, compared to 4.7%, 4.1%, and 5.9% for plcA, plcB, and plcC gene interruption, respectively. The association between the plc gene genotypes and disease presentation was adjusted for clustering using generalized estimating equations for both bivariate and multivariate analyses. After controlling for the genotypes of the plcABC genes and the host-related risk factors, interruption in the plcD gene remained significantly associated with extrathoracic tuberculosis (odds ratio, 3.27; 95% confidence interval, 1.32 to 8.14). The data suggest that the plcD gene might play a more important role in the pathogenesis of thoracic TB than it does in the pathogenesis of extrathoracic TB.

Persistence of a strain of Mycobacterium tuberculosis in a prison system.

SETTING: A prison system with an average year-end census of 9084 inmates. OBJECTIVE: To determine transmission dynamics of tuberculosis over a long period; to establish whether Mycobacterium tuberculosis strains responsible for disease in a prison system persist; and to determine whether patients in a community whose isolates cluster with those in a prison system are linked. DESIGN: Retrospective epidemiologic analysis was performed on tuberculosis cases reported in a prison system over a 9-year period. In addition, IS6110 RFLP patterns of M. tuberculosis isolates obtained from prisoners were compared with those of other cases from the state at large. The results of the RFLP analysis and the epidemiologic investigation were compared. RESULTS: Approximately 80% of tuberculosis cases in the prison system were clustered. Over 9 years, a single strain of M. tuberculosis accounted for more than 50% of cases. Patients from the community at large who were infected with the same strain were linked to the prison system. CONCLUSION: In spite of intensive tuberculosis control efforts, a single strain of M. tuberculosis has persisted in the prison system. Its persistence is accounted for by activation of latent infection in patients who, prior to being diagnosed and treated, infected other patients, who then sustained the transmission chain.

Automated analysis of paradoxical ribcage motion during sleep in infants.

Identification of thoracoabdominal asynchrony (TAS) during breathing is currently detected by visual coding of records of ribcage (RC) and abdominal (AB) movements. There is thus a need to automate this process in order to save time and improve TAS detection accuracy. We studied 15 infants of 39-49 weeks postconceptional age. RC and AB signals were recorded continuously by inductance plethysmography for 4-24 hr immediately after herniorraphy. In our novel analysis approach, the records were divided into 10 sec epochs, and the equation RC = alphaAB + beta was fit to each epoch, using recursive linear regression with an exponential memory time constant of 1 and 2 sec. This yielded 10 sec signals for alpha corresponding to each epoch. The fraction of time that each alpha signal was positive was taken as a measure of synchrony between RC and AB for that epoch, while asynchrony was indicated by the fraction of time the signal was negative. We also assessed synchrony and asynchrony using a conventional measure known as thoracic delay (TD), which is based on the degree to which the peaks in RC and AB are coincident in time. Using TD as the basis of comparison, we found that our new recursive least squares method gave a positive predictive value of 99%. We conclude that our recursive least squares method is able to accurately identify portions of the RC and AB records that correspond to TAS, and we speculate that it may be useful in automating detection of TAS.

Effects of deep inspiration on bronchoconstriction in the rat.

It is important to understand the mechanisms by which a deep inspiration (DI) affects bronchoconstriction in rodents so that their relevance as animal models of asthma can be assessed. We investigated the effect of DI on respiratory input impedance after methacholine inhalation in four groups of rats: a control group, a group receiving DI prior to challenge, and two groups receiving different degrees of DI after challenge. We measured respiratory input impedance for 15 min following a challenge. This provided time-courses approximating the resistance of the conducting airways and the impedance of the respiratory tissues. We found no significant difference in the peak changes in airway resistance comparing the control group and any of the DI groups following challenge. However, the peak increase in tissue impedance was reduced in the group receiving the largest DI after challenge. Our results thus suggest that the DIs that we administered were neither bronchodilatory nor bronchoprotective, but that they were able to reduce the amount of airway closure occurring following bronchoconstriction.

Fuzzy logic and mechanical ventilation.

Closed-loop control can achieve appropriate ventilation of the lungs in a healthy person by involving the continuous interaction of three components: sensors, controllers, and effectors. The sensors are the chemo-mechanoreceptors, which continuously monitor key bodily functions affected by ventilation. This information is relayed to the controllers, the respiratory centers in the brain, allowing them to determine how actual ventilation compares with that needed by the body. Finally, the controllers direct the effectors, the muscles of respiration, to adjust the ventilation accordingly. When a patient is in respiratory failure, the effector's role is taken over by a mechanical ventilator. The issue that is considered in this article is how the physician might be taken out of the feedback loop.

Mechanical output impedance of the lung determined from cardiogenic oscillations.

The beating heart naturally oscillates the lung because of the close juxtaposition between these organs producing cardiogenic oscillations in flow that can be measured at the mouth when the glottis is open. Correspondingly, if the mouth is occluded, the same phenomenon produces cardiogenic pressure oscillations that can be measured just distal to the site of occlusion. The Fourier-domain ratio of these oscillations in pressure and flow constitutes what we call cardiogenic respiratory impedance (Zc). We calculated Zc between about 1.5 and 10 Hz in relaxed normal subjects at functional residual capacity with open glottis. Zc was insensitive to heart rate changes induced by exercise and had an imaginary part close to zero at all frequencies investigated. Its real part was similar to or smaller than resistance determined by the forced oscillation technique. We speculate that Zc measures the flow resistance of the central and upper airways of the lung. Zc may be useful as a means of obtaining information about lung mechanics without the need for an external source of flow perturbations.

A clinic-based molecular epidemiologic study of tuberculosis in Monterrey, Mexico.

SETTING: A tuberculosis clinic associated with a university hospital in Monterrey, Mexico, an urban community with high tuberculosis incidence. OBJECTIVE: To determine the diversity of DNA fingerprint patterns and the extent of drug resistance of Mycobacterium tuberculosis isolates from patients who attended the clinic. DESIGN: Isolates of M. tuberculosis obtained from 186 patients during the period from 31 January 1996 to 31 March 1998 were tested for susceptibility to isoniazid, rifampicin, ethambutol and streptomycin. Demographic data and the social history of each patient were obtained prospectively by interview. The IS6110 DNA fingerprints were obtained for 166 of the 186 isolates. Secondary typing was carried out on isolates with fewer than six copies of IS6110. RESULTS: Thirty-two per cent of the tested isolates (60/ 186) were drug-resistant, and 18% (33/186) were multidrug-resistant. Approximately 55% of the resistant isolates (33/60) were attributed to acquired resistance. A total of 106 different IS6110 fingerprint patterns were observed among the 166 fingerprinted isolates. Based on both IS6110 and pTBN12 fingerprinting, 65 (39%) of the 166 isolates were part of 22 DNA fingerprint clusters. Various drug susceptibility patterns were seen in most clusters. CONCLUSION: Fingerprint clustering indicates extensive recent transmission of tuberculosis in patients attending the clinic. The prevalence of drug-resistant tuberculosis is high.

Secondary typing of Mycobacterium tuberculosis isolates with matching IS6110 fingerprints from different geographic regions of the United States.

Fifty-nine isolates of Mycobacterium tuberculosis obtained from different states in the United States and representing 25 interstate clusters were investigated. These clusters were identified by computer-assisted analysis of DNA fingerprints submitted during 1996 and 1997 by different laboratories participating in the CDC National Genotyping and Surveillance Network. Isolates were fingerprinted with the IS6110 right-hand probe (IS6110-3'), the IS6110 left-hand probe (IS6110-5'), and the probe pTBN12, containing the polymorphic GC-rich sequence (PGRS). Spoligotyping based on the polymorphism in the 36-bp direct-repeat locus was also performed. As a control, 43 M. tuberculosis isolates in 17 clusters obtained from patients in Arkansas during the study period were analyzed. Of the 25 interstate clusters, 19 were confirmed as correctly clustered when all the isolates were analyzed on the same gel using the IS6110-3' probe. Of the 19 true IS6110-3' clusters, 10 (53%) were subdivided by one or more secondary typing methods. Clustering of the control group was virtually identical by all methods. Of the three different secondary typing methods, spoligotyping was the least discriminating. IS6110-5' fingerprinting was as discriminating as PGRS fingerprinting. The data indicate that the IS6110-5' probe not only is a useful secondary typing method but also probably would prove to be a more useful primary typing method for a genotyping network which involves isolates from different geographic regions.